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Fats & FakesTowards improved control of malariaVisser, B.J.
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Citation for published version (APA):Visser, B. J. (2017). Fats & Fakes: Towards improved control of malaria.
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“The proportion of clay particles in the topsoil (i.e. mineral matter less than 0.002 mm in diameter).These tiny particles require microscopes to see them. The soil feels smooth when rubbed betweenone’s fingers. Clay-rich soils tend to contain more nutrients and because of their very high surfacearea can retain large amounts of moisture. As a result, they are favoured for agriculture. However,they can be difficult to cultivate when wet as they become very heavy and slow to drain. Can becomevery hard when dry. High clay content is generally indicative of the chemical weathering (andassociated transport) of parent material.” Adapted from: Soil Atlas of Africa, 2013. EuropeanCommission, Publications Office of the European Union, Luxembourg.1
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Chapter 5
The influence of pregnancy on the pharmacokinetic propertiesof artemisinin combination therapy (ACT): a systematic review
Renée J. Burger
Benjamin J. Visser
Martin P. Grobusch
Michèle van Vugt
Malaria Journal 2016 Feb 18;15(1):99
Appendices and supplementary material are available online at:http://malariajournal.biomedcentral.com/articles/10.1186/s12936-016-1160-6
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“The proportion of clay particles in the topsoil (i.e. mineral matter less than 0.002 mm in diameter).These tiny particles require microscopes to see them. The soil feels smooth when rubbed betweenone’s fingers. Clay-rich soils tend to contain more nutrients and because of their very high surfacearea can retain large amounts of moisture. As a result, they are favoured for agriculture. However,they can be difficult to cultivate when wet as they become very heavy and slow to drain. Can becomevery hard when dry. High clay content is generally indicative of the chemical weathering (andassociated transport) of parent material.” Adapted from: Soil Atlas of Africa, 2013. EuropeanCommission, Publications Office of the European Union, Luxembourg.1
115
Chapter 5
The influence of pregnancy on the pharmacokinetic propertiesof artemisinin combination therapy (ACT): a systematic review
Renée J. Burger
Benjamin J. Visser
Martin P. Grobusch
Michèle van Vugt
Malaria Journal 2016 Feb 18;15(1):99
Appendices and supplementary material are available online at:http://malariajournal.biomedcentral.com/articles/10.1186/s12936-016-1160-6
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Abstract
Background
Pregnancy has been reported to alter the pharmacokinetic properties of anti-malarial drugs,including the different components of artemisinin-based combination therapy (ACT).However, small sample sizes make it difficult to draw strong conclusions based on individualpharmacokinetic studies. The aim of this review is to summarize the evidence of theinfluence of pregnancy on the pharmacokinetic properties of different artemisinin-basedcombinations.
MethodsA PROSPERO-registered systematic review to identify clinical trials that investigated theinfluence of pregnancy on the pharmacokinetic properties of different forms of ACT wasconducted, following PRISMA guidelines. Without language restrictions, Medline/PubMed,Embase, Cochrane Central Register of Controlled Trials, Web of Science, LILACS, BiosisPreviews and the African Index Medicus were searched for studies published up toNovember 2015. The following components of ACT that are currently recommend by theWorld Health Organization as first-line treatment of malaria in pregnancy were reviewed:artemisinin, artesunate, dihydroartemisinin, lumefantrine, amodiaquine, mefloquine,sulfadoxine, pyrimethamine, piperaquine, atovaquone and proguanil.
ResultsThe literature search identified 121 reports, 27 original studies were included. 829 pregnantwomen were included in the analysis. Comparison of the available studies showed lowermaximum concentrations (Cmax) and exposure (AUC) of dihydroartemisinin, the activemetabolite of all artemisinin derivatives, after oral administration of artemether, artesunateand dihydroartemisinin in pregnant women. Low day 7 concentrations were commonly seenin lumefantrine studies, indicating a low exposure and possibly reduced efficacy. Theinfluence of pregnancy on amodiaquine and piperaquine seemed not to be clinically relevant.Sulfadoxine plasma concentration was significantly reduced and clearance rates were higherin pregnancy, while pyrimethamine and mefloquine need more research as no generalconclusion can be drawn based on the available evidence. For atovaquone, the available datashowed a lower maximum concentration and exposure. Finally, the maximum concentrationof cycloguanil, the active metabolite of proguanil, was significantly lower, possiblycompromising the efficacy.
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ConclusionThese findings suggest that reassessment of the dose of the artemisinin derivate and somecomponents of ACT are necessary to ensure the highest possible efficacy of malariatreatment in pregnant women. However, for most components of ACT, data were insufficientand extensive research with larger sample sizes will be necessary to identify the exactinfluences of pregnancy on the pharmacokinetic properties of different artemisinin-basedcombinations. In addition, different clinical studies used diverse study designs with variousreported relevant outcomes. Future pharmacokinetic studies could benefit from moreuniform designs, in order to increase quality, robustness and effectiveness.
Study registration
CRD42015023756 (PROSPERO)
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Abstract
Background
Pregnancy has been reported to alter the pharmacokinetic properties of anti-malarial drugs,including the different components of artemisinin-based combination therapy (ACT).However, small sample sizes make it difficult to draw strong conclusions based on individualpharmacokinetic studies. The aim of this review is to summarize the evidence of theinfluence of pregnancy on the pharmacokinetic properties of different artemisinin-basedcombinations.
MethodsA PROSPERO-registered systematic review to identify clinical trials that investigated theinfluence of pregnancy on the pharmacokinetic properties of different forms of ACT wasconducted, following PRISMA guidelines. Without language restrictions, Medline/PubMed,Embase, Cochrane Central Register of Controlled Trials, Web of Science, LILACS, BiosisPreviews and the African Index Medicus were searched for studies published up toNovember 2015. The following components of ACT that are currently recommend by theWorld Health Organization as first-line treatment of malaria in pregnancy were reviewed:artemisinin, artesunate, dihydroartemisinin, lumefantrine, amodiaquine, mefloquine,sulfadoxine, pyrimethamine, piperaquine, atovaquone and proguanil.
ResultsThe literature search identified 121 reports, 27 original studies were included. 829 pregnantwomen were included in the analysis. Comparison of the available studies showed lowermaximum concentrations (Cmax) and exposure (AUC) of dihydroartemisinin, the activemetabolite of all artemisinin derivatives, after oral administration of artemether, artesunateand dihydroartemisinin in pregnant women. Low day 7 concentrations were commonly seenin lumefantrine studies, indicating a low exposure and possibly reduced efficacy. Theinfluence of pregnancy on amodiaquine and piperaquine seemed not to be clinically relevant.Sulfadoxine plasma concentration was significantly reduced and clearance rates were higherin pregnancy, while pyrimethamine and mefloquine need more research as no generalconclusion can be drawn based on the available evidence. For atovaquone, the available datashowed a lower maximum concentration and exposure. Finally, the maximum concentrationof cycloguanil, the active metabolite of proguanil, was significantly lower, possiblycompromising the efficacy.
The influence of pregnancy on the pharmacokinetic properties of ACT: a systematic review
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ConclusionThese findings suggest that reassessment of the dose of the artemisinin derivate and somecomponents of ACT are necessary to ensure the highest possible efficacy of malariatreatment in pregnant women. However, for most components of ACT, data were insufficientand extensive research with larger sample sizes will be necessary to identify the exactinfluences of pregnancy on the pharmacokinetic properties of different artemisinin-basedcombinations. In addition, different clinical studies used diverse study designs with variousreported relevant outcomes. Future pharmacokinetic studies could benefit from moreuniform designs, in order to increase quality, robustness and effectiveness.
Study registration
CRD42015023756 (PROSPERO)
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Background
Malaria infection during pregnancy remains an important public health problem withpotential life-threatening risks for the pregnant woman, the foetus and the newborn child.403,
404 According to a systematic review to assess the burden of malaria in pregnancy,approximately 25 million pregnant women are at risk of Plasmodium falciparum infectionevery year.405 One in four women have evidence of placental infection at the time of delivery;of which a small fraction is encountered as an imported condition in non-endemic countriesin migrants and travellers.406 Imported cases of malaria in pregnancy are mainly P.falciparum acquired in sub-Saharan Africa.406 Malaria in pregnancy is caused by all fivespecies of Plasmodium infecting humans: P. falciparum, P. vivax, P. ovale, P.malariae and P. knowlesi. Most morbidity and mortality is caused by falciparum and vivaxmalaria. Plasmodium knowlesi malaria is endemic in parts of South East Asia and isrelatively rare in pregnancy.
Pregnancy increases the risk of both falciparum and vivax malaria.405, 407 The increasedsusceptibility has been attributed to broad hormonal and immunological changes that occurduring pregnancy.407 For P. falciparum, there is evidence that the increased susceptibility isdue to the lack of immunity to antigens expressed only by parasites infecting pregnantwomen.407, 408 It is unclear what causes the increased susceptibility for P. vivax malaria inpregnancy.407 The prevalence of both falciparum and vivax malaria is higher inprimigravidae than in non-pregnant women or multigravidae. As well, younger age isassociated with higher risk for malaria in pregnancy.405, 407 Plasmodium falciparum and P.vivax malaria are associated with maternal anaemia, lower birth weight and, in low-transmission areas, increased risks of spontaneous abortion, severe malaria and stillbirth.405,
409-412 The increased burden of malaria in pregnancy has been attributed to higher parasitedensities and the sequestration of P. falciparum infected erythrocytes (Pf-IEs) in theplacenta,405, 407, 408, 413-415 resulting in placental changes including inflammation anddisposition of pigment in fibrin or inflammatory cells, syncytial knotting and thickening ofthe trophoblastic basement membrane.407 Plasmodium vivax however, does not cytoadherein the placenta, but is associated with maternal anaemia and low birth weight.405
In order to reduce the burden of malaria in pregnancy, the WHO recommends a three-pronged approach. Women are recommended to sleep under long-lasting insecticide-impregnated nets (LLINs) and to use intermittent preventive treatment (IPTp) withsulfadoxine-pyrimethamine (SP) when living in areas with a high to moderate stabletransmission. The WHO emphasizes the importance of prompt diagnosis and effective casemanagement of malaria infections.416 Furthermore, all pregnant women should receive ironand folic acid supplementation as a part of routine antenatal care.
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In the “Guidelines for the treatment of malaria” (3rd edition, 2015), the WHO recommends38
the use of an artemisinin-based combination therapy (ACT) for the treatment ofuncomplicated falciparum malaria in the 2nd and 3rd trimester of pregnancy.417 Over thepast two decades multiple studies have been conducted to assess the efficacy and safety ofACT in the 2nd and 3rd trimester of pregnancy compared to other treatments.247-249, 252, 253,
262, 265, 418 However, pregnancy is known to cause physiologic and pharmacokinetic changesthat might influence the efficacy of drugs. Different organ systems undergo changes whichresult in pharmacokinetic changes.419 Pregnancy is associated with significantcardiovascular changes, especially in the first trimester of pregnancy. Cardiac output, strokevolume and heart rate increase, systemic and pulmonary vascular resistance decrease, as wellas colloid osmotic pressure and haemoglobin concentration. This can increase the volume ofdistribution of hydrophilic substrates. Clinically, pregnant women sometimes need higherinitial and subsequent dosage regimens, especially for hydrophilic drugs. In contrast, drugsthat are bound to proteins or albumin can double the fraction of active pharmaceuticalfraction. Respiratory changes in pregnancy include increased pulmonary vascularity, tidalvolumes, minute volumes. In later stages of pregnancy, lung capacity may decrease becauseof the pressure from a big uterus on the diaphragm, causing alveolar collapse and atelectasis.In addition, pH of maternal blood may be increased, resulting in lower serum bicarbonateconcentration and a lower buffering capacity. Furthermore, a rightward shift of the oxy-haemoglobin dissociation curve may affect protein binding of some drugs. Also the renalsystem is altered by pregnancy. In the first halve of pregnancy, the renal blood flow andGFR (glomerular filtration rate) is increased. Elimination rates can be higher for renalcleared drugs resulting in shorter half-lives. The bioavailability (e.g. Cmax, T1/2, Tmax) of oralanti-malarial drugs can also be changed by gastro-intestinal changes during pregnancy.There is delayed gastric emptying, and a longer small-bowel transit duration. These factorsmainly influence single dose malaria treatments. Nausea and vomiting, common in earlypregnancy, can also change the bioavailability of the anti-malarial drug caused by lowerplasma concentrations. Also (sex) hormones during pregnancy increase or decrease theplasma concentrations of anti-malarial drugs. In the liver for example, CYP3A4 andcytochrome P450 are upregulated, resulting in a changed metabolism of CYP3A4metabolized drugs (e.g. lumefantrine). Many other mechanisms have been described,however, the most important changes include increased maternal fat and total body water,decreased plasma protein concentrations, increased maternal blood volume and cardiacoutput and altered activity of hepatic drug-metabolizing enzymes.419
Multiple studies have been conducted to study the influence of pregnancy onpharmacokinetic properties of ACT. However, due to small sample sizes it is often hard todraw strong conclusions based on these individual studies.10, 420
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Background
Malaria infection during pregnancy remains an important public health problem withpotential life-threatening risks for the pregnant woman, the foetus and the newborn child.403,
404 According to a systematic review to assess the burden of malaria in pregnancy,approximately 25 million pregnant women are at risk of Plasmodium falciparum infectionevery year.405 One in four women have evidence of placental infection at the time of delivery;of which a small fraction is encountered as an imported condition in non-endemic countriesin migrants and travellers.406 Imported cases of malaria in pregnancy are mainly P.falciparum acquired in sub-Saharan Africa.406 Malaria in pregnancy is caused by all fivespecies of Plasmodium infecting humans: P. falciparum, P. vivax, P. ovale, P.malariae and P. knowlesi. Most morbidity and mortality is caused by falciparum and vivaxmalaria. Plasmodium knowlesi malaria is endemic in parts of South East Asia and isrelatively rare in pregnancy.
Pregnancy increases the risk of both falciparum and vivax malaria.405, 407 The increasedsusceptibility has been attributed to broad hormonal and immunological changes that occurduring pregnancy.407 For P. falciparum, there is evidence that the increased susceptibility isdue to the lack of immunity to antigens expressed only by parasites infecting pregnantwomen.407, 408 It is unclear what causes the increased susceptibility for P. vivax malaria inpregnancy.407 The prevalence of both falciparum and vivax malaria is higher inprimigravidae than in non-pregnant women or multigravidae. As well, younger age isassociated with higher risk for malaria in pregnancy.405, 407 Plasmodium falciparum and P.vivax malaria are associated with maternal anaemia, lower birth weight and, in low-transmission areas, increased risks of spontaneous abortion, severe malaria and stillbirth.405,
409-412 The increased burden of malaria in pregnancy has been attributed to higher parasitedensities and the sequestration of P. falciparum infected erythrocytes (Pf-IEs) in theplacenta,405, 407, 408, 413-415 resulting in placental changes including inflammation anddisposition of pigment in fibrin or inflammatory cells, syncytial knotting and thickening ofthe trophoblastic basement membrane.407 Plasmodium vivax however, does not cytoadherein the placenta, but is associated with maternal anaemia and low birth weight.405
In order to reduce the burden of malaria in pregnancy, the WHO recommends a three-pronged approach. Women are recommended to sleep under long-lasting insecticide-impregnated nets (LLINs) and to use intermittent preventive treatment (IPTp) withsulfadoxine-pyrimethamine (SP) when living in areas with a high to moderate stabletransmission. The WHO emphasizes the importance of prompt diagnosis and effective casemanagement of malaria infections.416 Furthermore, all pregnant women should receive ironand folic acid supplementation as a part of routine antenatal care.
The influence of pregnancy on the pharmacokinetic properties of ACT: a systematic review
119
In the “Guidelines for the treatment of malaria” (3rd edition, 2015), the WHO recommends38
the use of an artemisinin-based combination therapy (ACT) for the treatment ofuncomplicated falciparum malaria in the 2nd and 3rd trimester of pregnancy.417 Over thepast two decades multiple studies have been conducted to assess the efficacy and safety ofACT in the 2nd and 3rd trimester of pregnancy compared to other treatments.247-249, 252, 253,
262, 265, 418 However, pregnancy is known to cause physiologic and pharmacokinetic changesthat might influence the efficacy of drugs. Different organ systems undergo changes whichresult in pharmacokinetic changes.419 Pregnancy is associated with significantcardiovascular changes, especially in the first trimester of pregnancy. Cardiac output, strokevolume and heart rate increase, systemic and pulmonary vascular resistance decrease, as wellas colloid osmotic pressure and haemoglobin concentration. This can increase the volume ofdistribution of hydrophilic substrates. Clinically, pregnant women sometimes need higherinitial and subsequent dosage regimens, especially for hydrophilic drugs. In contrast, drugsthat are bound to proteins or albumin can double the fraction of active pharmaceuticalfraction. Respiratory changes in pregnancy include increased pulmonary vascularity, tidalvolumes, minute volumes. In later stages of pregnancy, lung capacity may decrease becauseof the pressure from a big uterus on the diaphragm, causing alveolar collapse and atelectasis.In addition, pH of maternal blood may be increased, resulting in lower serum bicarbonateconcentration and a lower buffering capacity. Furthermore, a rightward shift of the oxy-haemoglobin dissociation curve may affect protein binding of some drugs. Also the renalsystem is altered by pregnancy. In the first halve of pregnancy, the renal blood flow andGFR (glomerular filtration rate) is increased. Elimination rates can be higher for renalcleared drugs resulting in shorter half-lives. The bioavailability (e.g. Cmax, T1/2, Tmax) of oralanti-malarial drugs can also be changed by gastro-intestinal changes during pregnancy.There is delayed gastric emptying, and a longer small-bowel transit duration. These factorsmainly influence single dose malaria treatments. Nausea and vomiting, common in earlypregnancy, can also change the bioavailability of the anti-malarial drug caused by lowerplasma concentrations. Also (sex) hormones during pregnancy increase or decrease theplasma concentrations of anti-malarial drugs. In the liver for example, CYP3A4 andcytochrome P450 are upregulated, resulting in a changed metabolism of CYP3A4metabolized drugs (e.g. lumefantrine). Many other mechanisms have been described,however, the most important changes include increased maternal fat and total body water,decreased plasma protein concentrations, increased maternal blood volume and cardiacoutput and altered activity of hepatic drug-metabolizing enzymes.419
Multiple studies have been conducted to study the influence of pregnancy onpharmacokinetic properties of ACT. However, due to small sample sizes it is often hard todraw strong conclusions based on these individual studies.10, 420
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Objectives
The overall objective of this review was to summarize available evidence of the influence ofpregnancy on the pharmacokinetic properties of different artemisinin-based combinationsand the consequences these influences have on treatment dose and regime. The last reviewon this subject was published in 2009.421 The primary outcomes of interest for the analysisof the pharmacokinetics of the drugs in pregnancy were Cmax, Tmax, CL/F, V/F, T1/2 and totalexposure (Area Under the Curve: AUC).
MethodsThis review was conducted in June 2015. The last search was conducted on 10 November2015. Objectives and inclusion criteria were specified in advance and documented in aprotocol. Recommendations made by the Preferred Reporting Items for Systematic Reviewsand Meta-Analyses (PRISMA) group were followed.111 This review was registered inadvance in PROSPERO (International prospective register of systematic reviews).Registration number: CRD42015023756. An overview of ongoing or future trials is providedin Additional file 2 (additional file 1 is integrated in the methods section of this chapter).The costs of this literature study are not reported.402 The first and second author searched theelectronic databases Ovid Medline (1946 to November 2015), Ovid Embase (1947 toNovember 2015), Cochrane Central Register of Controlled Trials (November 2015), Web ofScience (1975 to November 2015), CINAHL Plus with Full Text (1937 to November 2015),African Index Medicus (1933 to November 2015), African Journals Online (AJOL) (frominception to November 2015), Google Scholar (without patents and citations), BiosisPreviews (1993 to November 2015) and PubMed (non-MEDLINE citations) (1947 toNovember 2015) to identify studies investigating the pharmacokinetics of ACTs in pregnantwomen. Also, major trial registries were searched to identify ongoing or future trials(Additional File 2). The search strategy consisted of free-text words and subject headingsrelated to pregnancy, malaria and seven different components of ACTs. The search strategyfor PubMed is depicted below. The search strategy was not limited by study design orlanguage. Only human studies were included. Unpublished data (e.g. conference or meetingabstracts) were excluded. The bibliographies of all identified articles were examined toidentify additional studies that were not identified during the computerized search. EndnoteX7.1 (Thomson Reuters) was used to manage, de-duplicate and screen the references foreligibility. Studies retrieved were eligible for inclusion if they satisfied all selection criteria.The study population consisted of pregnant females with malaria (P. falciparum, P. ovale,P. vivax, P. malariae & P. knowlesi) of all age groups. Treatment consisted of an artemisininderivate or artemisinin combination treatment. Furthermore, data was available to assess thepharmacokinetics of either artemether, artesunate, dihydroartemisinin (DHA), lumefantrine,mefloquine, amodiaquine, sulfadoxine-pyrimethamine (SP), piperaquine (PPQ) oratovaquone-proguanil (AP). Both studies performing a compartmental and a non-
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compartmental analysis were included in the review. Eligibility assessment of studies foundwas performed independently in an unblinded standardized manner by the first two authors.The first author extracted the following study characteristics: first author, year ofpublication, geographic location, time of the study, type of study, administered drug anddosing regimen, the pharmacokinetic sampling regimen, drug quantification method,pharmacokinetic analytic methodology, number of pregnant and non-pregnant womentreated with the drug, population characteristics including age, weight and estimatedgestational age (EGA), pharmacokinetic outcome measurements including total dose, Cmax,Cmax/dose, Tmax, oral plasma clearance rate (CL/F), apparent volume of distribution (V/F),t1/2, day 7, 14 and 28 concentrations and exposure (Area Under the Curve; AUC) overmultiple time spans for both pregnant and non-pregnant women and conclusion of thearticles. Data was double checked for all articles included in the qualitative synthesis by thesecond author. A validity assessment was performed by the first author using the Downs andBlack checklist for measuring study quality.422 Details are included in Additional file 3:Quality of included studies. In short, articles were scored for quality of reporting, externalvalidity, internal validity (bias and confounding) and statistical power. Quality was classifiedwith 0 (poor) to 31 points (excellent).
The included studies were separated in nine groups based on the type of drug administered.These nine groups were: artemether, artesunate, dihydroartemisinin (DHA), lumefantrine,mefloquine, amodiaquine, sulfadoxine-pyrimethamine (SP), piperaquine (PPQ) andatovaquone-proguanil (AP). Some studies were used in multiple groups. Within each group,results were compared, and a general conclusion was drawn. These groups represent thecomponents of first line drug therapies recommended by the WHO for pregnant women inthe second and third trimester for the treatment of uncomplicated P. falciparum treatment(artemether-lumefantrine, artesunate-amodiaquine, artesunate-mefloquine, artesunate-SPand DHA-PPQ), of drugs recommended for intermittent preventive treatment in pregnancy(IPTp) (SP) and as prophylaxis for travellers (AP).38, 423 In the first trimester of pregnancy,the WHO recommends the use of 7 days with quinine plus clindamycin (10mg/kg bw twicea day) for the treatment of uncomplicated P. falciparum malaria (“strong recommendation”).An ACT or oral artesunate + clindamycin is an acceptable alternative if quinine +clindamycin is not available or is ineffective. These drugs are not included in this systematicreview. The full PubMed search strategy was as follows: 1. "Malaria"[MeSH] OR"Plasmodium"[MeSH] OR "malaria"[tiab] OR "plasmodium"[tiab] AND2."Pregnancy"[MeSH] OR "Pregnan*"[tiab] AND 3."pharmacokinetics"[sh] OR"pharmacokinetics"[MeSH] OR "pharmacokinetic*"[tiab] OR “pharmacokinetics*”[tiab]AND 4. ("artemisinin*"[tiab] OR "artesunate*"[tiab] OR "artemether*"[tiab] OR"dihydroartemisinin*"[tiab]) OR 5. ("lumefantrine"[Supplementary Concept] OR"artemether-lumefantrine combination"[Supplementary Concept] OR"lumefantrine*"[tiab]) OR 6. ("Mefloquine"[Mesh] OR "Ro 21-5104"[SupplementaryConcept] OR "mefloquine-sulfadoxine-pyrimethamine"[Supplementary Concept] OR
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Objectives
The overall objective of this review was to summarize available evidence of the influence ofpregnancy on the pharmacokinetic properties of different artemisinin-based combinationsand the consequences these influences have on treatment dose and regime. The last reviewon this subject was published in 2009.421 The primary outcomes of interest for the analysisof the pharmacokinetics of the drugs in pregnancy were Cmax, Tmax, CL/F, V/F, T1/2 and totalexposure (Area Under the Curve: AUC).
MethodsThis review was conducted in June 2015. The last search was conducted on 10 November2015. Objectives and inclusion criteria were specified in advance and documented in aprotocol. Recommendations made by the Preferred Reporting Items for Systematic Reviewsand Meta-Analyses (PRISMA) group were followed.111 This review was registered inadvance in PROSPERO (International prospective register of systematic reviews).Registration number: CRD42015023756. An overview of ongoing or future trials is providedin Additional file 2 (additional file 1 is integrated in the methods section of this chapter).The costs of this literature study are not reported.402 The first and second author searched theelectronic databases Ovid Medline (1946 to November 2015), Ovid Embase (1947 toNovember 2015), Cochrane Central Register of Controlled Trials (November 2015), Web ofScience (1975 to November 2015), CINAHL Plus with Full Text (1937 to November 2015),African Index Medicus (1933 to November 2015), African Journals Online (AJOL) (frominception to November 2015), Google Scholar (without patents and citations), BiosisPreviews (1993 to November 2015) and PubMed (non-MEDLINE citations) (1947 toNovember 2015) to identify studies investigating the pharmacokinetics of ACTs in pregnantwomen. Also, major trial registries were searched to identify ongoing or future trials(Additional File 2). The search strategy consisted of free-text words and subject headingsrelated to pregnancy, malaria and seven different components of ACTs. The search strategyfor PubMed is depicted below. The search strategy was not limited by study design orlanguage. Only human studies were included. Unpublished data (e.g. conference or meetingabstracts) were excluded. The bibliographies of all identified articles were examined toidentify additional studies that were not identified during the computerized search. EndnoteX7.1 (Thomson Reuters) was used to manage, de-duplicate and screen the references foreligibility. Studies retrieved were eligible for inclusion if they satisfied all selection criteria.The study population consisted of pregnant females with malaria (P. falciparum, P. ovale,P. vivax, P. malariae & P. knowlesi) of all age groups. Treatment consisted of an artemisininderivate or artemisinin combination treatment. Furthermore, data was available to assess thepharmacokinetics of either artemether, artesunate, dihydroartemisinin (DHA), lumefantrine,mefloquine, amodiaquine, sulfadoxine-pyrimethamine (SP), piperaquine (PPQ) oratovaquone-proguanil (AP). Both studies performing a compartmental and a non-
The influence of pregnancy on the pharmacokinetic properties of ACT: a systematic review
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compartmental analysis were included in the review. Eligibility assessment of studies foundwas performed independently in an unblinded standardized manner by the first two authors.The first author extracted the following study characteristics: first author, year ofpublication, geographic location, time of the study, type of study, administered drug anddosing regimen, the pharmacokinetic sampling regimen, drug quantification method,pharmacokinetic analytic methodology, number of pregnant and non-pregnant womentreated with the drug, population characteristics including age, weight and estimatedgestational age (EGA), pharmacokinetic outcome measurements including total dose, Cmax,Cmax/dose, Tmax, oral plasma clearance rate (CL/F), apparent volume of distribution (V/F),t1/2, day 7, 14 and 28 concentrations and exposure (Area Under the Curve; AUC) overmultiple time spans for both pregnant and non-pregnant women and conclusion of thearticles. Data was double checked for all articles included in the qualitative synthesis by thesecond author. A validity assessment was performed by the first author using the Downs andBlack checklist for measuring study quality.422 Details are included in Additional file 3:Quality of included studies. In short, articles were scored for quality of reporting, externalvalidity, internal validity (bias and confounding) and statistical power. Quality was classifiedwith 0 (poor) to 31 points (excellent).
The included studies were separated in nine groups based on the type of drug administered.These nine groups were: artemether, artesunate, dihydroartemisinin (DHA), lumefantrine,mefloquine, amodiaquine, sulfadoxine-pyrimethamine (SP), piperaquine (PPQ) andatovaquone-proguanil (AP). Some studies were used in multiple groups. Within each group,results were compared, and a general conclusion was drawn. These groups represent thecomponents of first line drug therapies recommended by the WHO for pregnant women inthe second and third trimester for the treatment of uncomplicated P. falciparum treatment(artemether-lumefantrine, artesunate-amodiaquine, artesunate-mefloquine, artesunate-SPand DHA-PPQ), of drugs recommended for intermittent preventive treatment in pregnancy(IPTp) (SP) and as prophylaxis for travellers (AP).38, 423 In the first trimester of pregnancy,the WHO recommends the use of 7 days with quinine plus clindamycin (10mg/kg bw twicea day) for the treatment of uncomplicated P. falciparum malaria (“strong recommendation”).An ACT or oral artesunate + clindamycin is an acceptable alternative if quinine +clindamycin is not available or is ineffective. These drugs are not included in this systematicreview. The full PubMed search strategy was as follows: 1. "Malaria"[MeSH] OR"Plasmodium"[MeSH] OR "malaria"[tiab] OR "plasmodium"[tiab] AND2."Pregnancy"[MeSH] OR "Pregnan*"[tiab] AND 3."pharmacokinetics"[sh] OR"pharmacokinetics"[MeSH] OR "pharmacokinetic*"[tiab] OR “pharmacokinetics*”[tiab]AND 4. ("artemisinin*"[tiab] OR "artesunate*"[tiab] OR "artemether*"[tiab] OR"dihydroartemisinin*"[tiab]) OR 5. ("lumefantrine"[Supplementary Concept] OR"artemether-lumefantrine combination"[Supplementary Concept] OR"lumefantrine*"[tiab]) OR 6. ("Mefloquine"[Mesh] OR "Ro 21-5104"[SupplementaryConcept] OR "mefloquine-sulfadoxine-pyrimethamine"[Supplementary Concept] OR
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"mefloquine*"[tiab] OR "Lariam"[tiab] OR "ASMQ"[tiab] OR "artesunate-mefloquine"[tiab]) OR 7. ("Amodiaquine"[Mesh] OR "amodiaquine, artesunate drugcombination"[Supplementary Concept] OR "amodiaquine*"[tiab] OR "AQ*"[tiab]) OR 8.(("sulfadoxine-pyrimethamine-artesunate"[Supplementary Concept] OR "fanasil,pyrimethamine drug combination"[Supplementary Concept]) OR "SP"[tiab] OR(("sulfadoxine*"[tiab] OR "sulphadoxine*"[tiab]) AND "pyrimethamine*"[tiab])) OR 9.("piperaquine"[Supplementary Concept] OR "piperaquine*"[tiab]) OR 10. ("atovaquone,proguanil drug combination"[Supplementary Concept] OR "Atovaquone"[Mesh] OR"atovaquone*"[tiab] OR "Proguanil"[Mesh] OR "proguanil*"[tiab] OR "malarone*"[tiab])
ResultsThe initial search yielded 121 records (Fig. 1: PRISMA flow diagram of study selection). 27articles met the inclusion criteria and were included in the analysis (Table 1).241, 248, 251, 253,
256, 258, 259, 267, 268, 309, 311-313, 315-317, 424-434 The main study findings of the included trials can befound in Table 2.
The studies included were published between 1990 and 2015 and included a total of 829pregnant and 377 non-pregnant patients. Articles were categorized by the drug that wasevaluated. If more than one anti-malarial was administered, the study was included in bothcategories. In total, 34 patients received artemether (34 pregnant; 0 non-pregnant), 182artesunate (AS) (94 pregnant; 88 non-pregnant), 48 DHA (56 pregnant, 57 non-pregnant),341 lumefantrine (324 pregnant; 17 non-pregnant), 46 amodiaquine (27 pregnant, 19 non-pregnant), 85 mefloquine (53 pregnant; 32 non-pregnant), 279 SP (161 pregnant; 118 non-pregnant), 72 PPQ (68 pregnant; 69 non-pregnant) and 163 AP (105 pregnant, 58 non-pregnant).
Quality assessment of the included studiesDetails of the quality assessment are depicted in the table in Additional file 3. In summary,studies were given a median 23 points (range 16–29) out of 31. Most of the studies did notreport how patients were selected and did not report the percentage of patients who agreedto participate. This could compromise the representativeness of the study population. Therewas no blinding of patients, researchers or statistical analysis. Overall, the quality of theincluded studies could be evaluated as moderate to good.
Studies assessing the pharmacokinetics of ACTThe data sheet (excel file) of the included studies is provided as Additional file 4.
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Artemether and dihydroartemisininTwo studies investigated the pharmacokinetic properties of artemether in pregnant women,following oral administration of artemether-lumefantrine (AL) (80/480 mg b.i.d. for3 days).251, 258 Tarning et al.258 studied 21 pregnant women in the second or third trimesterof pregnancy with uncomplicated falciparum malaria. Both a compartmental (zero-orderabsorption followed by transit compartment absorption and a simultaneous one-compartment drug-metabolite model) and a noncompartmental analysis were performed.The first revealed no statistically significant covariates, indicating among others nodifference between second and third trimester. Results obtained by noncompartmentalanalysis were used to compare the pharmacokinetic properties of pregnant women with theliterature. Estimated exposure to artemether and its active metabolite DHA was similar tothat reported in pregnant Thai patients251 but lower than that reported in two studies in adultnon-pregnant patients from Thailand.127, 435 However, these results should be interpretedwith caution since ethnicity might have an impact on the pharmacokinetic properties of thesedrugs.
McGready et al.251 studied 13 women in the second and third trimester of pregnancy withrecrudescent uncomplicated multi-drug resistant falciparum malaria after 7-day quininetreatment. A noncompartmental analysis revealed no significant differences in thepharmacokinetic parameters of artemether and DHA between the second and third trimester.Comparison with data from the literature showed a lower exposure (AUC) and maximumconcentration (Cmax) of artemether compared to male Thai patients and of DHA comparedto non-pregnant patients.127
Artesunate and dihydroartemisininSix studies investigated the pharmacokinetics after administration of AS.241, 312, 316, 425, 427, 436
Three studies described the pharmacokinetic properties of AS as well as the pharmacokineticproperties of DHA, the active metabolite of AS, that is the principle source of anti-malarialactivity after AS administration.241, 425 McGready et al.241 compared the pharmacokinetics ofintravenous and oral AS in 20 women with malaria during pregnancy and 3 months post-partum without malaria. They found no significant differences in AS or DHApharmacokinetics after intravenous administration. After oral administration, the exposureof AS and DHA (AUC) was significantly higher in pregnant women with malaria than inpost-partum women without malaria. This can be explained by a higher bioavailability andlower oral clearance. The authors ascribed the differences to a disease related reduction inpre-systemic metabolism, as an active malaria infection tends to increase oral bioavailability,and not to the pregnancy. This assumption was supported by a decrease in DHA exposure atday 6 compared with day 0 and 1 in women with malaria but not in healthy women.
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"mefloquine*"[tiab] OR "Lariam"[tiab] OR "ASMQ"[tiab] OR "artesunate-mefloquine"[tiab]) OR 7. ("Amodiaquine"[Mesh] OR "amodiaquine, artesunate drugcombination"[Supplementary Concept] OR "amodiaquine*"[tiab] OR "AQ*"[tiab]) OR 8.(("sulfadoxine-pyrimethamine-artesunate"[Supplementary Concept] OR "fanasil,pyrimethamine drug combination"[Supplementary Concept]) OR "SP"[tiab] OR(("sulfadoxine*"[tiab] OR "sulphadoxine*"[tiab]) AND "pyrimethamine*"[tiab])) OR 9.("piperaquine"[Supplementary Concept] OR "piperaquine*"[tiab]) OR 10. ("atovaquone,proguanil drug combination"[Supplementary Concept] OR "Atovaquone"[Mesh] OR"atovaquone*"[tiab] OR "Proguanil"[Mesh] OR "proguanil*"[tiab] OR "malarone*"[tiab])
ResultsThe initial search yielded 121 records (Fig. 1: PRISMA flow diagram of study selection). 27articles met the inclusion criteria and were included in the analysis (Table 1).241, 248, 251, 253,
256, 258, 259, 267, 268, 309, 311-313, 315-317, 424-434 The main study findings of the included trials can befound in Table 2.
The studies included were published between 1990 and 2015 and included a total of 829pregnant and 377 non-pregnant patients. Articles were categorized by the drug that wasevaluated. If more than one anti-malarial was administered, the study was included in bothcategories. In total, 34 patients received artemether (34 pregnant; 0 non-pregnant), 182artesunate (AS) (94 pregnant; 88 non-pregnant), 48 DHA (56 pregnant, 57 non-pregnant),341 lumefantrine (324 pregnant; 17 non-pregnant), 46 amodiaquine (27 pregnant, 19 non-pregnant), 85 mefloquine (53 pregnant; 32 non-pregnant), 279 SP (161 pregnant; 118 non-pregnant), 72 PPQ (68 pregnant; 69 non-pregnant) and 163 AP (105 pregnant, 58 non-pregnant).
Quality assessment of the included studiesDetails of the quality assessment are depicted in the table in Additional file 3. In summary,studies were given a median 23 points (range 16–29) out of 31. Most of the studies did notreport how patients were selected and did not report the percentage of patients who agreedto participate. This could compromise the representativeness of the study population. Therewas no blinding of patients, researchers or statistical analysis. Overall, the quality of theincluded studies could be evaluated as moderate to good.
Studies assessing the pharmacokinetics of ACTThe data sheet (excel file) of the included studies is provided as Additional file 4.
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Artemether and dihydroartemisininTwo studies investigated the pharmacokinetic properties of artemether in pregnant women,following oral administration of artemether-lumefantrine (AL) (80/480 mg b.i.d. for3 days).251, 258 Tarning et al.258 studied 21 pregnant women in the second or third trimesterof pregnancy with uncomplicated falciparum malaria. Both a compartmental (zero-orderabsorption followed by transit compartment absorption and a simultaneous one-compartment drug-metabolite model) and a noncompartmental analysis were performed.The first revealed no statistically significant covariates, indicating among others nodifference between second and third trimester. Results obtained by noncompartmentalanalysis were used to compare the pharmacokinetic properties of pregnant women with theliterature. Estimated exposure to artemether and its active metabolite DHA was similar tothat reported in pregnant Thai patients251 but lower than that reported in two studies in adultnon-pregnant patients from Thailand.127, 435 However, these results should be interpretedwith caution since ethnicity might have an impact on the pharmacokinetic properties of thesedrugs.
McGready et al.251 studied 13 women in the second and third trimester of pregnancy withrecrudescent uncomplicated multi-drug resistant falciparum malaria after 7-day quininetreatment. A noncompartmental analysis revealed no significant differences in thepharmacokinetic parameters of artemether and DHA between the second and third trimester.Comparison with data from the literature showed a lower exposure (AUC) and maximumconcentration (Cmax) of artemether compared to male Thai patients and of DHA comparedto non-pregnant patients.127
Artesunate and dihydroartemisininSix studies investigated the pharmacokinetics after administration of AS.241, 312, 316, 425, 427, 436
Three studies described the pharmacokinetic properties of AS as well as the pharmacokineticproperties of DHA, the active metabolite of AS, that is the principle source of anti-malarialactivity after AS administration.241, 425 McGready et al.241 compared the pharmacokinetics ofintravenous and oral AS in 20 women with malaria during pregnancy and 3 months post-partum without malaria. They found no significant differences in AS or DHApharmacokinetics after intravenous administration. After oral administration, the exposureof AS and DHA (AUC) was significantly higher in pregnant women with malaria than inpost-partum women without malaria. This can be explained by a higher bioavailability andlower oral clearance. The authors ascribed the differences to a disease related reduction inpre-systemic metabolism, as an active malaria infection tends to increase oral bioavailability,and not to the pregnancy. This assumption was supported by a decrease in DHA exposure atday 6 compared with day 0 and 1 in women with malaria but not in healthy women.
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Kloprogge et al.436 used the same data as McGready et al. but used a noncompartmentalanalysis to dissect and quantify the individual contributions of malaria and pregnancy to thealtered pharmacokinetics. They found no effect of both malaria and pregnancy onpharmacokinetic properties of intravenous AS and DHA. However, their research showedopposite and independent effects for malaria (87 % increase) and pregnancy (23 % decrease)on the absolute oral bioavailability of artesunate. Both findings are in line with conclusionsdrawn by McGready et al. and ask for further dose optimization studies.
Valea et al.425 studied the pharmacokinetics of AS and DHA in 24 pregnant women and 24controls. They found a significantly lower oral clearance (CL/F) and higher exposure (AUC)of AS in pregnant women compared to the non-pregnant women. However, they did not findsignificant differences for DHA. It is important to notice that there was a significantly higherparasite density in the pregnant women’ group, possibly resulting in higher exposure, whichmight have masked the pregnancy-related effects.
Three other studies reported only the pharmacokinetic properties of DHA.312, 316, 427
Onyamboko et al.427 compared 26 pregnant women with malaria with the same women threemonths post-partum and with 25 non-pregnant parasitaemic controls. After a single dose oforally administred AS, there appeared to be no significant and clinically relevant differencesin DHA pharmacokinetics between the women in pregnant and post-partum state. However,the exposure of DHA (AUCfree) was significantly lower in pregnant women compared tonon-pregnant controls (the authors used a 90 % confidence interval), which is consistent witha significantly increased clearance (CL/F) in the pregnant group. The authors described acouple of reasons for this apparent difference between pregnant women and non-pregnantcontrols and the absence of this difference between pregnant and post-partum women,namely that the physiological changes that occur during pregnancy might remain 3 monthspost-partum, that lactation influences pharmacokinetics, that most post-partum women werenot parasitaemic and that a comparison in the same women mitigates the effects of potentialother confounders.
The investigation by Morris et al.312 is based on the same clinical study, but used acompartmental analysis (one compartmental analysis with mixed zero order, lagged first-order absorption for AS) instead of a non-compartmental analysis to describe the data. In thefinal model, pregnancy status was the only covariate that had a significant influence on DHAclearance, suggesting a faster clearance of DHA in pregnant women. Together with the datafrom Onyamboko et al., the authors conclude that this provides further evidence that higherdoses of AS would be required in pregnant women. Another study by McGready et al.316
from 2006 (n = 24) showed lower exposure (AUC) to DHA and higher rates of clearanceand apparent volume of distribution in pregnant women compared to literature on non-
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pregnant women, although this should be interpreted with caution as differences inmethodology of the studies might explain (part of) the differences.437
DihydroartemisininThree articles report the pharmacokinetic properties of oral DHA.267, 268, 434 Rijken et al. andTarning et al. papers are based on one study into the pharmacokinetics of DHA after the oraladministration of DHA-PQ (6.4 and 51.2 mg/kg p.o. q.d. for 3 days).267, 268 Rijken et al.267
used a noncompartmental analysis to describe the pharmacokinetic properties in 24 pregnantwomen and 24 controls with acute falciparum malaria. They report no significant differencesin total DHA exposure or maximum concentration between the two groups, although theDHA exposure after the first dose was significantly lower among the pregnant women, andthere was seemingly a trend of lower exposure after the other doses. As well, there was atrend towards higher clearance in pregnant women, but this did not reach statisticalsignificance. However, the authors warn for the potentially masking effect of the high inter-individual variability.
Using a mono-compartmental disposition model, Tarning et al.268 report a 38% lower totalexposure to DHA in pregnant women compared to the controls (p = 0.001), consistent witha significantly higher apparent volume of distribution (p = 0.008) and clearance rate(p = 0.001). This could be explained by pregnancy related induction of hepaticglucuronidation enzymes resulting in an increased first-pass metabolism and acceleratedclearance.
Benjamin et al.434 report no differences in pharmacokinetic properties of DHA betweenpregnant and non-pregnant women without malaria after oral DHA-PQ (7 and 58 mg/kg q.d.for 3 days).
LumefantrineThe pharmacokinetic properties of lumefantrine were investigated in six studies.248, 251, 253,
315, 426, 438 A study by McGready et al.251 in 13 pregnant women with recrudescent falciparummalaria showed significantly lower lumefantrine AUC values in pregnant women than innon-pregnant patients from studies with uncomplicated malaria, caused by more rapidlumefantrine elimination in pregnant women. The large proportion of smokers among thenon-pregnant patients made it difficult to draw strong conclusions on the cause of thisdifference. Also, they reported a proportion of 38 % of pregnant women with a day 7lumefantrine concentration below 280 ng/ml, which is associated with high failure rates(49%).439
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Kloprogge et al.436 used the same data as McGready et al. but used a noncompartmentalanalysis to dissect and quantify the individual contributions of malaria and pregnancy to thealtered pharmacokinetics. They found no effect of both malaria and pregnancy onpharmacokinetic properties of intravenous AS and DHA. However, their research showedopposite and independent effects for malaria (87 % increase) and pregnancy (23 % decrease)on the absolute oral bioavailability of artesunate. Both findings are in line with conclusionsdrawn by McGready et al. and ask for further dose optimization studies.
Valea et al.425 studied the pharmacokinetics of AS and DHA in 24 pregnant women and 24controls. They found a significantly lower oral clearance (CL/F) and higher exposure (AUC)of AS in pregnant women compared to the non-pregnant women. However, they did not findsignificant differences for DHA. It is important to notice that there was a significantly higherparasite density in the pregnant women’ group, possibly resulting in higher exposure, whichmight have masked the pregnancy-related effects.
Three other studies reported only the pharmacokinetic properties of DHA.312, 316, 427
Onyamboko et al.427 compared 26 pregnant women with malaria with the same women threemonths post-partum and with 25 non-pregnant parasitaemic controls. After a single dose oforally administred AS, there appeared to be no significant and clinically relevant differencesin DHA pharmacokinetics between the women in pregnant and post-partum state. However,the exposure of DHA (AUCfree) was significantly lower in pregnant women compared tonon-pregnant controls (the authors used a 90 % confidence interval), which is consistent witha significantly increased clearance (CL/F) in the pregnant group. The authors described acouple of reasons for this apparent difference between pregnant women and non-pregnantcontrols and the absence of this difference between pregnant and post-partum women,namely that the physiological changes that occur during pregnancy might remain 3 monthspost-partum, that lactation influences pharmacokinetics, that most post-partum women werenot parasitaemic and that a comparison in the same women mitigates the effects of potentialother confounders.
The investigation by Morris et al.312 is based on the same clinical study, but used acompartmental analysis (one compartmental analysis with mixed zero order, lagged first-order absorption for AS) instead of a non-compartmental analysis to describe the data. In thefinal model, pregnancy status was the only covariate that had a significant influence on DHAclearance, suggesting a faster clearance of DHA in pregnant women. Together with the datafrom Onyamboko et al., the authors conclude that this provides further evidence that higherdoses of AS would be required in pregnant women. Another study by McGready et al.316
from 2006 (n = 24) showed lower exposure (AUC) to DHA and higher rates of clearanceand apparent volume of distribution in pregnant women compared to literature on non-
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pregnant women, although this should be interpreted with caution as differences inmethodology of the studies might explain (part of) the differences.437
DihydroartemisininThree articles report the pharmacokinetic properties of oral DHA.267, 268, 434 Rijken et al. andTarning et al. papers are based on one study into the pharmacokinetics of DHA after the oraladministration of DHA-PQ (6.4 and 51.2 mg/kg p.o. q.d. for 3 days).267, 268 Rijken et al.267
used a noncompartmental analysis to describe the pharmacokinetic properties in 24 pregnantwomen and 24 controls with acute falciparum malaria. They report no significant differencesin total DHA exposure or maximum concentration between the two groups, although theDHA exposure after the first dose was significantly lower among the pregnant women, andthere was seemingly a trend of lower exposure after the other doses. As well, there was atrend towards higher clearance in pregnant women, but this did not reach statisticalsignificance. However, the authors warn for the potentially masking effect of the high inter-individual variability.
Using a mono-compartmental disposition model, Tarning et al.268 report a 38% lower totalexposure to DHA in pregnant women compared to the controls (p = 0.001), consistent witha significantly higher apparent volume of distribution (p = 0.008) and clearance rate(p = 0.001). This could be explained by pregnancy related induction of hepaticglucuronidation enzymes resulting in an increased first-pass metabolism and acceleratedclearance.
Benjamin et al.434 report no differences in pharmacokinetic properties of DHA betweenpregnant and non-pregnant women without malaria after oral DHA-PQ (7 and 58 mg/kg q.d.for 3 days).
LumefantrineThe pharmacokinetic properties of lumefantrine were investigated in six studies.248, 251, 253,
315, 426, 438 A study by McGready et al.251 in 13 pregnant women with recrudescent falciparummalaria showed significantly lower lumefantrine AUC values in pregnant women than innon-pregnant patients from studies with uncomplicated malaria, caused by more rapidlumefantrine elimination in pregnant women. The large proportion of smokers among thenon-pregnant patients made it difficult to draw strong conclusions on the cause of thisdifference. Also, they reported a proportion of 38 % of pregnant women with a day 7lumefantrine concentration below 280 ng/ml, which is associated with high failure rates(49%).439
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The study by McGready et al. from 2006 was nested in a larger trial to assess the efficacy,safety, tolerability and pregnancy outcomes of AL in pregnant women.248 Apart from theseoutcomes, the study by McGready et al.248 from 2008 describes day 7 capillary plasmalumefantrine concentrations in 85 patients. In total, 35 % of patients had a day 7 capillaryplasma concentration below 355 ng/ml (which corresponds with 280 ng/ml in venousplasma). All 21 (100 %) patients with levels over 600 ng/ml were cured, while patients withlower values had recrudescent infections (p < 0.001).
A third study nested in the trial mentioned above investigated the populationpharmacokinetics of lumefantrine in 103 pregnant women with uncomplicated multidrug-resistant falciparum malaria.315 Using a two-compartment model with first-order absorptionand elimination, they predicted a 12 % odds increase in recrudescence and 7.2 % increase inapparent volume of distribution for each successive week of EGA on admission for pregnantwomen. Also, they showed a non-significant trend (p = 0.26) for the predicted day 7 mediancapillary lumefantrine concentrations to be lower in women with a recrudescent [n = 17;median concentration: 388 ng/ml (range 126–536)] or new infection [n = 21; medianconcentration: 377 ng/ml (range 136–1210)] compared to women who had no recrudescence[n = 65, median concentration: 427 ng/ml (range 135–1600)]. Based on different doseregime simulations using their final model, they recommend a 5-day regime instead of a 3-day regime to increase exposure to artemether and DHA and increase day 7 plasmalumefantrine concentration.
The study by Piola et al.253 reports the data of a large efficacy study conducted in 304pregnant women with uncomplicated falciparum malaria, of whom 152 received quinine and152 received AL. For 97 of the women who received AL, the day 7 plasma lumefantrineconcentration was available. 32 % of women had a lumefantrine concentration below280 ng/ml (venous plasma). Also the reappearance of malaria was significantly associatedwith decreased plasma concentrations of lumefantrine [Reappearance: 422 ng/ml (range 15–3246) vs no reappearance: 240 ng/ml (range 123–454); p = 0.01].
Nested into this efficacy trial was a pharmacokinetic study, which comparedpharmacokinetics of lumefantrine in pregnant (n = 26) and non-pregnant (n = 17) women.426
This study by Tarning et al. showed no statistical difference in total lumefantrine exposure,apparent volume of distribution of elimination clearance between the two groups. Tmax andT1/2were significantly shorter in pregnant women. The day 7 concentration of lumefantrinewas lower among pregnant women (488 ng/ml [range 30.7–3550] in pregnant women vs 720[range 339–2150] in non-pregnant women), but this difference was not statisticallysignificant (p = 0.128). Fifteen percent of the pregnant women had a day 7 lumefantrinevenous plasma concentration below 280 ng/ml, while none of the women in the non-pregnant control group had day 7 lumefantrine venous plasma concentrations below
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280 ng/ml. With this in view, the study suggested no significant correlation between weekof EGA and drug exposure.
A third study, nested in the efficacy trial, was performed by Kloprogge et al.438 The samedata as Tarning et al. was used, plus day 7 capillary lumefantrine concentrations of 89pregnant women with P. falciparum malaria. Based on a transit-compartment absorptionmodel followed by a two-compartment disposition mode, a 27 % lower day 7 lumefantrineconcentration in pregnant women was found compared to non-pregnant women., caused bya 36.5 % decrease in intercompartmental clearance during pregnancy. Although thiscorresponded with a previous study in Thailand,251 the cure rate was higher in this study,possibly resulting from higher background immunity or less lumefantrine resistance inUganda compared to Thailand.
AmodiaquineThe pharmacokinetics of amodiaquine were investigated in two studies.259, 309 Rijken et al.259
reported no difference in pharmacokinetic parameters between pregnant women with P.vivax malaria (n = 24) and post-partum women (n = 19), except for the maximumconcentration (Cmax) of desethylamodiaquine (DEAQ), the principle metabolite ofamodiaquine, that was significantly lower in pregnant women (p = 0.019). However,because the difference was below 10 % and the total exposure to (desethyl)amodiaquine didnot differ significantly, the clinical impact of this difference was considered limited. Therewas no significant difference in pharmacokinetic parameters between the 2nd and 3rdtrimester of pregnancy. Also, there was no significant pharmacokinetic difference betweenpost-partum women with P. vivax malaria and those without it, making it unlikely that adisease effect masked the differences between pregnant and post-partum women. Pregnantwomen with recurrent P. vivax malaria did have a significantly lower dose-normalizedamodiaquine exposure than post-partum women (p = 0.036), suggesting that high drugexposure suppresses recurrent malaria.
Tarning et al.259 did a compartmental analysis of the same data using a lagged first-orderabsorption with a two-compartment disposition model followed by a three-compartmentdisposition of desethylamodiaquine. They found a relatively small effect of age ofamodiaquine clearance (1.36 % reduction per year), which might be related to an increasedimmunity in older patients and reflect reduced severity of the disease. Also, pregnant patientshad a reduced absorption lag time (41.6 % decrease), possibly as a result of increased cardiacoutput resulting in an increased blood flow to the stomach and small intestine.440 Neitherpregnancy status nor estimated gestational age resulted in a clinically relevant impact onother pharmacokinetic parameters.
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The study by McGready et al. from 2006 was nested in a larger trial to assess the efficacy,safety, tolerability and pregnancy outcomes of AL in pregnant women.248 Apart from theseoutcomes, the study by McGready et al.248 from 2008 describes day 7 capillary plasmalumefantrine concentrations in 85 patients. In total, 35 % of patients had a day 7 capillaryplasma concentration below 355 ng/ml (which corresponds with 280 ng/ml in venousplasma). All 21 (100 %) patients with levels over 600 ng/ml were cured, while patients withlower values had recrudescent infections (p < 0.001).
A third study nested in the trial mentioned above investigated the populationpharmacokinetics of lumefantrine in 103 pregnant women with uncomplicated multidrug-resistant falciparum malaria.315 Using a two-compartment model with first-order absorptionand elimination, they predicted a 12 % odds increase in recrudescence and 7.2 % increase inapparent volume of distribution for each successive week of EGA on admission for pregnantwomen. Also, they showed a non-significant trend (p = 0.26) for the predicted day 7 mediancapillary lumefantrine concentrations to be lower in women with a recrudescent [n = 17;median concentration: 388 ng/ml (range 126–536)] or new infection [n = 21; medianconcentration: 377 ng/ml (range 136–1210)] compared to women who had no recrudescence[n = 65, median concentration: 427 ng/ml (range 135–1600)]. Based on different doseregime simulations using their final model, they recommend a 5-day regime instead of a 3-day regime to increase exposure to artemether and DHA and increase day 7 plasmalumefantrine concentration.
The study by Piola et al.253 reports the data of a large efficacy study conducted in 304pregnant women with uncomplicated falciparum malaria, of whom 152 received quinine and152 received AL. For 97 of the women who received AL, the day 7 plasma lumefantrineconcentration was available. 32 % of women had a lumefantrine concentration below280 ng/ml (venous plasma). Also the reappearance of malaria was significantly associatedwith decreased plasma concentrations of lumefantrine [Reappearance: 422 ng/ml (range 15–3246) vs no reappearance: 240 ng/ml (range 123–454); p = 0.01].
Nested into this efficacy trial was a pharmacokinetic study, which comparedpharmacokinetics of lumefantrine in pregnant (n = 26) and non-pregnant (n = 17) women.426
This study by Tarning et al. showed no statistical difference in total lumefantrine exposure,apparent volume of distribution of elimination clearance between the two groups. Tmax andT1/2were significantly shorter in pregnant women. The day 7 concentration of lumefantrinewas lower among pregnant women (488 ng/ml [range 30.7–3550] in pregnant women vs 720[range 339–2150] in non-pregnant women), but this difference was not statisticallysignificant (p = 0.128). Fifteen percent of the pregnant women had a day 7 lumefantrinevenous plasma concentration below 280 ng/ml, while none of the women in the non-pregnant control group had day 7 lumefantrine venous plasma concentrations below
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280 ng/ml. With this in view, the study suggested no significant correlation between weekof EGA and drug exposure.
A third study, nested in the efficacy trial, was performed by Kloprogge et al.438 The samedata as Tarning et al. was used, plus day 7 capillary lumefantrine concentrations of 89pregnant women with P. falciparum malaria. Based on a transit-compartment absorptionmodel followed by a two-compartment disposition mode, a 27 % lower day 7 lumefantrineconcentration in pregnant women was found compared to non-pregnant women., caused bya 36.5 % decrease in intercompartmental clearance during pregnancy. Although thiscorresponded with a previous study in Thailand,251 the cure rate was higher in this study,possibly resulting from higher background immunity or less lumefantrine resistance inUganda compared to Thailand.
AmodiaquineThe pharmacokinetics of amodiaquine were investigated in two studies.259, 309 Rijken et al.259
reported no difference in pharmacokinetic parameters between pregnant women with P.vivax malaria (n = 24) and post-partum women (n = 19), except for the maximumconcentration (Cmax) of desethylamodiaquine (DEAQ), the principle metabolite ofamodiaquine, that was significantly lower in pregnant women (p = 0.019). However,because the difference was below 10 % and the total exposure to (desethyl)amodiaquine didnot differ significantly, the clinical impact of this difference was considered limited. Therewas no significant difference in pharmacokinetic parameters between the 2nd and 3rdtrimester of pregnancy. Also, there was no significant pharmacokinetic difference betweenpost-partum women with P. vivax malaria and those without it, making it unlikely that adisease effect masked the differences between pregnant and post-partum women. Pregnantwomen with recurrent P. vivax malaria did have a significantly lower dose-normalizedamodiaquine exposure than post-partum women (p = 0.036), suggesting that high drugexposure suppresses recurrent malaria.
Tarning et al.259 did a compartmental analysis of the same data using a lagged first-orderabsorption with a two-compartment disposition model followed by a three-compartmentdisposition of desethylamodiaquine. They found a relatively small effect of age ofamodiaquine clearance (1.36 % reduction per year), which might be related to an increasedimmunity in older patients and reflect reduced severity of the disease. Also, pregnant patientshad a reduced absorption lag time (41.6 % decrease), possibly as a result of increased cardiacoutput resulting in an increased blood flow to the stomach and small intestine.440 Neitherpregnancy status nor estimated gestational age resulted in a clinically relevant impact onother pharmacokinetic parameters.
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MefloquineThe pharmacokinetics of mefloquine in pregnancy have been investigated initially in the90s, and been re-examined recently.425, 428, 429 Nosten et al.428 investigated thepharmacokinetics in 20 pregnant women who received either 125 of 250 mg of oralmefloquine monotherapy. They compared their outcomes with the literature and found ahigher oral clearance and a shorter terminal elimination half-life in pregnant women. Therewas no evidence of delayed absorption. Mean maximum concentrations of mefloquine inwomen who received 250 mg of AS were significantly lower than previously reported in sixhealthy Brazilian volunteers.441-453
Na Bangchang et al.429 compared nine pregnant women with eight non-pregnant women, allsuffering from uncomplicated falciparum malaria, who received a single-dose treatment ofmefloquine (15 mg/kg). They found a significantly lower maximum concentration of wholeblood mefloquine (p = 0.015) and an increased total apparent volume of distribution(p = 0.046) in the pregnant women. The pregnant women also tended to have increased timesto peak concentration (Tmax) compared to non-pregnant women. However, this differencewas not statistically significant. Systematic clearance and terminal elimination half-life’swere similar in both groups. No correlation between EGA and apparent V/F, t1/2 of CL/Fwere seen.
Valea et al.425 investigated the pharmacokinetic properties of mefloquine in combinationwith AS. They compared the pharmacokinetic parameters of 24 pregnant and 24 non-pregnant women with uncomplicated falciparum malaria, treated with a fixed-dosecombination of oral mefloquine and AS (8/3.6 mg/kg per day for 3 days). They found verysimilar values for Cmax, Tmax and V/F in pregnant and non-pregnant women. However,t1/2 was significantly longer in pregnant women than in non-pregnant women (390.2 vs289.2 h; p < 0.001). Also, pregnant women tended to have longer clearance time and higherexposure to mefloquine, but these differences were not statistically significant. The exposureto carboxymefloquine (an inactive metabolite of mefloquine), however, was lower inpregnant women, consistent with a higher apparent volume of distribution and clearance.These findings suggest that the higher exposure to mefloquine may be a result of decreasedcarboxylation of mefloquine, although the increase in exposure to mefloquine was notcompletely proportional to the decrease in exposure to carboxymefloquine.
Sulfadoxine-pyrimethamineThree studies investigated the pharmacokinetic properties of SP.313, 431, 433 Green et al.433
used a one-compartmental analysis to compare the outcome of 33 pregnant (n = 11:parasitaemic; n = 22: aparasitaemic) and 11 post-partum women without symptomaticmalaria (n = 1: parasitaemic; n = 10: aparasitaemic) treated with the standard single dose SP(1500/75 mg). Linear regression showed a significant effect of parity status on sulfadoxine
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half-life as well as on exposure (AUC). The half-life of sulfadoxine was significantly shorter(148 vs 256 h; p < 0.0001); exposure (AUC) was significantly lower (22,816 vs40,106 µg/ml/h; p < 0.001); and the plasma clearance rate was significantly higher (65.9 vs36.9 ml/h; p < 0.001) during pregnancy compared with the post-partum period. Pregnancystatus showed no significant effect on the distribution volume. For pyrimethamine, none ofthe pharmacokinetic parameters differed significantly between the pregnant and post-partumwomen, although the median half-life and exposure (AUC) were lower, yet not significantly.
Karunajeewa et al.431 compared the pharmacokinetic properties of SP in 30 pregnant and 30age-matched non-pregnant women who received IPTp (SP 1500/75 mg once andchloroquine 1350 mg q.d. for 3 days). They found a significantly lower exposure (AUC) forsulfadoxine (33 %), for N-acetylsulfadoxine (a metabolite of sulfadoxine) and forpyrimethamine (32 %) in the pregnant group; which is in line with the significantly higherclearance rates for (N-acetyl)sulfadoxine and pyrimethamine found in this study. The totalapparent volume of distribution was significantly higher in pregnant women for (N-acetyl)sulfadoxine and pyrimethamine. The terminal elimination rate of sulfadoxine and N-acetylsulfadoxine was significantly higher in pregnant women, while the terminalelimination rate of pyrimethamine was significantly lower in this group.
Nyunt et al.313 investigated the pharmacokinetics of SP in Intermittent Preventive Treatment(IPTp) of malaria in 98 pregnant and 77 post-partum women from four African countries.Using a one-compartment model, they found significantly higher maximum concentrationsof sulfadoxine in pregnant women, but lower exposure (AUC), faster clearance, smallervolume of distribution and shorter elimination half-life’s during pregnancy, all statisticallysignificant. Day 7 concentrations of sulfadoxine did not differ significantly; however, afteradjusting for potential covariates, they were significantly lower during pregnancy. Day 7concentrations appeared to be lower in the third than in the second trimester, but thisdifference was not statistically significant. For pyrimethamine, drug exposure was higherduring pregnancy, which is consistent with a significantly slower total clearance, longerelimination half-life and an apparently smaller distribution volume during pregnancy. Aswell, the unadjusted day 7 concentration of pyrimethamine was significantly higher inpregnant women. All pharmacokinetic parameters varied significantly between the studysites.
PiperaquineFive articles report the pharmacokinetic properties of PQ. Two studies conducted by Rijkenet al. and Tarning et al. are based on one study of the pharmacokinetics of PQ after the oraladministration of DHA-PPQ (6.4 and 51.2 mg/kg q.d. divided over 3 days).267, 268 Thefindings for DHA are described above. Rijken et al.267 used a non-compartmental analysisto describe the pharmacokinetic properties of PPQ in 24 pregnant and 24 non-pregnant
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MefloquineThe pharmacokinetics of mefloquine in pregnancy have been investigated initially in the90s, and been re-examined recently.425, 428, 429 Nosten et al.428 investigated thepharmacokinetics in 20 pregnant women who received either 125 of 250 mg of oralmefloquine monotherapy. They compared their outcomes with the literature and found ahigher oral clearance and a shorter terminal elimination half-life in pregnant women. Therewas no evidence of delayed absorption. Mean maximum concentrations of mefloquine inwomen who received 250 mg of AS were significantly lower than previously reported in sixhealthy Brazilian volunteers.441-453
Na Bangchang et al.429 compared nine pregnant women with eight non-pregnant women, allsuffering from uncomplicated falciparum malaria, who received a single-dose treatment ofmefloquine (15 mg/kg). They found a significantly lower maximum concentration of wholeblood mefloquine (p = 0.015) and an increased total apparent volume of distribution(p = 0.046) in the pregnant women. The pregnant women also tended to have increased timesto peak concentration (Tmax) compared to non-pregnant women. However, this differencewas not statistically significant. Systematic clearance and terminal elimination half-life’swere similar in both groups. No correlation between EGA and apparent V/F, t1/2 of CL/Fwere seen.
Valea et al.425 investigated the pharmacokinetic properties of mefloquine in combinationwith AS. They compared the pharmacokinetic parameters of 24 pregnant and 24 non-pregnant women with uncomplicated falciparum malaria, treated with a fixed-dosecombination of oral mefloquine and AS (8/3.6 mg/kg per day for 3 days). They found verysimilar values for Cmax, Tmax and V/F in pregnant and non-pregnant women. However,t1/2 was significantly longer in pregnant women than in non-pregnant women (390.2 vs289.2 h; p < 0.001). Also, pregnant women tended to have longer clearance time and higherexposure to mefloquine, but these differences were not statistically significant. The exposureto carboxymefloquine (an inactive metabolite of mefloquine), however, was lower inpregnant women, consistent with a higher apparent volume of distribution and clearance.These findings suggest that the higher exposure to mefloquine may be a result of decreasedcarboxylation of mefloquine, although the increase in exposure to mefloquine was notcompletely proportional to the decrease in exposure to carboxymefloquine.
Sulfadoxine-pyrimethamineThree studies investigated the pharmacokinetic properties of SP.313, 431, 433 Green et al.433
used a one-compartmental analysis to compare the outcome of 33 pregnant (n = 11:parasitaemic; n = 22: aparasitaemic) and 11 post-partum women without symptomaticmalaria (n = 1: parasitaemic; n = 10: aparasitaemic) treated with the standard single dose SP(1500/75 mg). Linear regression showed a significant effect of parity status on sulfadoxine
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half-life as well as on exposure (AUC). The half-life of sulfadoxine was significantly shorter(148 vs 256 h; p < 0.0001); exposure (AUC) was significantly lower (22,816 vs40,106 µg/ml/h; p < 0.001); and the plasma clearance rate was significantly higher (65.9 vs36.9 ml/h; p < 0.001) during pregnancy compared with the post-partum period. Pregnancystatus showed no significant effect on the distribution volume. For pyrimethamine, none ofthe pharmacokinetic parameters differed significantly between the pregnant and post-partumwomen, although the median half-life and exposure (AUC) were lower, yet not significantly.
Karunajeewa et al.431 compared the pharmacokinetic properties of SP in 30 pregnant and 30age-matched non-pregnant women who received IPTp (SP 1500/75 mg once andchloroquine 1350 mg q.d. for 3 days). They found a significantly lower exposure (AUC) forsulfadoxine (33 %), for N-acetylsulfadoxine (a metabolite of sulfadoxine) and forpyrimethamine (32 %) in the pregnant group; which is in line with the significantly higherclearance rates for (N-acetyl)sulfadoxine and pyrimethamine found in this study. The totalapparent volume of distribution was significantly higher in pregnant women for (N-acetyl)sulfadoxine and pyrimethamine. The terminal elimination rate of sulfadoxine and N-acetylsulfadoxine was significantly higher in pregnant women, while the terminalelimination rate of pyrimethamine was significantly lower in this group.
Nyunt et al.313 investigated the pharmacokinetics of SP in Intermittent Preventive Treatment(IPTp) of malaria in 98 pregnant and 77 post-partum women from four African countries.Using a one-compartment model, they found significantly higher maximum concentrationsof sulfadoxine in pregnant women, but lower exposure (AUC), faster clearance, smallervolume of distribution and shorter elimination half-life’s during pregnancy, all statisticallysignificant. Day 7 concentrations of sulfadoxine did not differ significantly; however, afteradjusting for potential covariates, they were significantly lower during pregnancy. Day 7concentrations appeared to be lower in the third than in the second trimester, but thisdifference was not statistically significant. For pyrimethamine, drug exposure was higherduring pregnancy, which is consistent with a significantly slower total clearance, longerelimination half-life and an apparently smaller distribution volume during pregnancy. Aswell, the unadjusted day 7 concentration of pyrimethamine was significantly higher inpregnant women. All pharmacokinetic parameters varied significantly between the studysites.
PiperaquineFive articles report the pharmacokinetic properties of PQ. Two studies conducted by Rijkenet al. and Tarning et al. are based on one study of the pharmacokinetics of PQ after the oraladministration of DHA-PPQ (6.4 and 51.2 mg/kg q.d. divided over 3 days).267, 268 Thefindings for DHA are described above. Rijken et al.267 used a non-compartmental analysisto describe the pharmacokinetic properties of PPQ in 24 pregnant and 24 non-pregnant
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women with falciparum malaria. They found no significant difference in total PPQ exposurebetween the pregnant and non-pregnant women. However, the exposure in the first 72 h(AUC0-24 h; AUC24-48 h and AUC48-72 h) was significantly higher in the pregnantwomen; as well, the day 7 concentration was significantly elevated. The apparent volume ofdistribution was significantly smaller (602 vs 877 L/kg; p = 0.0057) and the terminalelimination half-life was significantly shorter (17.8 vs 25.6 days; p = 0.0023) in the pregnantgroup. No statistically significant difference was found in clearance rate. The Cmax waselevated after each dose, but only significantly after the first two doses.
Tarning et al.268 did a compartmental analysis with the same data, using a three-compartmentdisposition model with a 45 % higher elimination clearance and a 47 % increase in relativebioavailability in pregnant women compared with non-pregnant women. They found noeffect of pregnancy on exposure of PPQ. However, the terminal elimination half-life wasshorter (17.5 vs 24.0 days; p < 0.001), the apparent volume of distribution lower (529 vs829 L/kg; p < 0.001) and the maximum concentration higher (291 vs 216 ng/ml; p = 0.035)in the pregnant women. The time to maximum concentration, clearance rate and day 7 and28 concentration did not differ significantly between the two groups.
Adam et al.311 reported a significantly higher exposure (AUC0-24; 1.8 vs 0.86 µg h/ml;p = 0.01) and a longer time to maximum concentration (Tmax; 4.00 vs 1.50; p = 0.02) afterthe first dose of DHA-PPQ (24/20 mg/kg q.d. for 3 days) in 12 pregnant women comparedto 12 non-pregnant women with uncomplicated falciparum malaria. No other significantdifferences were observed, including no difference in total exposure (AUC0-∞). Thatnotwithstanding, there was a trend towards higher maximum concentrations of PPQ and ashorter half-life in pregnant women, compared to non-pregnant women.
A compartmental analysis using a three-compartment disposition model with a transit-absorption model of the same data was performed by Hoglund et al.432 They found asignificantly higher maximum concentration (Cmax; 185 vs 102 ng/ml; p = 0.021) and longertime to maximum concentration (Tmax; 30.7 vs 1.48 h; p = 0.018) in the 12 pregnant womencompared to the 12 non-pregnant women. The terminal elimination half-life was shorter inthe pregnant group (t1/2; 22.1 vs 25.7 days; p = 0.001). However, no significant differencesin exposure to PPQ and day 7 and 28 concentrations were observed.
Benjamin et al.434 reported a 33 % lower exposure (AUC; 23.721 vs 35.644 µg h/L;p < 0.001) in pregnant women compared to non-pregnant women, consistent with asignificantly shorter half-life (t1/2; 382 vs 488 h; p < 0.001) and a higher clearance rate(CL/F; 73.5 vs 53.8 L/h; p < 0.001).
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Atovaquone-proguanil (AP)The pharmacokinetic properties of proguanil (PG) were first studied in 1993 byWangboonskul et al.424 The pharmacokinetic parameters of PG (pro-drug), cycloguanil (CG)(active metabolite) and 4-chlorophenylbiguanide (inactive metabolite) were compared in 10healthy pregnant women, four post-partum women and nine male patients; all treated withPG (200 mg p.o. once).454 They found a significantly lower maximum concentration of CGin pregnant women (Cmax; 12.5 vs 28.4 (post-partum) and 39.3 (male) ng/ml; p < 0.05) anda significantly shorter terminal elimination half-life for PG (t1/2; 12.3 vs 17.1 (post-partum)and 16.1 (male) h; p < 0.01) in the pregnant group. The total exposure (AUC) of CG inpregnant women was approximately half of the exposure in male and post-partum patients.The mean ratio of the exposure of PG to CG was 18.0 in pregnancy, compared to 7.8 post-partum. The 4-chlorophenylbiguanide maximum concentration was lower in the pregnantwomen than in the post-partum and male patients, but not significantly. All theseobservations seemed to indicate an impaired conversion of pro-drug to (active) metabolite.
McGready et al.256 investigated the pharmacokinetic properties of AS-AP (4/20/8 mg/kg p.o.q.d. for 3 days) in 24 pregnant patients with recrudescent multi-drug resistant uncomplicatedmalaria. A noncompartmental and compartmental analysis was performed. For atovaquone,PG and CG, they found a lower (corrected) maximum concentration (Cmax) and totalexposure (AUC) in pregnant women compared with healthy volunteers from the samepopulation455 and compared with Thai children with malaria.456 The terminal eliminationhalf-life of atovaquone was significantly longer in the pregnant women. The non-compartmental analysis for PG showed 40 % lower maximum concentrations (Cmax) andexposure (AUC) in pregnant women with acute malaria than in non-pregnant healthy adults.The lower PG concentrations were attributed in the population pharmacokinetic assessmentto increased apparent volume of distribution and clearance rate.
Another study by McGready et al.430 investigated the influences of pregnancy onbiotransformation of PG to CG. They found similar PG plasma concentrations 6 h afteradministration of a single dose of PG (200 mg p.o.) in 45 women during pregnancy and thesame 45 women at least two months post partum. Plasma concentrations (corrected for dose)of CG 6 h after administration of PG were significantly lower during pregnancy than postpartum (25.0 vs 37.4 ng/ml; p < 0.01). The ratio of plasma and urine PG and CGconcentrations increased significantly in pregnancy. The urine concentration of PG and CGwere significantly higher during pregnancy.
Na Bangchang et al.317 studied the pharmacokinetics of atovaquone and PG in pregnantwomen from Thailand (n = 8) and Zambia (n = 18) treated with AP (1000/400 mg p.o. q.d.for 3 days) for uncomplicated falciparum malaria. They found no significant differences inany of the pharmacokinetic parameters of atovaquone, PG or CG between patients from
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women with falciparum malaria. They found no significant difference in total PPQ exposurebetween the pregnant and non-pregnant women. However, the exposure in the first 72 h(AUC0-24 h; AUC24-48 h and AUC48-72 h) was significantly higher in the pregnantwomen; as well, the day 7 concentration was significantly elevated. The apparent volume ofdistribution was significantly smaller (602 vs 877 L/kg; p = 0.0057) and the terminalelimination half-life was significantly shorter (17.8 vs 25.6 days; p = 0.0023) in the pregnantgroup. No statistically significant difference was found in clearance rate. The Cmax waselevated after each dose, but only significantly after the first two doses.
Tarning et al.268 did a compartmental analysis with the same data, using a three-compartmentdisposition model with a 45 % higher elimination clearance and a 47 % increase in relativebioavailability in pregnant women compared with non-pregnant women. They found noeffect of pregnancy on exposure of PPQ. However, the terminal elimination half-life wasshorter (17.5 vs 24.0 days; p < 0.001), the apparent volume of distribution lower (529 vs829 L/kg; p < 0.001) and the maximum concentration higher (291 vs 216 ng/ml; p = 0.035)in the pregnant women. The time to maximum concentration, clearance rate and day 7 and28 concentration did not differ significantly between the two groups.
Adam et al.311 reported a significantly higher exposure (AUC0-24; 1.8 vs 0.86 µg h/ml;p = 0.01) and a longer time to maximum concentration (Tmax; 4.00 vs 1.50; p = 0.02) afterthe first dose of DHA-PPQ (24/20 mg/kg q.d. for 3 days) in 12 pregnant women comparedto 12 non-pregnant women with uncomplicated falciparum malaria. No other significantdifferences were observed, including no difference in total exposure (AUC0-∞). Thatnotwithstanding, there was a trend towards higher maximum concentrations of PPQ and ashorter half-life in pregnant women, compared to non-pregnant women.
A compartmental analysis using a three-compartment disposition model with a transit-absorption model of the same data was performed by Hoglund et al.432 They found asignificantly higher maximum concentration (Cmax; 185 vs 102 ng/ml; p = 0.021) and longertime to maximum concentration (Tmax; 30.7 vs 1.48 h; p = 0.018) in the 12 pregnant womencompared to the 12 non-pregnant women. The terminal elimination half-life was shorter inthe pregnant group (t1/2; 22.1 vs 25.7 days; p = 0.001). However, no significant differencesin exposure to PPQ and day 7 and 28 concentrations were observed.
Benjamin et al.434 reported a 33 % lower exposure (AUC; 23.721 vs 35.644 µg h/L;p < 0.001) in pregnant women compared to non-pregnant women, consistent with asignificantly shorter half-life (t1/2; 382 vs 488 h; p < 0.001) and a higher clearance rate(CL/F; 73.5 vs 53.8 L/h; p < 0.001).
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Atovaquone-proguanil (AP)The pharmacokinetic properties of proguanil (PG) were first studied in 1993 byWangboonskul et al.424 The pharmacokinetic parameters of PG (pro-drug), cycloguanil (CG)(active metabolite) and 4-chlorophenylbiguanide (inactive metabolite) were compared in 10healthy pregnant women, four post-partum women and nine male patients; all treated withPG (200 mg p.o. once).454 They found a significantly lower maximum concentration of CGin pregnant women (Cmax; 12.5 vs 28.4 (post-partum) and 39.3 (male) ng/ml; p < 0.05) anda significantly shorter terminal elimination half-life for PG (t1/2; 12.3 vs 17.1 (post-partum)and 16.1 (male) h; p < 0.01) in the pregnant group. The total exposure (AUC) of CG inpregnant women was approximately half of the exposure in male and post-partum patients.The mean ratio of the exposure of PG to CG was 18.0 in pregnancy, compared to 7.8 post-partum. The 4-chlorophenylbiguanide maximum concentration was lower in the pregnantwomen than in the post-partum and male patients, but not significantly. All theseobservations seemed to indicate an impaired conversion of pro-drug to (active) metabolite.
McGready et al.256 investigated the pharmacokinetic properties of AS-AP (4/20/8 mg/kg p.o.q.d. for 3 days) in 24 pregnant patients with recrudescent multi-drug resistant uncomplicatedmalaria. A noncompartmental and compartmental analysis was performed. For atovaquone,PG and CG, they found a lower (corrected) maximum concentration (Cmax) and totalexposure (AUC) in pregnant women compared with healthy volunteers from the samepopulation455 and compared with Thai children with malaria.456 The terminal eliminationhalf-life of atovaquone was significantly longer in the pregnant women. The non-compartmental analysis for PG showed 40 % lower maximum concentrations (Cmax) andexposure (AUC) in pregnant women with acute malaria than in non-pregnant healthy adults.The lower PG concentrations were attributed in the population pharmacokinetic assessmentto increased apparent volume of distribution and clearance rate.
Another study by McGready et al.430 investigated the influences of pregnancy onbiotransformation of PG to CG. They found similar PG plasma concentrations 6 h afteradministration of a single dose of PG (200 mg p.o.) in 45 women during pregnancy and thesame 45 women at least two months post partum. Plasma concentrations (corrected for dose)of CG 6 h after administration of PG were significantly lower during pregnancy than postpartum (25.0 vs 37.4 ng/ml; p < 0.01). The ratio of plasma and urine PG and CGconcentrations increased significantly in pregnancy. The urine concentration of PG and CGwere significantly higher during pregnancy.
Na Bangchang et al.317 studied the pharmacokinetics of atovaquone and PG in pregnantwomen from Thailand (n = 8) and Zambia (n = 18) treated with AP (1000/400 mg p.o. q.d.for 3 days) for uncomplicated falciparum malaria. They found no significant differences inany of the pharmacokinetic parameters of atovaquone, PG or CG between patients from
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Thailand and Zambia. Atovaquone was slowly absorbed and slowly eliminated withconsiderable variation among individuals. The maximum concentration (Cmax) and exposure(AUC) of atovaquone found in this study were approximately half of those found in otherstudies in healthy volunteers and Thai children with malaria.456, 457 No significant differenceswere seen in the pharmacokinetics of PG. Both the maximum concentration (Cmax) andexposure (AUC) of CG were considerably lower in this study compared to other studies.456-
458
Discussion
This systematic review synthesized and compiled data on ACT pharmacokinetics anddynamics during pregnancy, and the consequences thereof on treatment dose and regime.The previous systematic review on this subject was published in 2009.421 The present reviewencompasses 27 reports with a total of 829 pregnant and 377 non-pregnant women.241, 248,
251, 253, 256, 258, 259, 267, 268, 309, 311-313, 315-317, 424-433 The number of trials that were found are ratherlimited and disproportional low in view of to the large number of pregnant women withmalaria infections worldwide. This has several reasons, first of all, pregnant women aresystematically excluded from clinical trials (because of the risk of the unborn child to beexposed to harmful effects). Furthermore, there is a limited research funding available fortrials, especially pharmacokinetic studies. Funding organizations prefer phase III orrandomized clinical trials over pharmacokinetic studies. The identified studies also differedin quality (see Additional file 3). However, in general, study quality was moderate to good,and the evidence is strong enough to draw conclusions regarding pharmacokinetic changesthat are exhibited in pregnant women. Although current WHO guidelines stronglyrecommend to treat malaria in the first trimester with quinine (combined with clindamycine),these will not be discussed in this review which is focussed on ACT.
Artemether, artesunate and dihydroartemisininArtemisinin-based compounds have been investigated in good quality studies. Two studieson the pharmacokinetic properties of artemether and its principle metabolite DHA suggestthat the maximum concentration (Cmax) and exposure (AUC) of artemether and DHAfollowing treatment with oral AL are lower in pregnant women than in non-pregnantpatients. It also showed that there is no significant difference between the second and thirdtrimester of pregnancy.251, 258 However, since there has been no direct comparative trial,these results should be interpreted with caution. A larger sample size comparative trialshould be conducted to statistically confirm or rule out any clinically important effect ofpregnancy on pharmacokinetic parameters.
Although the outcome of the studies on the pharmacokinetic properties of AS seemconflicting, they provide substantial evidence that pregnancy induces clearance and thus
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leads to lower exposure to AS and DHA. While three studies found a higher DHAexposure241 or no significant differences in DHA pharmacokinetics between the twogroups,425, 427 other studies provided enough evidence to explain this apparent contradictionby the independent and opposite effect of malaria infection on pharmacokineticproperties.251, 312, 427, 436 The higher bioavailability and exposure resulting from malarialinfection in thought to have masked the pregnancy related effects on pharmacokinetics. Thisconclusion is worrying as pregnant women might be at risk of under dosing, resulting inlower cure rates and a more rapid development of resistance to DHA, and urgently calls forreassessment of the treatment dose of artesunate. The exact mechanisms are unfortunatelycurrently unknown. A dose optimization study will be necessary to find the ideal dose ofartesunate-containing ACT in pregnancy in order to augment clinical efficacy and ensuresafety.
Pharmacokinetic properties after administration of oral DHA were investigated in twostudies. A non-compartmental analysis of the data of the first study showed a trend of lowerexposure. However, the differences were only statistically significant after the first dose,possibly because of small sample sizes and high inter-individual variability. Thecompartmental analysis of the same data showed 38 % lower total exposure and significantlyhigher clearance rates and apparent volume of distribution. The second study reported nodifferences in pharmacokinetic properties between pregnant and non-pregnant women. Ofinterest, the first study included women with falciparum malaria, while the parasitaemic rateof the participants was very low in the second study. Further studies with larger sample sizesof the effect of pregnancy on DHA pharmacokinetics are recommended.
LumefantrineAn important development in the past 5 years are that several controlled studies werepublished on lumefantrine. Studies investigating the pharmacokinetic properties oflumefantrine show a low day 7 concentration and large proportions of concentrations belowvalues that are associated with high failure rates.248, 251, 253, 315, 426, 438 One study also showeda significantly lower lumefantrine exposure in pregnant women,251 while another studyshowed significantly shorter Tmaxand T1/2, but no statistically significant differences inlumefantrine exposure.426 Especially the lower day 7 concentrations are reason for concernand ask for more extensive research and reconsideration of the drug dose. Future studiesshould investigate whether drug exposure improves with a standard six-dose regimen oflumefantrine given over 5 days compared to the standard regimen of 3 days. Important tonote is that still much remains unknown regarding the variable absorption of lumefantrine(which is a lipophilic compound) in the digestive tract affecting pharmacokinetic values. Inthe included trials in this review, the absorption of lumefantrine was maximized by providingfatty foods (e.g. milk). However, in daily clinical practice in endemic countries, it iscompletely unknown which percentage of (pregnant) women co-administer high-fat foods.
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Thailand and Zambia. Atovaquone was slowly absorbed and slowly eliminated withconsiderable variation among individuals. The maximum concentration (Cmax) and exposure(AUC) of atovaquone found in this study were approximately half of those found in otherstudies in healthy volunteers and Thai children with malaria.456, 457 No significant differenceswere seen in the pharmacokinetics of PG. Both the maximum concentration (Cmax) andexposure (AUC) of CG were considerably lower in this study compared to other studies.456-
458
Discussion
This systematic review synthesized and compiled data on ACT pharmacokinetics anddynamics during pregnancy, and the consequences thereof on treatment dose and regime.The previous systematic review on this subject was published in 2009.421 The present reviewencompasses 27 reports with a total of 829 pregnant and 377 non-pregnant women.241, 248,
251, 253, 256, 258, 259, 267, 268, 309, 311-313, 315-317, 424-433 The number of trials that were found are ratherlimited and disproportional low in view of to the large number of pregnant women withmalaria infections worldwide. This has several reasons, first of all, pregnant women aresystematically excluded from clinical trials (because of the risk of the unborn child to beexposed to harmful effects). Furthermore, there is a limited research funding available fortrials, especially pharmacokinetic studies. Funding organizations prefer phase III orrandomized clinical trials over pharmacokinetic studies. The identified studies also differedin quality (see Additional file 3). However, in general, study quality was moderate to good,and the evidence is strong enough to draw conclusions regarding pharmacokinetic changesthat are exhibited in pregnant women. Although current WHO guidelines stronglyrecommend to treat malaria in the first trimester with quinine (combined with clindamycine),these will not be discussed in this review which is focussed on ACT.
Artemether, artesunate and dihydroartemisininArtemisinin-based compounds have been investigated in good quality studies. Two studieson the pharmacokinetic properties of artemether and its principle metabolite DHA suggestthat the maximum concentration (Cmax) and exposure (AUC) of artemether and DHAfollowing treatment with oral AL are lower in pregnant women than in non-pregnantpatients. It also showed that there is no significant difference between the second and thirdtrimester of pregnancy.251, 258 However, since there has been no direct comparative trial,these results should be interpreted with caution. A larger sample size comparative trialshould be conducted to statistically confirm or rule out any clinically important effect ofpregnancy on pharmacokinetic parameters.
Although the outcome of the studies on the pharmacokinetic properties of AS seemconflicting, they provide substantial evidence that pregnancy induces clearance and thus
The influence of pregnancy on the pharmacokinetic properties of ACT: a systematic review
133
leads to lower exposure to AS and DHA. While three studies found a higher DHAexposure241 or no significant differences in DHA pharmacokinetics between the twogroups,425, 427 other studies provided enough evidence to explain this apparent contradictionby the independent and opposite effect of malaria infection on pharmacokineticproperties.251, 312, 427, 436 The higher bioavailability and exposure resulting from malarialinfection in thought to have masked the pregnancy related effects on pharmacokinetics. Thisconclusion is worrying as pregnant women might be at risk of under dosing, resulting inlower cure rates and a more rapid development of resistance to DHA, and urgently calls forreassessment of the treatment dose of artesunate. The exact mechanisms are unfortunatelycurrently unknown. A dose optimization study will be necessary to find the ideal dose ofartesunate-containing ACT in pregnancy in order to augment clinical efficacy and ensuresafety.
Pharmacokinetic properties after administration of oral DHA were investigated in twostudies. A non-compartmental analysis of the data of the first study showed a trend of lowerexposure. However, the differences were only statistically significant after the first dose,possibly because of small sample sizes and high inter-individual variability. Thecompartmental analysis of the same data showed 38 % lower total exposure and significantlyhigher clearance rates and apparent volume of distribution. The second study reported nodifferences in pharmacokinetic properties between pregnant and non-pregnant women. Ofinterest, the first study included women with falciparum malaria, while the parasitaemic rateof the participants was very low in the second study. Further studies with larger sample sizesof the effect of pregnancy on DHA pharmacokinetics are recommended.
LumefantrineAn important development in the past 5 years are that several controlled studies werepublished on lumefantrine. Studies investigating the pharmacokinetic properties oflumefantrine show a low day 7 concentration and large proportions of concentrations belowvalues that are associated with high failure rates.248, 251, 253, 315, 426, 438 One study also showeda significantly lower lumefantrine exposure in pregnant women,251 while another studyshowed significantly shorter Tmaxand T1/2, but no statistically significant differences inlumefantrine exposure.426 Especially the lower day 7 concentrations are reason for concernand ask for more extensive research and reconsideration of the drug dose. Future studiesshould investigate whether drug exposure improves with a standard six-dose regimen oflumefantrine given over 5 days compared to the standard regimen of 3 days. Important tonote is that still much remains unknown regarding the variable absorption of lumefantrine(which is a lipophilic compound) in the digestive tract affecting pharmacokinetic values. Inthe included trials in this review, the absorption of lumefantrine was maximized by providingfatty foods (e.g. milk). However, in daily clinical practice in endemic countries, it iscompletely unknown which percentage of (pregnant) women co-administer high-fat foods.
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AmodiaquineThe reported studies with oral amodiaquine for the treatment of vivax malaria in Thailandrevealed no clinically relevant differences in pharmacokinetic parameters between pregnantand post-partum women. There was no significant difference between post-partum womenwith malaria and without malaria, making it unlikely that a disease effect masked possibledifferences. Therefore, no dosage adjustments are recommended.
MefloquineTwo studies dating from 1990 and 1994 report significantly lower maximum concentrationsof mefloquine in pregnant women compared to healthy Brazilian volunteers428, 441 and non-pregnant women.429 In contrast to a recent study that showed similar values for Cmax inpregnant and non-pregnant women with falciparum malaria and a non-significant trendtowards longer clearance and higher exposure to mefloquine. In the first two studies, patientsreceived one dose of oral AS in a low dose as prophylaxis428 or in a higher dose as treatmentfor chloroquine-resistant falciparum malaria,429 while in the recent study a 3 days course oftreatment of given.425 These differences in drug regimes, besides other variables, might havean influence on the pharmacokinetic parameters. It was thought that altered plasmaconcentrations of mefloquine were caused by the increased volume of distribution. Theresults of the most recent trial425 suggests that although the exposure was higher, thecarboxymefloquine concentration was reduced (with simultaneous increase in V/F andremoval of the metabolite). The reduced carboxylation might be partially responsible for theof the compound in pregnant women. Larger trials with comparative drug regimens,metabolite profiles and compartmental analysis and patient groups would thus be necessaryto draw strong conclusions on the effect of pregnancy on the pharmacokinetic properties ofmefloquine.
Sulfadoxine-pyrimethamineThe reported studies with SP (used for IPTp) all show a significant lower exposure, higherclearance rates and shorter terminal half-life of sulfadoxine in pregnant women comparedwith post-partum women.313, 431, 433 This suggests that higher doses of sulfadoxine would bebeneficial for the efficacy of IPTp even when the parasites are fully susceptible to sulfa drugcombinations.
No general conclusion can be drawn for the pyrimethamine pharmacokinetics, since a studyin Kenya showed no differences in pharmacokinetic parameters between pregnant and post-partum women,433 while a study in Papua New Guinea (PNG) reported significantly lowerexposure and higher clearance rates.431 A study in four African countries describedsignificantly higher exposure and lower clearance rates in pregnant women. Possibleexplanations could be the different rates of parasitaemia between the studies (0–43 %) and
The influence of pregnancy on the pharmacokinetic properties of ACT: a systematic review
135
the concurrent administration of chloroquine in the study in PNG. Further (observational orinterventional) research will be necessary to assess the influence of pregnancy on thepharmacokinetic properties of pyrimethamine. However, with resistance hampering its use,the prospects for an extended PK evaluation of sulfa drug combinations used for IPTp appearto be limited.459 The search for suitable alternative drug (combinations) for IPTp isongoing.460
PiperaquineThe reported studies suggest an influence of pregnancy on the pharmacokinetic propertiesof PQ. Four of the five studies show either an elevated exposure after the first dose,267, 311 a(significantly) higher Cmax and shorter terminal elimination half-lifes.267, 268, 311, 432 However,none of the studies showed a significantly higher total exposure, probably limiting theclinical consequences of the influence of pregnancy. Thereby, one study reported asignificantly lower exposure in the pregnant group, a shorter half-life and a higher apparentvolume of distribution. These discrepancies emphasize the need for further research.
AtovaquoneThe studies investigating atovaquone pharmacokinetics show a more than 50 % lowerCmax and total exposure in pregnant women with falciparum malaria compared to healthyvolunteers.256, 317 Although these results should be interpreted with caution due to smallsample sizes, higher dosing of atovaquone ought to be considered.
ProguanilThe pharmacokinetic parameters of PG did not differ significantly in most studies, but themaximum concentration and terminal elimination half-life of the active metabolite of PG,CG, were significantly lower and shorter in pregnant women. Also, the PG–CG-ratio wassignificantly elevated in two studies, suggesting an impaired conversion of PG to CG. SinceCG is mainly responsible for the therapeutic effect of PG, this might compromise theefficacy; and as well, the dose of the PG portion in the AP combination may have to be re-considered.
Limitations
This systematic review is subject to several limitations. First, there is a considerable degreeof heterogeneity in the outcomes and parameters that were reported in the articles. Forexample, time intervals for exposure differed significantly between the studies; which makesit more difficult to compare the outcomes of different studies. Also, different units andmethods of measurement for the outcomes were used in different studies, complicating directcomparisons. Secondly, there was a large heterogeneity in the control groups. In some
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AmodiaquineThe reported studies with oral amodiaquine for the treatment of vivax malaria in Thailandrevealed no clinically relevant differences in pharmacokinetic parameters between pregnantand post-partum women. There was no significant difference between post-partum womenwith malaria and without malaria, making it unlikely that a disease effect masked possibledifferences. Therefore, no dosage adjustments are recommended.
MefloquineTwo studies dating from 1990 and 1994 report significantly lower maximum concentrationsof mefloquine in pregnant women compared to healthy Brazilian volunteers428, 441 and non-pregnant women.429 In contrast to a recent study that showed similar values for Cmax inpregnant and non-pregnant women with falciparum malaria and a non-significant trendtowards longer clearance and higher exposure to mefloquine. In the first two studies, patientsreceived one dose of oral AS in a low dose as prophylaxis428 or in a higher dose as treatmentfor chloroquine-resistant falciparum malaria,429 while in the recent study a 3 days course oftreatment of given.425 These differences in drug regimes, besides other variables, might havean influence on the pharmacokinetic parameters. It was thought that altered plasmaconcentrations of mefloquine were caused by the increased volume of distribution. Theresults of the most recent trial425 suggests that although the exposure was higher, thecarboxymefloquine concentration was reduced (with simultaneous increase in V/F andremoval of the metabolite). The reduced carboxylation might be partially responsible for theof the compound in pregnant women. Larger trials with comparative drug regimens,metabolite profiles and compartmental analysis and patient groups would thus be necessaryto draw strong conclusions on the effect of pregnancy on the pharmacokinetic properties ofmefloquine.
Sulfadoxine-pyrimethamineThe reported studies with SP (used for IPTp) all show a significant lower exposure, higherclearance rates and shorter terminal half-life of sulfadoxine in pregnant women comparedwith post-partum women.313, 431, 433 This suggests that higher doses of sulfadoxine would bebeneficial for the efficacy of IPTp even when the parasites are fully susceptible to sulfa drugcombinations.
No general conclusion can be drawn for the pyrimethamine pharmacokinetics, since a studyin Kenya showed no differences in pharmacokinetic parameters between pregnant and post-partum women,433 while a study in Papua New Guinea (PNG) reported significantly lowerexposure and higher clearance rates.431 A study in four African countries describedsignificantly higher exposure and lower clearance rates in pregnant women. Possibleexplanations could be the different rates of parasitaemia between the studies (0–43 %) and
The influence of pregnancy on the pharmacokinetic properties of ACT: a systematic review
135
the concurrent administration of chloroquine in the study in PNG. Further (observational orinterventional) research will be necessary to assess the influence of pregnancy on thepharmacokinetic properties of pyrimethamine. However, with resistance hampering its use,the prospects for an extended PK evaluation of sulfa drug combinations used for IPTp appearto be limited.459 The search for suitable alternative drug (combinations) for IPTp isongoing.460
PiperaquineThe reported studies suggest an influence of pregnancy on the pharmacokinetic propertiesof PQ. Four of the five studies show either an elevated exposure after the first dose,267, 311 a(significantly) higher Cmax and shorter terminal elimination half-lifes.267, 268, 311, 432 However,none of the studies showed a significantly higher total exposure, probably limiting theclinical consequences of the influence of pregnancy. Thereby, one study reported asignificantly lower exposure in the pregnant group, a shorter half-life and a higher apparentvolume of distribution. These discrepancies emphasize the need for further research.
AtovaquoneThe studies investigating atovaquone pharmacokinetics show a more than 50 % lowerCmax and total exposure in pregnant women with falciparum malaria compared to healthyvolunteers.256, 317 Although these results should be interpreted with caution due to smallsample sizes, higher dosing of atovaquone ought to be considered.
ProguanilThe pharmacokinetic parameters of PG did not differ significantly in most studies, but themaximum concentration and terminal elimination half-life of the active metabolite of PG,CG, were significantly lower and shorter in pregnant women. Also, the PG–CG-ratio wassignificantly elevated in two studies, suggesting an impaired conversion of PG to CG. SinceCG is mainly responsible for the therapeutic effect of PG, this might compromise theefficacy; and as well, the dose of the PG portion in the AP combination may have to be re-considered.
Limitations
This systematic review is subject to several limitations. First, there is a considerable degreeof heterogeneity in the outcomes and parameters that were reported in the articles. Forexample, time intervals for exposure differed significantly between the studies; which makesit more difficult to compare the outcomes of different studies. Also, different units andmethods of measurement for the outcomes were used in different studies, complicating directcomparisons. Secondly, there was a large heterogeneity in the control groups. In some
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studies, the pregnant women acted as their own post-partum controls, with or without(symptomatic) malaria, while in other studies non-pregnant women or men were used, alsowith or without (symptomatic) malaria. In some studies no control group was available, sodata were compared with literature values. There was a large heterogeneity between thepregnant women, especially regarding parasite density and gestational age estimates.Furthermore, the pharmacokinetic sampling schemes differed among studies, which mighthave had an effect on the outcome parameters. Last, the relatively small sample sizes of allstudies made it difficult to statistically confirm differences in pharmacokinetic properties.For these reasons, a meta-analysis could unfortunately not be conducted.
Conclusion
This systematic review suggests that reassessment of the dose of some components of ACTis necessary to ensure the highest possible efficacy of malaria treatment in pregnant women.Especially for artesunate, lumefantrine, sulfadoxine, atovaquone and proguanil evidencesuggest that with current regimes, pregnant women are under-dosed. Evidence also indicatesthat the effect of pregnancy on amodiaquine and piperaquine is clinically not relevant anddose thus does not have to be changed. For artemether, dihydroartemisinin, lumefantrine,mefloquine and pyrimethamine more extensive research with larger sample sizes is neededto draw strong conclusions on the effect of pregnancy on the pharmacokinetic parameters ofthese components of ACT. Novel approaches such as sampling methods using lower bloodvolumes and minimal preparation (e.g. dried blood spots, high sensitive drug assays), andpopulation pharmacokinetics analysis that are able to investigate the effect of variables suchas age, pregnancy, simultaneously administered drugs, can generate solid data that caninform treatment of malaria in pregnancy.461
Electronic supplementary material
Additional file 1. Methods section. This additional file describes the full methods and searchstrategy.
Additional file 2. Ongoing trials. This additional file summarized ongoing clinical trials onthe subject.
Additional file 3. Quality of included studies. This additional file shows the results of thequality assessment of the individual included studies.
Additional file 4. Data sheet. This additional file shows the original data as extracted fromthe included studies.
Tab
le 1
.Ove
rvie
w a
nd su
mm
ary
of in
clud
ed st
udie
s
Aut
hor
(yea
r)C
ount
ry(t
ime
peri
od)
Typ
e of
stud
yPo
pula
tion
Dru
g (d
ose)
Num
ber
ofw
omen
Phar
mac
okin
etic
anal
ytic
met
hodo
log
y
Phar
mac
okin
etic
vari
able
s
Rem
arks
Ben
jam
in(2
015)
Papu
a N
ewG
uine
e (n
otre
port
ed)
Clin
ical
trial
Preg
nant
wom
en in
seco
ndan
d th
ird tr
imes
ter o
fpr
egna
ncy
(EG
A>1
4wks
)an
d ag
e-m
atch
ed n
on-
preg
nant
wom
en w
ithun
com
plic
ated
with
mal
aria
infe
ctio
n.
Gro
up 1
DH
A-P
PQ(7
/58
mg/
kgp.
o. q
.d. f
or3
days
)
Gro
up 2
PPQ
(128
0mg
p.o.
q.d
. for
3 da
ys) +
SP
(25m
g/kg
once
)
32 p
regn
ant
wom
en33
non
-pr
egna
ntw
omen
Com
partm
ent
al a
naly
sis
MTT
, NN
,C
L/F,
Vc/
F,Q
/F, V
p/F,
t 1/2,
AU
C0-
∞.
Klo
prog
ge(2
015)
Thai
land
(Apr
il 20
08–
Mar
ch20
09)
Clin
ical
trial
Preg
nant
wom
en in
seco
ndan
d th
ird tr
imes
ter o
fpr
egna
ncy
(Ht>
25%
) with
unco
mpl
icat
edP.
falc
ipar
umm
alar
ia &
the
sam
e w
omen
post
par
tum
(3 m
onth
s)w
ithou
t mal
aria
.
Gro
up 1
Arte
suna
te(4
mg/
kg)
i.v. q
.d. o
nda
y 0;
arte
suna
te(4
mg/
kg)
20 p
regn
ant
wom
enG
roup
1: 1
0w
omen Gro
up 2
: 10
wom
en14
pos
tpar
tum
Com
partm
ent
al a
naly
sis
AU
C0-
12,
Cm
ax, T
max
,t 1/
2, C
L/F,
Vd/
F.
Bas
ed o
n th
esa
me
clin
ical
stud
y as
McG
read
y(2
012)
.
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136
studies, the pregnant women acted as their own post-partum controls, with or without(symptomatic) malaria, while in other studies non-pregnant women or men were used, alsowith or without (symptomatic) malaria. In some studies no control group was available, sodata were compared with literature values. There was a large heterogeneity between thepregnant women, especially regarding parasite density and gestational age estimates.Furthermore, the pharmacokinetic sampling schemes differed among studies, which mighthave had an effect on the outcome parameters. Last, the relatively small sample sizes of allstudies made it difficult to statistically confirm differences in pharmacokinetic properties.For these reasons, a meta-analysis could unfortunately not be conducted.
Conclusion
This systematic review suggests that reassessment of the dose of some components of ACTis necessary to ensure the highest possible efficacy of malaria treatment in pregnant women.Especially for artesunate, lumefantrine, sulfadoxine, atovaquone and proguanil evidencesuggest that with current regimes, pregnant women are under-dosed. Evidence also indicatesthat the effect of pregnancy on amodiaquine and piperaquine is clinically not relevant anddose thus does not have to be changed. For artemether, dihydroartemisinin, lumefantrine,mefloquine and pyrimethamine more extensive research with larger sample sizes is neededto draw strong conclusions on the effect of pregnancy on the pharmacokinetic parameters ofthese components of ACT. Novel approaches such as sampling methods using lower bloodvolumes and minimal preparation (e.g. dried blood spots, high sensitive drug assays), andpopulation pharmacokinetics analysis that are able to investigate the effect of variables suchas age, pregnancy, simultaneously administered drugs, can generate solid data that caninform treatment of malaria in pregnancy.461
Electronic supplementary material
Additional file 1. Methods section. This additional file describes the full methods and searchstrategy.
Additional file 2. Ongoing trials. This additional file summarized ongoing clinical trials onthe subject.
Additional file 3. Quality of included studies. This additional file shows the results of thequality assessment of the individual included studies.
Additional file 4. Data sheet. This additional file shows the original data as extracted fromthe included studies.
Tab
le 1
.Ove
rvie
w a
nd su
mm
ary
of in
clud
ed st
udie
s
Aut
hor
(yea
r)C
ount
ry(t
ime
peri
od)
Typ
e of
stud
yPo
pula
tion
Dru
g (d
ose)
Num
ber
ofw
omen
Phar
mac
okin
etic
anal
ytic
met
hodo
log
y
Phar
mac
okin
etic
vari
able
s
Rem
arks
Ben
jam
in(2
015)
Papu
a N
ewG
uine
e (n
otre
port
ed)
Clin
ical
trial
Preg
nant
wom
en in
seco
ndan
d th
ird tr
imes
ter o
fpr
egna
ncy
(EG
A>1
4wks
)an
d ag
e-m
atch
ed n
on-
preg
nant
wom
en w
ithun
com
plic
ated
with
mal
aria
infe
ctio
n.
Gro
up 1
DH
A-P
PQ(7
/58
mg/
kgp.
o. q
.d. f
or3
days
)
Gro
up 2
PPQ
(128
0mg
p.o.
q.d
. for
3 da
ys) +
SP
(25m
g/kg
once
)
32 p
regn
ant
wom
en33
non
-pr
egna
ntw
omen
Com
partm
ent
al a
naly
sis
MTT
, NN
,C
L/F,
Vc/
F,Q
/F, V
p/F,
t 1/2,
AU
C0-
∞.
Klo
prog
ge(2
015)
Thai
land
(Apr
il 20
08–
Mar
ch20
09)
Clin
ical
trial
Preg
nant
wom
en in
seco
ndan
d th
ird tr
imes
ter o
fpr
egna
ncy
(Ht>
25%
) with
unco
mpl
icat
edP.
falc
ipar
umm
alar
ia &
the
sam
e w
omen
post
par
tum
(3 m
onth
s)w
ithou
t mal
aria
.
Gro
up 1
Arte
suna
te(4
mg/
kg)
i.v. q
.d. o
nda
y 0;
arte
suna
te(4
mg/
kg)
20 p
regn
ant
wom
enG
roup
1: 1
0w
omen Gro
up 2
: 10
wom
en14
pos
tpar
tum
Com
partm
ent
al a
naly
sis
AU
C0-
12,
Cm
ax, T
max
,t 1/
2, C
L/F,
Vd/
F.
Bas
ed o
n th
esa
me
clin
ical
stud
y as
McG
read
y(2
012)
.
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507377-L-bw-Visser507377-L-bw-Visser507377-L-bw-Visser507377-L-bw-Visser
Aut
hor
(yea
r)C
ount
ry(t
ime
peri
od)
Typ
e of
stud
yPo
pula
tion
Dru
g (d
ose)
Num
ber
ofw
omen
Phar
mac
okin
etic
anal
ytic
met
hodo
log
y
Phar
mac
okin
etic
vari
able
s
Rem
arks
p.o
q.d.
on
day
1-6
Gro
up 2
Arte
suna
te(4
mg/
kg)
p.o.
q.d
. on
day
0;ar
tesu
nate
(4m
g/kg
) i.v
.q.
d. o
n da
y1,
arte
suna
te(4
mg/
kg)
p.o.
q.d
. on
day
2-6)
wom
en
Val
ea(2
014)
Bur
kina
Faso
(Sep
t20
08-J
an20
09)
Clin
ical
trial
Preg
nant
wom
en in
seco
ndan
d th
ird tr
imes
ter o
fpr
egna
ncy
with
unco
mpl
icat
edP.
falc
ipar
umm
onoi
nfec
tion
& m
atch
edno
n-pr
egna
nt w
omen
with
P.
Mef
loqu
ine
+ A
rtesu
nate
(8/3
.6m
g/kg
q.d
.fo
r 3 d
ays)
24 p
regn
ant
wom
en23
non
-pr
egna
ntw
omen
Non
com
part
men
tal
anal
ysis
Tota
l dos
e,C
max
,C
max
/dos
e,T m
ax, C
L/F,
V/F
, t1/
2,A
UC
0-la
st,
Aut
hor
(yea
r)C
ount
ry(t
ime
peri
od)
Typ
e of
stud
yPo
pula
tion
Dru
g (d
ose)
Num
ber
ofw
omen
Phar
mac
okin
etic
anal
ytic
met
hodo
log
y
Phar
mac
okin
etic
vari
able
s
Rem
arks
falc
ipar
umin
fect
ion.
AU
C0-
∞,
AU
C-
∞/d
ose.
Klo
prog
ge(2
013)
Uga
nda
(Mar
ch20
08–
Sept
2008
)
Clin
ical
trial
Preg
nant
wom
en in
seco
ndan
d th
ird tr
imes
ter o
fpr
egna
ncy
(EG
A>1
3wks
)w
ith u
ncom
plic
ated
P.fa
lcip
arum
mal
aria
.
AL
(80/
480
mg
p.o.
b.i.d
. for
3da
ys) +
200
mL
milk
tea
115
preg
nant
wom
en26
ven
ous
sam
ples
89 c
apill
ary
sam
ples
17 n
on-
preg
nant
wom
en(a
ll ve
nous
sam
ples
)
Com
partm
ent
al a
naly
sis
AU
C0-
∞,
Cm
ax, T
1/2,
day
7co
ncen
tratio
n.
Nes
ted
inla
rger
effic
acy
/sa
fety
stud
yby
Pio
la(2
010)
.
Tarn
ing
(201
3)U
gand
a(O
ct20
06–
May
2009
)
Clin
ical
trial
Preg
nant
wom
en w
ithun
com
plic
ated
P. fa
lcip
arum
infe
ctio
n w
ith a
nEG
A>1
3wks
& n
on-
preg
nant
wom
en m
atch
ed fo
rhi
stor
y of
feve
r, te
mp.
>
AL
(80/
480
mg
p.o.
b.i.d
. for
3da
ys) +
200
mL
milk
tea
OR
AL:
21 p
regn
ant
wom
en
Lum
efan
trine
:26
pre
gnan
t
Non
com
part
men
tal
anal
ysis
Tota
l dos
e,C
max
,C
max
/dos
e,T m
ax, C
L/F,
V/F
, t1/
2,A
UC
0-la
st,
Res
ults
for
arte
met
her
and
dihy
droa
rtem
isi
nin
are
repo
rted
by
Processed on: 19-1-2017Processed on: 19-1-2017Processed on: 19-1-2017Processed on: 19-1-2017
507377-L-bw-Visser507377-L-bw-Visser507377-L-bw-Visser507377-L-bw-Visser
5
Aut
hor
(yea
r)C
ount
ry(t
ime
peri
od)
Typ
e of
stud
yPo
pula
tion
Dru
g (d
ose)
Num
ber
ofw
omen
Phar
mac
okin
etic
anal
ytic
met
hodo
log
y
Phar
mac
okin
etic
vari
able
s
Rem
arks
p.o
q.d.
on
day
1-6
Gro
up 2
Arte
suna
te(4
mg/
kg)
p.o.
q.d
. on
day
0;ar
tesu
nate
(4m
g/kg
) i.v
.q.
d. o
n da
y1,
arte
suna
te(4
mg/
kg)
p.o.
q.d
. on
day
2-6)
wom
en
Val
ea(2
014)
Bur
kina
Faso
(Sep
t20
08-J
an20
09)
Clin
ical
trial
Preg
nant
wom
en in
seco
ndan
d th
ird tr
imes
ter o
fpr
egna
ncy
with
unco
mpl
icat
edP.
falc
ipar
umm
onoi
nfec
tion
& m
atch
edno
n-pr
egna
nt w
omen
with
P.
Mef
loqu
ine
+ A
rtesu
nate
(8/3
.6m
g/kg
q.d
.fo
r 3 d
ays)
24 p
regn
ant
wom
en23
non
-pr
egna
ntw
omen
Non
com
part
men
tal
anal
ysis
Tota
l dos
e,C
max
,C
max
/dos
e,T m
ax, C
L/F,
V/F
, t1/
2,A
UC
0-la
st,
Aut
hor
(yea
r)C
ount
ry(t
ime
peri
od)
Typ
e of
stud
yPo
pula
tion
Dru
g (d
ose)
Num
ber
ofw
omen
Phar
mac
okin
etic
anal
ytic
met
hodo
log
y
Phar
mac
okin
etic
vari
able
s
Rem
arks
falc
ipar
umin
fect
ion.
AU
C0-
∞,
AU
C-
∞/d
ose.
Klo
prog
ge(2
013)
Uga
nda
(Mar
ch20
08–
Sept
2008
)
Clin
ical
trial
Preg
nant
wom
en in
seco
ndan
d th
ird tr
imes
ter o
fpr
egna
ncy
(EG
A>1
3wks
)w
ith u
ncom
plic
ated
P.fa
lcip
arum
mal
aria
.
AL
(80/
480
mg
p.o.
b.i.d
. for
3da
ys) +
200
mL
milk
tea
115
preg
nant
wom
en26
ven
ous
sam
ples
89 c
apill
ary
sam
ples
17 n
on-
preg
nant
wom
en(a
ll ve
nous
sam
ples
)
Com
partm
ent
al a
naly
sis
AU
C0-
∞,
Cm
ax, T
1/2,
day
7co
ncen
tratio
n.
Nes
ted
inla
rger
effic
acy
/sa
fety
stud
yby
Pio
la(2
010)
.
Tarn
ing
(201
3)U
gand
a(O
ct20
06–
May
2009
)
Clin
ical
trial
Preg
nant
wom
en w
ithun
com
plic
ated
P. fa
lcip
arum
infe
ctio
n w
ith a
nEG
A>1
3wks
& n
on-
preg
nant
wom
en m
atch
ed fo
rhi
stor
y of
feve
r, te
mp.
>
AL
(80/
480
mg
p.o.
b.i.d
. for
3da
ys) +
200
mL
milk
tea
OR
AL:
21 p
regn
ant
wom
en
Lum
efan
trine
:26
pre
gnan
t
Non
com
part
men
tal
anal
ysis
Tota
l dos
e,C
max
,C
max
/dos
e,T m
ax, C
L/F,
V/F
, t1/
2,A
UC
0-la
st,
Res
ults
for
arte
met
her
and
dihy
droa
rtem
isi
nin
are
repo
rted
by
Processed on: 19-1-2017Processed on: 19-1-2017Processed on: 19-1-2017Processed on: 19-1-2017
507377-L-bw-Visser507377-L-bw-Visser507377-L-bw-Visser507377-L-bw-Visser
Aut
hor
(yea
r)C
ount
ry(t
ime
peri
od)
Typ
e of
stud
yPo
pula
tion
Dru
g (d
ose)
Num
ber
ofw
omen
Phar
mac
okin
etic
anal
ytic
met
hodo
log
y
Phar
mac
okin
etic
vari
able
s
Rem
arks
37.5
°C, s
mok
ing
stat
us a
ndle
vel o
f par
asita
emia
.Q
uini
ne (1
0m
g/kg
p.o
.t.i
.d. f
or 7
days
)
wom
en17
non
-pr
egna
ntw
omen
Qui
nine
:21
pre
gnan
tw
omen
AU
C0-
∞,
AU
C-
∞/d
ose,
AU
C72
-last
,A
UC
72-∞
,da
y 7
conc
entra
tion.
Tarn
ing
(201
2-2)
.N
este
d in
larg
eref
ficac
y /
safe
ty st
udy
by P
iola
(201
0).
Ada
m(2
012)
Suda
n(A
ug20
07-F
eb20
08)
Clin
ical
trail
Preg
nant
wom
en in
seco
ndan
d th
ird tr
imes
ter o
fpr
egna
ncy
(EG
A 1
5-40
wks
)w
ith u
ncom
plic
ated
P.fa
lcip
arum
mal
aria
and
Hb>
7g/d
L. &
age
-and
wei
ght-m
atch
ed n
on-
preg
nant
wom
en w
ithun
com
plic
ated
P. fa
lcip
arum
mal
aria
.
DH
A-P
PQ(2
.4/2
0m
g/kg
q.d
.fo
r 3 d
ays)
12 p
regn
ant
wom
en12
non
-pr
egna
ntw
omen
Non
com
part
men
tal
anal
ysis
Tota
l dos
e,C
max
(afte
rdo
se 1
, 2an
d 3)
, Tm
ax
(afte
r dos
e1,
2 a
nd 3
),C
L/F,
V/F
,T 1
/2, A
UC
0-la
st, A
UC
0-∞
, AU
C-
∞/d
ose,
AU
C0-
24,
AU
C24
-48,
Bas
ed o
n th
esa
me
clin
ical
stud
y as
Hog
lund
(201
2).
Aut
hor
(yea
r)C
ount
ry(t
ime
peri
od)
Typ
e of
stud
yPo
pula
tion
Dru
g (d
ose)
Num
ber
ofw
omen
Phar
mac
okin
etic
anal
ytic
met
hodo
log
y
Phar
mac
okin
etic
vari
able
s
Rem
arks
AU
C48
-72,
AU
C72
-∞,
day
7 an
d 14
conc
entra
tion.
Hog
lund
(201
2)Su
dan
(Aug
2007
-Feb
2008
)
Clin
ical
trial
Preg
nant
wom
en in
seco
ndan
d th
ird tr
imes
ter o
fpr
egna
ncy
(EG
A 1
5-40
wks
)w
ith u
ncom
plic
ated
P.fa
lcip
arum
mal
aria
and
Hb>
7g/d
L. &
age
-and
wei
ght-m
atch
ed n
on-
preg
nant
wom
en w
ithun
com
plic
ated
P. fa
lcip
arum
mal
aria
.
DH
A-P
PQ(2
.4/2
0m
g/kg
q.d
.fo
r 3 d
ays)
12 p
regn
ant
wom
en12
non
-pr
egna
ntw
omen
Com
partm
ent
al a
naly
sis
Cm
ax, T
max
,t 1/
2, A
UC
48-9
0,A
UC
0-90
,da
y 7
and
28co
ncen
tratio
n.
Bas
ed o
n th
esa
me
clin
ical
stud
y as
Ada
m (2
012)
.
McG
read
y(2
012)
Thai
land
(Apr
il 20
08–
Mar
ch20
09)
Clin
ical
trial
Preg
nant
wom
en in
seco
ndan
d th
ird tr
imes
ter o
fpr
egna
ncy
(Ht>
25%
) with
unco
mpl
icat
edP.
falc
ipar
umm
alar
ia &
the
sam
e w
omen
post
par
tum
(3 m
onth
s)
Gro
up 1
Arte
suna
te(4
mg/
kg)
i.v. q
.d. o
nda
y 0;
arte
suna
te
20 p
regn
ant
wom
enG
roup
1: 1
0w
omen Gro
up 2
: 10
wom
en
Non
com
part
men
tal
anal
ysis
Tota
l dos
e,C
max
,C
max
/dos
e,T m
ax, C
L/F,
V/F
, t1/
2,A
UC
0-∞
,
Bas
ed o
n th
esa
me
clin
ical
stud
y as
Klo
prog
ge(2
015)
.
Processed on: 19-1-2017Processed on: 19-1-2017Processed on: 19-1-2017Processed on: 19-1-2017
507377-L-bw-Visser507377-L-bw-Visser507377-L-bw-Visser507377-L-bw-Visser
5
Aut
hor
(yea
r)C
ount
ry(t
ime
peri
od)
Typ
e of
stud
yPo
pula
tion
Dru
g (d
ose)
Num
ber
ofw
omen
Phar
mac
okin
etic
anal
ytic
met
hodo
log
y
Phar
mac
okin
etic
vari
able
s
Rem
arks
37.5
°C, s
mok
ing
stat
us a
ndle
vel o
f par
asita
emia
.Q
uini
ne (1
0m
g/kg
p.o
.t.i
.d. f
or 7
days
)
wom
en17
non
-pr
egna
ntw
omen
Qui
nine
:21
pre
gnan
tw
omen
AU
C0-
∞,
AU
C-
∞/d
ose,
AU
C72
-last
,A
UC
72-∞
,da
y 7
conc
entra
tion.
Tarn
ing
(201
2-2)
.N
este
d in
larg
eref
ficac
y /
safe
ty st
udy
by P
iola
(201
0).
Ada
m(2
012)
Suda
n(A
ug20
07-F
eb20
08)
Clin
ical
trail
Preg
nant
wom
en in
seco
ndan
d th
ird tr
imes
ter o
fpr
egna
ncy
(EG
A 1
5-40
wks
)w
ith u
ncom
plic
ated
P.fa
lcip
arum
mal
aria
and
Hb>
7g/d
L. &
age
-and
wei
ght-m
atch
ed n
on-
preg
nant
wom
en w
ithun
com
plic
ated
P. fa
lcip
arum
mal
aria
.
DH
A-P
PQ(2
.4/2
0m
g/kg
q.d
.fo
r 3 d
ays)
12 p
regn
ant
wom
en12
non
-pr
egna
ntw
omen
Non
com
part
men
tal
anal
ysis
Tota
l dos
e,C
max
(afte
rdo
se 1
, 2an
d 3)
, Tm
ax
(afte
r dos
e1,
2 a
nd 3
),C
L/F,
V/F
,T 1
/2, A
UC
0-la
st, A
UC
0-∞
, AU
C-
∞/d
ose,
AU
C0-
24,
AU
C24
-48,
Bas
ed o
n th
esa
me
clin
ical
stud
y as
Hog
lund
(201
2).
Aut
hor
(yea
r)C
ount
ry(t
ime
peri
od)
Typ
e of
stud
yPo
pula
tion
Dru
g (d
ose)
Num
ber
ofw
omen
Phar
mac
okin
etic
anal
ytic
met
hodo
log
y
Phar
mac
okin
etic
vari
able
s
Rem
arks
AU
C48
-72,
AU
C72
-∞,
day
7 an
d 14
conc
entra
tion.
Hog
lund
(201
2)Su
dan
(Aug
2007
-Feb
2008
)
Clin
ical
trial
Preg
nant
wom
en in
seco
ndan
d th
ird tr
imes
ter o
fpr
egna
ncy
(EG
A 1
5-40
wks
)w
ith u
ncom
plic
ated
P.fa
lcip
arum
mal
aria
and
Hb>
7g/d
L. &
age
-and
wei
ght-m
atch
ed n
on-
preg
nant
wom
en w
ithun
com
plic
ated
P. fa
lcip
arum
mal
aria
.
DH
A-P
PQ(2
.4/2
0m
g/kg
q.d
.fo
r 3 d
ays)
12 p
regn
ant
wom
en12
non
-pr
egna
ntw
omen
Com
partm
ent
al a
naly
sis
Cm
ax, T
max
,t 1/
2, A
UC
48-9
0,A
UC
0-90
,da
y 7
and
28co
ncen
tratio
n.
Bas
ed o
n th
esa
me
clin
ical
stud
y as
Ada
m (2
012)
.
McG
read
y(2
012)
Thai
land
(Apr
il 20
08–
Mar
ch20
09)
Clin
ical
trial
Preg
nant
wom
en in
seco
ndan
d th
ird tr
imes
ter o
fpr
egna
ncy
(Ht>
25%
) with
unco
mpl
icat
edP.
falc
ipar
umm
alar
ia &
the
sam
e w
omen
post
par
tum
(3 m
onth
s)
Gro
up 1
Arte
suna
te(4
mg/
kg)
i.v. q
.d. o
nda
y 0;
arte
suna
te
20 p
regn
ant
wom
enG
roup
1: 1
0w
omen Gro
up 2
: 10
wom
en
Non
com
part
men
tal
anal
ysis
Tota
l dos
e,C
max
,C
max
/dos
e,T m
ax, C
L/F,
V/F
, t1/
2,A
UC
0-∞
,
Bas
ed o
n th
esa
me
clin
ical
stud
y as
Klo
prog
ge(2
015)
.
Processed on: 19-1-2017Processed on: 19-1-2017Processed on: 19-1-2017Processed on: 19-1-2017
507377-L-bw-Visser507377-L-bw-Visser507377-L-bw-Visser507377-L-bw-Visser
Aut
hor
(yea
r)C
ount
ry(t
ime
peri
od)
Typ
e of
stud
yPo
pula
tion
Dru
g (d
ose)
Num
ber
ofw
omen
Phar
mac
okin
etic
anal
ytic
met
hodo
log
y
Phar
mac
okin
etic
vari
able
s
Rem
arks
preg
nant
wom
en w
ithP.
falc
ipar
umm
alar
ia.
and
28co
ncen
tratio
n.Ta
rnin
g(2
012-
2)U
gand
a(M
arch
2008
–Se
pt20
08)
Clin
ical
trial
Preg
nant
wom
en in
seco
ndan
d th
ird tr
imes
ter o
fpr
egna
ncy
(EG
A>1
3wks
)w
ith u
ncom
plic
ated
P.fa
lcip
arum
mal
aria
.
AL
(80/
480
mg
p.o.
b.i.d
. for
3da
ys) +
200
mL
milk
tea
21 p
regn
ant
wom
enC
ompa
rtme
ntal
ana
lysi
sTo
tal d
ose,
Cm
ax, T
max
,C
L/F,
V/F
,t 1/
2, A
UC
60-
last
,A
UC
/dos
e.
Nes
ted
inla
rger
effic
acy
stud
yby
Pio
la(2
010)
.
Tarn
ing
(201
2-3)
Thai
land
(Oct
200
7-M
ay 2
008)
Clin
ical
trial
Preg
nant
wom
en in
seco
ndan
d th
ird tr
imes
ters
of
preg
nanc
y w
ith a
cute
P.vi
vax
mon
oinf
ectio
n &
sam
ew
omen
pos
t par
tum
(84-
173
days
) with
(n=7
) or w
ithou
t(n
=12)
P. v
ivax
mal
aria
.
Am
odia
quin
e (1
0 m
g/kg
p.o.
q.d
. for
3 da
ys)
27 p
regn
ant
wom
en19
pos
tpar
tum
wom
en
Com
partm
ent
al a
naly
sis
Cm
ax, T
max
,t 1/
2, A
UC
-la
st.
Bas
ed o
n th
esa
me
clin
ical
stud
y as
Rijk
en (2
011-
1).
Mor
ris(2
011)
DR
C(M
ay20
07-N
ov20
08)
Clin
ical
trial
Preg
nant
wom
en in
seco
nd(2
2-26
wks
) and
third
(32-
36w
ks) t
rimes
ter o
fpr
egna
ncy
with
Arte
suna
te(2
00 m
g)p.
o. q
.d. o
nda
y 0
+ SP
26 p
regn
ant
wom
en26
pos
tpar
tum
wom
en
Com
partm
ent
al a
naly
sis
T 1/2, C
L/F,
V/F
.B
ased
on
the
sam
e cl
inic
alst
udy
asO
nyam
boko
Aut
hor
(yea
r)C
ount
ry(t
ime
peri
od)
Typ
e of
stud
yPo
pula
tion
Dru
g (d
ose)
Num
ber
ofw
omen
Phar
mac
okin
etic
anal
ytic
met
hodo
log
y
Phar
mac
okin
etic
vari
able
s
Rem
arks
with
out m
alar
ia.
(4m
g/kg
)p.
o q.
d. o
nda
y 1-
6
Gro
up 2
Arte
suna
te(4
mg/
kg)
p.o.
q.d
. on
day
0;ar
tesu
nate
(4m
g/kg
) i.v
.q.
d. o
n da
y1,
arte
suna
te(4
mg/
kg)
p.o.
q.d
. on
day
2-6)
14 p
ostp
artu
mw
omen
AU
C0-
∞/d
ose.
Tarn
ing
(201
2-1)
Thai
land
(Jun
e 20
08-
Dec
200
8)
Clin
ical
trial
Preg
nant
wom
en in
seco
ndan
d th
ird tr
imes
ter o
fpr
egna
ncy
(Ht>
25%
) with
unco
mpl
icat
edP.
falc
ipar
umm
alar
ia &
mat
ched
non
-
DH
A-P
PQ(6
.4/5
1.2
mg/
kg p
.o.
q.d.
for 3
days
)
24 p
regn
ant
wom
en24
non
-pr
egna
ntw
omen
Com
partm
ent
al a
naly
sis
Cm
ax, T
max
,C
L/F,
V/F
,t 1/
2, A
UC
0-24
, AU
C0-
92, d
ay 7
Bas
ed o
n th
esa
me
clin
ical
stud
y as
Rijk
en (2
011-
2).
Processed on: 19-1-2017Processed on: 19-1-2017Processed on: 19-1-2017Processed on: 19-1-2017
507377-L-bw-Visser507377-L-bw-Visser507377-L-bw-Visser507377-L-bw-Visser
5
Aut
hor
(yea
r)C
ount
ry(t
ime
peri
od)
Typ
e of
stud
yPo
pula
tion
Dru
g (d
ose)
Num
ber
ofw
omen
Phar
mac
okin
etic
anal
ytic
met
hodo
log
y
Phar
mac
okin
etic
vari
able
s
Rem
arks
preg
nant
wom
en w
ithP.
falc
ipar
umm
alar
ia.
and
28co
ncen
tratio
n.Ta
rnin
g(2
012-
2)U
gand
a(M
arch
2008
–Se
pt20
08)
Clin
ical
trial
Preg
nant
wom
en in
seco
ndan
d th
ird tr
imes
ter o
fpr
egna
ncy
(EG
A>1
3wks
)w
ith u
ncom
plic
ated
P.fa
lcip
arum
mal
aria
.
AL
(80/
480
mg
p.o.
b.i.d
. for
3da
ys) +
200
mL
milk
tea
21 p
regn
ant
wom
enC
ompa
rtme
ntal
ana
lysi
sTo
tal d
ose,
Cm
ax, T
max
,C
L/F,
V/F
,t 1/
2, A
UC
60-
last
,A
UC
/dos
e.
Nes
ted
inla
rger
effic
acy
stud
yby
Pio
la(2
010)
.
Tarn
ing
(201
2-3)
Thai
land
(Oct
200
7-M
ay 2
008)
Clin
ical
trial
Preg
nant
wom
en in
seco
ndan
d th
ird tr
imes
ters
of
preg
nanc
y w
ith a
cute
P.vi
vax
mon
oinf
ectio
n &
sam
ew
omen
pos
t par
tum
(84-
173
days
) with
(n=7
) or w
ithou
t(n
=12)
P. v
ivax
mal
aria
.
Am
odia
quin
e (1
0 m
g/kg
p.o.
q.d
. for
3 da
ys)
27 p
regn
ant
wom
en19
pos
tpar
tum
wom
en
Com
partm
ent
al a
naly
sis
Cm
ax, T
max
,t 1/
2, A
UC
-la
st.
Bas
ed o
n th
esa
me
clin
ical
stud
y as
Rijk
en (2
011-
1).
Mor
ris(2
011)
DR
C(M
ay20
07-N
ov20
08)
Clin
ical
trial
Preg
nant
wom
en in
seco
nd(2
2-26
wks
) and
third
(32-
36w
ks) t
rimes
ter o
fpr
egna
ncy
with
Arte
suna
te(2
00 m
g)p.
o. q
.d. o
nda
y 0
+ SP
26 p
regn
ant
wom
en26
pos
tpar
tum
wom
en
Com
partm
ent
al a
naly
sis
T 1/2, C
L/F,
V/F
.B
ased
on
the
sam
e cl
inic
alst
udy
asO
nyam
boko
Aut
hor
(yea
r)C
ount
ry(t
ime
peri
od)
Typ
e of
stud
yPo
pula
tion
Dru
g (d
ose)
Num
ber
ofw
omen
Phar
mac
okin
etic
anal
ytic
met
hodo
log
y
Phar
mac
okin
etic
vari
able
s
Rem
arks
with
out m
alar
ia.
(4m
g/kg
)p.
o q.
d. o
nda
y 1-
6
Gro
up 2
Arte
suna
te(4
mg/
kg)
p.o.
q.d
. on
day
0;ar
tesu
nate
(4m
g/kg
) i.v
.q.
d. o
n da
y1,
arte
suna
te(4
mg/
kg)
p.o.
q.d
. on
day
2-6)
14 p
ostp
artu
mw
omen
AU
C0-
∞/d
ose.
Tarn
ing
(201
2-1)
Thai
land
(Jun
e 20
08-
Dec
200
8)
Clin
ical
trial
Preg
nant
wom
en in
seco
ndan
d th
ird tr
imes
ter o
fpr
egna
ncy
(Ht>
25%
) with
unco
mpl
icat
edP.
falc
ipar
umm
alar
ia &
mat
ched
non
-
DH
A-P
PQ(6
.4/5
1.2
mg/
kg p
.o.
q.d.
for 3
days
)
24 p
regn
ant
wom
en24
non
-pr
egna
ntw
omen
Com
partm
ent
al a
naly
sis
Cm
ax, T
max
,C
L/F,
V/F
,t 1/
2, A
UC
0-24
, AU
C0-
92, d
ay 7
Bas
ed o
n th
esa
me
clin
ical
stud
y as
Rijk
en (2
011-
2).
Processed on: 19-1-2017Processed on: 19-1-2017Processed on: 19-1-2017Processed on: 19-1-2017
507377-L-bw-Visser507377-L-bw-Visser507377-L-bw-Visser507377-L-bw-Visser
Aut
hor
(yea
r)C
ount
ry(t
ime
peri
od)
Typ
e of
stud
yPo
pula
tion
Dru
g (d
ose)
Num
ber
ofw
omen
Phar
mac
okin
etic
anal
ytic
met
hodo
log
y
Phar
mac
okin
etic
vari
able
s
Rem
arks
para
sita
emia
& n
on-p
regn
ant
fem
ale
volu
ntee
rs w
ithas
ympt
omat
icP.
falc
ipar
umpa
rasi
taem
ia (2
00-3
00,0
00p/
µL).
Rijk
en(2
011-
1)Th
aila
nd(O
ct 2
007-
May
200
8)
Clin
ical
trial
Preg
nant
wom
en in
seco
ndan
d th
ird tr
imes
ters
of
preg
nanc
y w
ith a
cute
P.vi
vax
mon
oinf
ectio
n &
sam
ew
omen
pos
t par
tum
(84-
173
days
) with
(n=7
) or w
ithou
t(n
=12)
P. v
ivax
mal
aria
.
Am
odia
quin
e (1
0 m
g/kg
p.o.
q.d
. for
3 da
ys)
24 p
regn
ant
wom
en18
pos
tpar
tum
wom
en
Non
com
part
men
tal
anal
ysis
Tota
l dos
e,C
max
,C
max
/dos
e,T m
ax, C
L/F,
V/F
, t1/
2,A
UC
0-la
st,
AU
C0-
∞,
AU
C0-
∞/d
ose,
day
7 conc
entra
tion.
Bas
edon
the
sam
e cl
inic
alst
udy
asTa
rnin
g(2
012-
3)
Rijk
en(2
011-
2)Th
aila
nd(J
une
2008
-D
ec 2
008)
Clin
ical
trial
Preg
nant
wom
en in
seco
ndan
d th
ird tr
imes
ter o
fpr
egna
ncy
(Ht<
25%
) with
unco
mpl
icat
edP.
falc
ipar
um
DH
A-P
PQ(6
.4/5
1.2
mg/
kg p
.o.
q.d.
for 3
24 p
regn
ant
wom
en24
non
-pr
egna
nt
Non
com
part
men
tal
anal
ysis
Tota
l dos
e,C
max
,C
max
/dos
e,C
L/F,
V/F
,
Bas
ed o
n th
esa
me
clin
ical
stud
y as
Tarn
ing
2012
-
Aut
hor
(yea
r)C
ount
ry(t
ime
peri
od)
Typ
e of
stud
yPo
pula
tion
Dru
g (d
ose)
Num
ber
ofw
omen
Phar
mac
okin
etic
anal
ytic
met
hodo
log
y
Phar
mac
okin
etic
vari
able
s
Rem
arks
asym
ptom
atic
P. fa
lcip
arum
para
sita
emia
(200
-300
,000
p/µL
; Ht>
30%
) & sa
me
wom
en p
ost p
artu
m (3
mon
ths)
with
(n=2
) or
with
out (
n=24
)P. f
alci
paru
mpa
rasi
taem
ia &
non
-pre
gnan
tfe
mal
e vo
lunt
eers
with
asym
ptom
atic
P. fa
lcip
arum
para
sita
emia
(200
-300
,000
p/µL
).
(172
5 m
g)p.
o. q
.d. o
nda
y 1
25 n
on-
preg
nant
wom
en
(201
1).
Ony
ambo
ko(2
011)
DR
C(M
ay20
07-N
ov20
08)
Clin
ical
trial
Preg
nant
wom
en in
seco
nd(2
2-26
wks
) and
third
(32-
36w
ks) t
rimes
ter o
fpr
egna
ncy
with
asym
ptom
atic
P. fa
lcip
arum
para
sita
emia
(200
-300
,000
p/µL
; Ht>
30%
) & sa
me
wom
en p
ost p
artu
m (3
mon
ths)
with
(n=2
) or
with
out (
n=24
)P. f
alci
paru
m
Arte
suna
te(2
00 m
g)p.
o. q
.d. o
nda
y 0
+ SP
(172
5 m
g)p.
o. q
.d. o
nda
y 1
26 p
regn
ant
wom
en26
pos
tpar
tum
wom
en25
non
-pr
egna
ntw
omen
Non
com
part
men
tal
anal
ysis
Tota
l dos
e,C
max
, Tm
ax,
CL/
F,V
/F,
t 1/2,
AU
C0-
∞.
Bas
ed o
n th
esa
me
clin
ical
stud
y as
Mor
ris(2
011)
.
Processed on: 19-1-2017Processed on: 19-1-2017Processed on: 19-1-2017Processed on: 19-1-2017
507377-L-bw-Visser507377-L-bw-Visser507377-L-bw-Visser507377-L-bw-Visser
5
Aut
hor
(yea
r)C
ount
ry(t
ime
peri
od)
Typ
e of
stud
yPo
pula
tion
Dru
g (d
ose)
Num
ber
ofw
omen
Phar
mac
okin
etic
anal
ytic
met
hodo
log
y
Phar
mac
okin
etic
vari
able
s
Rem
arks
para
sita
emia
& n
on-p
regn
ant
fem
ale
volu
ntee
rs w
ithas
ympt
omat
icP.
falc
ipar
umpa
rasi
taem
ia (2
00-3
00,0
00p/
µL).
Rijk
en(2
011-
1)Th
aila
nd(O
ct 2
007-
May
200
8)
Clin
ical
trial
Preg
nant
wom
en in
seco
ndan
d th
ird tr
imes
ters
of
preg
nanc
y w
ith a
cute
P.vi
vax
mon
oinf
ectio
n &
sam
ew
omen
pos
t par
tum
(84-
173
days
) with
(n=7
) or w
ithou
t(n
=12)
P. v
ivax
mal
aria
.
Am
odia
quin
e (1
0 m
g/kg
p.o.
q.d
. for
3 da
ys)
24 p
regn
ant
wom
en18
pos
tpar
tum
wom
en
Non
com
part
men
tal
anal
ysis
Tota
l dos
e,C
max
,C
max
/dos
e,T m
ax, C
L/F,
V/F
, t1/
2,A
UC
0-la
st,
AU
C0-
∞,
AU
C0-
∞/d
ose,
day
7 conc
entra
tion.
Bas
edon
the
sam
e cl
inic
alst
udy
asTa
rnin
g(2
012-
3)
Rijk
en(2
011-
2)Th
aila
nd(J
une
2008
-D
ec 2
008)
Clin
ical
trial
Preg
nant
wom
en in
seco
ndan
d th
ird tr
imes
ter o
fpr
egna
ncy
(Ht<
25%
) with
unco
mpl
icat
edP.
falc
ipar
um
DH
A-P
PQ(6
.4/5
1.2
mg/
kg p
.o.
q.d.
for 3
24 p
regn
ant
wom
en24
non
-pr
egna
nt
Non
com
part
men
tal
anal
ysis
Tota
l dos
e,C
max
,C
max
/dos
e,C
L/F,
V/F
,
Bas
ed o
n th
esa
me
clin
ical
stud
y as
Tarn
ing
2012
-
Aut
hor
(yea
r)C
ount
ry(t
ime
peri
od)
Typ
e of
stud
yPo
pula
tion
Dru
g (d
ose)
Num
ber
ofw
omen
Phar
mac
okin
etic
anal
ytic
met
hodo
log
y
Phar
mac
okin
etic
vari
able
s
Rem
arks
asym
ptom
atic
P. fa
lcip
arum
para
sita
emia
(200
-300
,000
p/µL
; Ht>
30%
) & sa
me
wom
en p
ost p
artu
m (3
mon
ths)
with
(n=2
) or
with
out (
n=24
)P. f
alci
paru
mpa
rasi
taem
ia &
non
-pre
gnan
tfe
mal
e vo
lunt
eers
with
asym
ptom
atic
P. fa
lcip
arum
para
sita
emia
(200
-300
,000
p/µL
).
(172
5 m
g)p.
o. q
.d. o
nda
y 1
25 n
on-
preg
nant
wom
en
(201
1).
Ony
ambo
ko(2
011)
DR
C(M
ay20
07-N
ov20
08)
Clin
ical
trial
Preg
nant
wom
en in
seco
nd(2
2-26
wks
) and
third
(32-
36w
ks) t
rimes
ter o
fpr
egna
ncy
with
asym
ptom
atic
P. fa
lcip
arum
para
sita
emia
(200
-300
,000
p/µL
; Ht>
30%
) & sa
me
wom
en p
ost p
artu
m (3
mon
ths)
with
(n=2
) or
with
out (
n=24
)P. f
alci
paru
m
Arte
suna
te(2
00 m
g)p.
o. q
.d. o
nda
y 0
+ SP
(172
5 m
g)p.
o. q
.d. o
nda
y 1
26 p
regn
ant
wom
en26
pos
tpar
tum
wom
en25
non
-pr
egna
ntw
omen
Non
com
part
men
tal
anal
ysis
Tota
l dos
e,C
max
, Tm
ax,
CL/
F,V
/F,
t 1/2,
AU
C0-
∞.
Bas
ed o
n th
esa
me
clin
ical
stud
y as
Mor
ris(2
011)
.
Processed on: 19-1-2017Processed on: 19-1-2017Processed on: 19-1-2017Processed on: 19-1-2017
507377-L-bw-Visser507377-L-bw-Visser507377-L-bw-Visser507377-L-bw-Visser
Aut
hor
(yea
r)C
ount
ry(t
ime
peri
od)
Typ
e of
stud
yPo
pula
tion
Dru
g (d
ose)
Num
ber
ofw
omen
Phar
mac
okin
etic
anal
ytic
met
hodo
log
y
Phar
mac
okin
etic
vari
able
s
Rem
arks
mon
ths)
with
outP
.fa
lcip
arum
para
sita
emia
and
with
Hb>
8g/d
L(M
ozam
biqu
e &
Sud
an) &
mat
ched
non
-pre
gnan
tw
omen
with
acu
teun
com
plic
ated
falc
ipar
umm
alar
ia (M
ozam
biqu
e).
Piol
a (2
010)
Uga
nda
(Oct
2006
-May
2009
)
Clin
ical
trial
Preg
nant
wom
en w
ithun
com
plic
ated
P. fa
lcip
arum
infe
ctio
n (<
250,
000
p/µL
)w
ith a
n EG
A>1
3wks
and
Hb
> 7g
/dL.
AL
(80/
480
mg
p.o.
b.i.d
. for
3da
ys) +
200
mL
milk
97 p
regn
ant
wom
enN
onco
mpa
rtm
enta
lan
alys
is
Day
7co
ncen
tratio
n.
Bas
ed o
n th
esa
me
clin
ical
stud
y as
Tarn
ing
(201
2-2)
and
Tarn
ing
(201
3).
Kar
unaj
eew
a (2
009)
Papu
a N
ewG
uine
e(F
eb20
06-J
uly
2006
)
Clin
ical
trial
Preg
nant
wom
en in
seco
ndor
third
trim
este
r of
preg
nanc
y w
ithou
t sev
ere
mal
aria
(n=1
7:P.
falc
ipar
um/ v
ivax
/ m
alar
iae
para
sita
emia
; n=1
3: n
o
SP (1
500/
75m
g p.
o.on
ce) +
Chl
oroq
uine
(135
0 m
gp.
o. q
.d. f
or
30 p
regn
ant
wom
en30
non
-pr
egna
ntw
omen
Com
partm
ent
al a
naly
sis
CL/
F, V
/F,
t 1/2,
AU
C0-
∞.
Aut
hor
(yea
r)C
ount
ry(t
ime
peri
od)
Typ
e of
stud
yPo
pula
tion
Dru
g (d
ose)
Num
ber
ofw
omen
Phar
mac
okin
etic
anal
ytic
met
hodo
log
y
Phar
mac
okin
etic
vari
able
s
Rem
arks
mal
aria
& m
atch
ed n
on-
preg
nant
wom
en w
ithP.
f alc
ipar
umm
alar
ia.
days
)w
omen
t 1/2,
AU
C0-
last
, AU
C0-
∞, A
UC
0-∞
/dos
e,A
UC
0-24
,A
UC
24-4
8,A
UC
48-7
2,A
UC
72-∞
,da
y 7,
14
and
28co
ncen
tratio
n.
1.
Nyu
nt(2
010)
Mal
i,M
ozam
biqu
e, S
udan
&Za
mbi
a(n
otre
port
ed)
Clin
ical
trial
Preg
nant
wom
en w
ith a
nEG
A 1
5-36
wks
with
outP
.fa
lcip
arum
para
sita
emia
(Hb>
8g/d
L) &
sam
e w
omen
post
par
tum
(6-4
3wks
)w
ithou
tP. f
alci
paru
mpa
rasi
taem
ia a
nd w
ithH
b>8g
/dL
(Mal
i & Z
ambi
a)/ p
ostp
artu
m w
omen
(> 6
SP (1
500/
75m
g p.
o.on
ce)
97 p
regn
ant
wom
en77
pos
tpar
tum
wom
en
Com
partm
ent
al a
naly
sis
Tota
l dos
e,C
max
, CL/
F,V
/F, t
1/2,
AU
C0-
∞,
day
7co
ncen
tratio
n.
Processed on: 19-1-2017Processed on: 19-1-2017Processed on: 19-1-2017Processed on: 19-1-2017
507377-L-bw-Visser507377-L-bw-Visser507377-L-bw-Visser507377-L-bw-Visser
5
Aut
hor
(yea
r)C
ount
ry(t
ime
peri
od)
Typ
e of
stud
yPo
pula
tion
Dru
g (d
ose)
Num
ber
ofw
omen
Phar
mac
okin
etic
anal
ytic
met
hodo
log
y
Phar
mac
okin
etic
vari
able
s
Rem
arks
mon
ths)
with
outP
.fa
lcip
arum
para
sita
emia
and
with
Hb>
8g/d
L(M
ozam
biqu
e &
Sud
an) &
mat
ched
non
-pre
gnan
tw
omen
with
acu
teun
com
plic
ated
falc
ipar
umm
alar
ia (M
ozam
biqu
e).
Piol
a (2
010)
Uga
nda
(Oct
2006
-May
2009
)
Clin
ical
trial
Preg
nant
wom
en w
ithun
com
plic
ated
P. fa
lcip
arum
infe
ctio
n (<
250,
000
p/µL
)w
ith a
n EG
A>1
3wks
and
Hb
> 7g
/dL.
AL
(80/
480
mg
p.o.
b.i.d
. for
3da
ys) +
200
mL
milk
97 p
regn
ant
wom
enN
onco
mpa
rtm
enta
lan
alys
is
Day
7co
ncen
tratio
n.
Bas
ed o
n th
esa
me
clin
ical
stud
y as
Tarn
ing
(201
2-2)
and
Tarn
ing
(201
3).
Kar
unaj
eew
a (2
009)
Papu
a N
ewG
uine
e(F
eb20
06-J
uly
2006
)
Clin
ical
trial
Preg
nant
wom
en in
seco
ndor
third
trim
este
r of
preg
nanc
y w
ithou
t sev
ere
mal
aria
(n=1
7:P.
falc
ipar
um/ v
ivax
/ m
alar
iae
para
sita
emia
; n=1
3: n
o
SP (1
500/
75m
g p.
o.on
ce) +
Chl
oroq
uine
(135
0 m
gp.
o. q
.d. f
or
30 p
regn
ant
wom
en30
non
-pr
egna
ntw
omen
Com
partm
ent
al a
naly
sis
CL/
F, V
/F,
t 1/2,
AU
C0-
∞.
Aut
hor
(yea
r)C
ount
ry(t
ime
peri
od)
Typ
e of
stud
yPo
pula
tion
Dru
g (d
ose)
Num
ber
ofw
omen
Phar
mac
okin
etic
anal
ytic
met
hodo
log
y
Phar
mac
okin
etic
vari
able
s
Rem
arks
mal
aria
& m
atch
ed n
on-
preg
nant
wom
en w
ithP.
falc
ipar
umm
alar
ia.
days
)w
omen
t 1/2,
AU
C0-
last
, AU
C0-
∞, A
UC
0-∞
/dos
e,A
UC
0-24
,A
UC
24-4
8,A
UC
48-7
2,A
UC
72-∞
,da
y 7,
14
and
28co
ncen
tratio
n.
1.
Nyu
nt(2
010)
Mal
i,M
ozam
biqu
e, S
udan
&Za
mbi
a(n
otre
port
ed)
Clin
ical
trial
Preg
nant
wom
en w
ith a
nEG
A 1
5-36
wks
with
outP
.fa
lcip
arum
para
sita
emia
(Hb>
8g/d
L) &
sam
e w
omen
post
par
tum
(6-4
3wks
)w
ithou
tP. f
alci
paru
mpa
rasi
taem
ia a
nd w
ithH
b>8g
/dL
(Mal
i & Z
ambi
a)/ p
ostp
artu
m w
omen
(> 6
SP (1
500/
75m
g p.
o.on
ce)
97 p
regn
ant
wom
en77
pos
tpar
tum
wom
en
Com
partm
ent
al a
naly
sis
Tota
l dos
e,C
max
, CL/
F,V
/F, t
1/2,
AU
C0-
∞,
day
7co
ncen
tratio
n.
Processed on: 19-1-2017Processed on: 19-1-2017Processed on: 19-1-2017Processed on: 19-1-2017
507377-L-bw-Visser507377-L-bw-Visser507377-L-bw-Visser507377-L-bw-Visser
Aut
hor
(yea
r)C
ount
ry(t
ime
peri
od)
Typ
e of
stud
yPo
pula
tion
Dru
g (d
ose)
Num
ber
ofw
omen
Phar
mac
okin
etic
anal
ytic
met
hodo
log
y
Phar
mac
okin
etic
vari
able
s
Rem
arks
para
sita
emia
) & m
atch
edno
n-pr
egna
nt w
omen
(n=9
:fa
lcip
arum
/ vi
vax
/ mal
aria
epa
rasi
taem
ia; n
=21:
no
para
sita
emia
).
3 da
ys)
Tarn
ing
(200
9)Th
aila
nd(n
otre
port
ed)
Clin
ical
trial
Preg
nant
wom
en in
seco
ndor
third
trim
este
r of
preg
nanc
y w
ithun
com
plic
ated
sym
ptom
atic
P. fa
lcip
arum
mal
aria
.
AL
(80/
480
mg
p.o.
b.i.d
. for
3da
ys) +
200
-25
0 m
lch
ocol
ate
milk
(6-7
gfa
t)
103
preg
nant
wom
enC
ompa
rtme
ntal
ana
lysi
sTo
tal d
ose,
CL/
F, V
/F,
day
7co
ncen
tratio
n.
Nes
ted
inla
rger
effic
acy
/sa
fety
stud
yby
McG
read
y(2
008)
.
McG
read
y(2
008)
Thai
land
(Apr
il 20
04-
Aug
2006
)
Clin
ical
trial
Preg
nant
wom
en in
seco
ndor
third
trim
este
r of
preg
nanc
y w
ith a
cute
unco
mpl
icat
edP.
falc
ipar
umm
alar
ia.
AL
(80/
480
mg
p.o.
b.i.d
. for
3da
ys) +
250
ml c
hoco
late
milk
(7g
fat)
85 p
regn
ant
wom
enN
onco
mpa
rtm
enta
lan
alys
is
Day
7co
ncen
tratio
n.
Bas
ed o
n th
esa
me
clin
ical
stud
y as
McG
read
y(2
006-
2) a
ndTa
rnin
g(2
009)
.
Aut
hor
(yea
r)C
ount
ry(t
ime
peri
od)
Typ
e of
stud
yPo
pula
tion
Dru
g (d
ose)
Num
ber
ofw
omen
Phar
mac
okin
etic
anal
ytic
met
hodo
log
y
Phar
mac
okin
etic
vari
able
s
Rem
arks
Gre
en(2
007)
Ken
ya(1
999-
2000
)C
linic
altri
alPr
imi-
and
secu
ndig
ravi
dw
omen
with
unc
ompl
icat
edsi
ngle
ton
preg
nanc
ies w
ithEG
A 1
6-28
wks
and
Hb>
8g/d
Lw
ithou
tsy
mpt
omat
ic m
alar
ia (n
=11:
para
sita
emic
; n=2
2:ap
aras
itaem
ic) &
sam
ew
omen
pos
t par
tum
(2-3
mon
ths)
with
out
sym
ptom
atic
mal
aria
(n=1
:pa
rasi
taem
ic; n
=10:
apar
asita
emic
).
SP (1
500/
75m
g p.
o.on
ce)
33 p
regn
ant
wom
en16
HIV
-po
sitiv
e17
HIV
-ne
gativ
e11
pos
tpar
tum
wom
en6
HIV
-po
sitiv
e5
HIV
-ne
gativ
e
Com
partm
ent
al a
naly
sis
CL/
F, V
/F,
t 1/2,
AU
C0-
∞.
McG
read
y(2
006-
1)Th
aila
nd(O
ct 2
000-
July
200
1)
Clin
ical
trial
Preg
nant
wom
en in
seco
ndor
third
trim
este
r of
preg
nanc
y w
ith re
crud
esce
ntun
com
plic
ated
P. fa
lcip
arum
mal
aria
afte
r 7-d
ay q
uini
netre
atm
ent a
nd H
t>25
%.
Arte
suna
te-
AP
(4/2
0/8
mg/
kg p
.o.
q.d.
for 3
days
) + 2
00m
Lch
ocol
ate
milk
(8%
24N
onco
mpa
rtm
enta
l &co
mpa
rtmen
tal a
naly
sis
Tota
l dos
e,C
max
, Tm
ax,
CL/
F, V
/F,
t 1/2,
AU
C48
-72
.
Processed on: 19-1-2017Processed on: 19-1-2017Processed on: 19-1-2017Processed on: 19-1-2017
507377-L-bw-Visser507377-L-bw-Visser507377-L-bw-Visser507377-L-bw-Visser
5
Aut
hor
(yea
r)C
ount
ry(t
ime
peri
od)
Typ
e of
stud
yPo
pula
tion
Dru
g (d
ose)
Num
ber
ofw
omen
Phar
mac
okin
etic
anal
ytic
met
hodo
log
y
Phar
mac
okin
etic
vari
able
s
Rem
arks
para
sita
emia
) & m
atch
edno
n-pr
egna
nt w
omen
(n=9
:fa
lcip
arum
/ vi
vax
/ mal
aria
epa
rasi
taem
ia; n
=21:
no
para
sita
emia
).
3 da
ys)
Tarn
ing
(200
9)Th
aila
nd(n
otre
port
ed)
Clin
ical
trial
Preg
nant
wom
en in
seco
ndor
third
trim
este
r of
preg
nanc
y w
ithun
com
plic
ated
sym
ptom
atic
P. fa
lcip
arum
mal
aria
.
AL
(80/
480
mg
p.o.
b.i.d
. for
3da
ys) +
200
-25
0 m
lch
ocol
ate
milk
(6-7
gfa
t)
103
preg
nant
wom
enC
ompa
rtme
ntal
ana
lysi
sTo
tal d
ose,
CL/
F, V
/F,
day
7co
ncen
tratio
n.
Nes
ted
inla
rger
effic
acy
/sa
fety
stud
yby
McG
read
y(2
008)
.
McG
read
y(2
008)
Thai
land
(Apr
il 20
04-
Aug
2006
)
Clin
ical
trial
Preg
nant
wom
en in
seco
ndor
third
trim
este
r of
preg
nanc
y w
ith a
cute
unco
mpl
icat
edP.
falc
ipar
umm
alar
ia.
AL
(80/
480
mg
p.o.
b.i.d
. for
3da
ys) +
250
ml c
hoco
late
milk
(7g
fat)
85 p
regn
ant
wom
enN
onco
mpa
rtm
enta
lan
alys
is
Day
7co
ncen
tratio
n.
Bas
ed o
n th
esa
me
clin
ical
stud
y as
McG
read
y(2
006-
2) a
ndTa
rnin
g(2
009)
.
Aut
hor
(yea
r)C
ount
ry(t
ime
peri
od)
Typ
e of
stud
yPo
pula
tion
Dru
g (d
ose)
Num
ber
ofw
omen
Phar
mac
okin
etic
anal
ytic
met
hodo
log
y
Phar
mac
okin
etic
vari
able
s
Rem
arks
Gre
en(2
007)
Ken
ya(1
999-
2000
)C
linic
altri
alPr
imi-
and
secu
ndig
ravi
dw
omen
with
unc
ompl
icat
edsi
ngle
ton
preg
nanc
ies w
ithEG
A 1
6-28
wks
and
Hb>
8g/d
Lw
ithou
tsy
mpt
omat
ic m
alar
ia (n
=11:
para
sita
emic
; n=2
2:ap
aras
itaem
ic) &
sam
ew
omen
pos
t par
tum
(2-3
mon
ths)
with
out
sym
ptom
atic
mal
aria
(n=1
:pa
rasi
taem
ic; n
=10:
apar
asita
emic
).
SP (1
500/
75m
g p.
o.on
ce)
33 p
regn
ant
wom
en16
HIV
-po
sitiv
e17
HIV
-ne
gativ
e11
pos
tpar
tum
wom
en6
HIV
-po
sitiv
e5
HIV
-ne
gativ
e
Com
partm
ent
al a
naly
sis
CL/
F, V
/F,
t 1/2,
AU
C0-
∞.
McG
read
y(2
006-
1)Th
aila
nd(O
ct 2
000-
July
200
1)
Clin
ical
trial
Preg
nant
wom
en in
seco
ndor
third
trim
este
r of
preg
nanc
y w
ith re
crud
esce
ntun
com
plic
ated
P. fa
lcip
arum
mal
aria
afte
r 7-d
ay q
uini
netre
atm
ent a
nd H
t>25
%.
Arte
suna
te-
AP
(4/2
0/8
mg/
kg p
.o.
q.d.
for 3
days
) + 2
00m
Lch
ocol
ate
milk
(8%
24N
onco
mpa
rtm
enta
l &co
mpa
rtmen
tal a
naly
sis
Tota
l dos
e,C
max
, Tm
ax,
CL/
F, V
/F,
t 1/2,
AU
C48
-72
.
Processed on: 19-1-2017Processed on: 19-1-2017Processed on: 19-1-2017Processed on: 19-1-2017
507377-L-bw-Visser507377-L-bw-Visser507377-L-bw-Visser507377-L-bw-Visser
Aut
hor
(yea
r)C
ount
ry(t
ime
peri
od)
Typ
e of
stud
yPo
pula
tion
Dru
g (d
ose)
Num
ber
ofw
omen
Phar
mac
okin
etic
anal
ytic
met
hodo
log
y
Phar
mac
okin
etic
vari
able
s
Rem
arks
fat)
McG
read
y(2
006-
2)Th
aila
nd(A
pril
2004
-Au
g 20
04)
Clin
ical
trial
Preg
nant
wom
en in
the
seco
nd a
nd th
ird tr
imes
ter o
fpr
egna
ncy
with
recr
udes
cent
unco
mpl
icat
ed m
ulti-
drug
resi
stan
tP. f
alci
paru
mm
alar
ia a
fter 7
-day
qui
nine
treat
men
t.
AL
(80/
480
mg
p.o.
b.i.d
. for
3da
ys) +
250
ml c
hoco
late
milk
(7g
fat)
13 p
regn
ant
wom
enN
onco
mpa
rtm
enta
l &co
mpa
rtmen
tal a
naly
sis
Tota
l dos
e,C
max
, Tm
ax,
CL/
F, V
/F,
t 1/2,
AU
C0-
24, A
UC
60-8
4,A
UC
/dos
e.
Na
Ban
gcha
ng(2
005)
Thai
land
(Nov
200
0-A
pril
2001
)
Clin
ical
trial
Preg
nant
wom
en in
third
trim
este
r of p
regn
ancy
with
acut
e sy
mpt
omat
icP.
falc
ipar
umm
onoi
nfec
tion
and
Hb>
8g/d
L.
AP
(100
0/40
0m
g p.
o. q
.d.
for 3
day
s)
26 p
regn
ant
wom
enC
ompa
rtme
ntal
ana
lysi
sC
max
, Tm
ax,
AU
C0-
∞,
PG-C
Gra
tio.
McG
read
y(2
003-
1)Th
aila
nd(n
otre
port
ed)
Clin
ical
trial
Preg
nant
wom
en in
seco
ndor
third
trim
este
r of
preg
nanc
y w
ith re
crud
esce
ntm
ulti-
drug
resi
stan
tun
com
plic
ated
P. fa
lcip
arum
mal
aria
afte
r 7-d
ay q
uini
netre
atm
ent a
nd H
t>25
%.
Arte
suna
te-
AP
(4/2
0/8
mg/
kg p
.o.
q.d.
for 3
days
) + 3
00m
Lch
ocol
ate
24 p
regn
ant
wom
enN
onco
mpa
rtm
enta
l &co
mpa
rtmen
tal a
naly
sis
Cm
ax, T
max
,C
L/F,
V/F
,A
UC
0-∞
,A
UC
48-∞
.
Aut
hor
(yea
r)C
ount
ry(t
ime
peri
od)
Typ
e of
stud
yPo
pula
tion
Dru
g (d
ose)
Num
ber
ofw
omen
Phar
mac
okin
etic
anal
ytic
met
hodo
log
y
Phar
mac
okin
etic
vari
able
s
Rem
arks
milk
(8%
fat)
McG
read
y(2
003-
2)Th
aila
nd(n
otre
port
ed)
Clin
ical
trial
Hea
lthy
preg
nant
wom
enw
ith a
n EG
A>3
5wks
& sa
me
wom
en p
ost p
artu
m (>
2m
onth
s).
Prog
uani
l(2
00 m
g p.
o.on
ce)
45 p
regn
ant
wom
en45
pos
tpar
tum
wom
en
Non
com
part
men
tal
anal
ysis
Tota
l dos
e,C
max
(pla
sma
and
urin
e),
6h conc
entra
tion
(pla
sma
and
urin
e).
Na
Ban
gcha
ng(1
994)
Thai
land
(Sep
t 198
6-Ju
ne 1
988)
Clin
ical
trial
Preg
nant
wom
en in
firs
t(n
=2) a
nd th
ird (n
=7)
trim
este
r of p
regn
ancy
with
P. fa
lcip
arum
para
sita
emia
& n
on-p
regn
ant w
omen
mat
ched
for a
ge w
ithP.
falc
ipar
umpa
rasi
taem
ia.
Mef
loqu
ine
(15
mg/
kg)
9 pr
egna
ntw
omen
8 no
n-pr
egna
ntw
omen
Com
partm
ent
al a
naly
sis
Tota
l dos
e,C
max
, Tm
ax,
CL/
F, V
/F,
t 1/2.
Wan
gboo
nsku
l (19
93)
Thai
land
(not
repo
rted
)
Clin
ical
trial
Preg
nant
wom
en in
third
trim
este
r of p
regn
ancy
with
outP
. fal
cipa
rum
mal
aria
& sa
me
wom
en p
ost
partu
m (>
2 m
onth
s) w
ithou
t
Prog
uani
l(2
00 m
g p.
o.on
ce)
10 p
regn
ant
wom
en4
post
partu
mw
omen
9 m
ale
Com
partm
ent
al a
naly
sis
Cm
ax, T
max
,C
L/F,
t 1/2,
AU
C.
Processed on: 19-1-2017Processed on: 19-1-2017Processed on: 19-1-2017Processed on: 19-1-2017
507377-L-bw-Visser507377-L-bw-Visser507377-L-bw-Visser507377-L-bw-Visser
5
Aut
hor
(yea
r)C
ount
ry(t
ime
peri
od)
Typ
e of
stud
yPo
pula
tion
Dru
g (d
ose)
Num
ber
ofw
omen
Phar
mac
okin
etic
anal
ytic
met
hodo
log
y
Phar
mac
okin
etic
vari
able
s
Rem
arks
fat)
McG
read
y(2
006-
2)Th
aila
nd(A
pril
2004
-Au
g 20
04)
Clin
ical
trial
Preg
nant
wom
en in
the
seco
nd a
nd th
ird tr
imes
ter o
fpr
egna
ncy
with
recr
udes
cent
unco
mpl
icat
ed m
ulti-
drug
resi
stan
tP. f
alci
paru
mm
alar
ia a
fter 7
-day
qui
nine
treat
men
t.
AL
(80/
480
mg
p.o.
b.i.d
. for
3da
ys) +
250
ml c
hoco
late
milk
(7g
fat)
13 p
regn
ant
wom
enN
onco
mpa
rtm
enta
l &co
mpa
rtmen
tal a
naly
sis
Tota
l dos
e,C
max
, Tm
ax,
CL/
F, V
/F,
t 1/2,
AU
C0-
24, A
UC
60-8
4,A
UC
/dos
e.
Na
Ban
gcha
ng(2
005)
Thai
land
(Nov
200
0-A
pril
2001
)
Clin
ical
trial
Preg
nant
wom
en in
third
trim
este
r of p
regn
ancy
with
acut
e sy
mpt
omat
icP.
falc
ipar
umm
onoi
nfec
tion
and
Hb>
8g/d
L.
AP
(100
0/40
0m
g p.
o. q
.d.
for 3
day
s)
26 p
regn
ant
wom
enC
ompa
rtme
ntal
ana
lysi
sC
max
, Tm
ax,
AU
C0-
∞,
PG-C
Gra
tio.
McG
read
y(2
003-
1)Th
aila
nd(n
otre
port
ed)
Clin
ical
trial
Preg
nant
wom
en in
seco
ndor
third
trim
este
r of
preg
nanc
y w
ith re
crud
esce
ntm
ulti-
drug
resi
stan
tun
com
plic
ated
P. fa
lcip
arum
mal
aria
afte
r 7-d
ay q
uini
netre
atm
ent a
nd H
t>25
%.
Arte
suna
te-
AP
(4/2
0/8
mg/
kg p
.o.
q.d.
for 3
days
) + 3
00m
Lch
ocol
ate
24 p
regn
ant
wom
enN
onco
mpa
rtm
enta
l &co
mpa
rtmen
tal a
naly
sis
Cm
ax, T
max
,C
L/F,
V/F
,A
UC
0-∞
,A
UC
48-∞
.
Aut
hor
(yea
r)C
ount
ry(t
ime
peri
od)
Typ
e of
stud
yPo
pula
tion
Dru
g (d
ose)
Num
ber
ofw
omen
Phar
mac
okin
etic
anal
ytic
met
hodo
log
y
Phar
mac
okin
etic
vari
able
s
Rem
arks
milk
(8%
fat)
McG
read
y(2
003-
2)Th
aila
nd(n
otre
port
ed)
Clin
ical
trial
Hea
lthy
preg
nant
wom
enw
ith a
n EG
A>3
5wks
& sa
me
wom
en p
ost p
artu
m (>
2m
onth
s).
Prog
uani
l(2
00 m
g p.
o.on
ce)
45 p
regn
ant
wom
en45
pos
tpar
tum
wom
en
Non
com
part
men
tal
anal
ysis
Tota
l dos
e,C
max
(pla
sma
and
urin
e),
6h conc
entra
tion
(pla
sma
and
urin
e).
Na
Ban
gcha
ng(1
994)
Thai
land
(Sep
t 198
6-Ju
ne 1
988)
Clin
ical
trial
Preg
nant
wom
en in
firs
t(n
=2) a
nd th
ird (n
=7)
trim
este
r of p
regn
ancy
with
P. fa
lcip
arum
para
sita
emia
& n
on-p
regn
ant w
omen
mat
ched
for a
ge w
ithP.
falc
ipar
umpa
rasi
taem
ia.
Mef
loqu
ine
(15
mg/
kg)
9 pr
egna
ntw
omen
8 no
n-pr
egna
ntw
omen
Com
partm
ent
al a
naly
sis
Tota
l dos
e,C
max
, Tm
ax,
CL/
F, V
/F,
t 1/2.
Wan
gboo
nsku
l (19
93)
Thai
land
(not
repo
rted
)
Clin
ical
trial
Preg
nant
wom
en in
third
trim
este
r of p
regn
ancy
with
outP
. fal
cipa
rum
mal
aria
& sa
me
wom
en p
ost
partu
m (>
2 m
onth
s) w
ithou
t
Prog
uani
l(2
00 m
g p.
o.on
ce)
10 p
regn
ant
wom
en4
post
partu
mw
omen
9 m
ale
Com
partm
ent
al a
naly
sis
Cm
ax, T
max
,C
L/F,
t 1/2,
AU
C.
Processed on: 19-1-2017Processed on: 19-1-2017Processed on: 19-1-2017Processed on: 19-1-2017
507377-L-bw-Visser507377-L-bw-Visser507377-L-bw-Visser507377-L-bw-Visser
Aut
hor
(yea
r)C
ount
ry(t
ime
peri
od)
Typ
e of
stud
yPo
pula
tion
Dru
g (d
ose)
Num
ber
ofw
omen
Phar
mac
okin
etic
anal
ytic
met
hodo
log
y
Phar
mac
okin
etic
vari
able
s
Rem
arks
P. fa
lcip
arum
mal
aria
&he
alth
y ad
ult m
ale
volu
ntee
rsw
ithou
tP. f
alci
paru
mm
alar
ia*.
patie
nts*
Nos
ten
(199
0)Th
aila
nd(n
otre
port
ed)
Clin
ical
trial
Preg
nant
wom
en in
third
trim
este
r of p
regn
ancy
.G
roup
1:
Mef
loqu
ine
(250
mg
per
wee
k)
Gro
up 2
:M
eflo
quin
e(1
25 m
g pe
rw
eek)
20 p
regn
ant
wom
enC
ompa
rtme
ntal
ana
lysi
sC
max
, Tm
ax,
CL/
F, t 1
/2,
AU
C.
q.d.
= o
nce
a da
y; b
.i.d.
= tw
ice
ada
y; t.
i.d. =
thre
e tim
es a
day
; p.o
. = p
er o
s (or
al);
i.v. (
intra
veno
us);
AL
= ar
tem
ethe
r-lu
mef
antri
ne; D
HA
-PPQ
=di
hydr
oarte
mis
inin
-pip
eraq
uine
; SP
= Su
lfado
xine
-Pyr
imet
ham
ine;
AP
= at
ovaq
uone
-pro
guan
il; P
G =
pro
guan
il; C
G =
cyc
logu
anil;
Cm
ax=
max
imum
c onc
entra
tion
afte
r adm
inis
tratio
n; T
max
= tim
e to
max
imum
con
cent
ratio
n af
ter a
dmin
istra
tion;
CL/
F =
oral
cle
aran
ce; V
/F =
app
aren
t vol
ume
ofdi
strib
utio
n; t 1
/2=
half-
life;
AU
C =
are
a un
der t
he c
urve
(exp
osur
e); H
b =
haem
oglo
bin;
Ht =
hae
mat
ocrit
; wks
= w
eeks
;*
Dat
a fo
r mal
e su
bjec
ts w
ere
incl
uded
from
a pr
evio
us st
udy
for c
ompa
rison
.
Tab
le 2
.Prim
ary
stud
y ou
tcom
es p
er c
ompo
und
Art
emet
her
Aut
hor
(yea
r)C
ount
ry (t
ime
peri
od)
Popu
latio
nD
rug
(dos
e)N
umbe
r of
wom
enR
esul
t
Tarn
ing
(201
3)U
gand
a(O
ct20
06–
May
2009
)
Preg
nant
wom
en w
ithun
com
plic
ated
P. fa
lcip
arum
infe
ctio
n w
ith a
n EG
A>1
3wks
& n
on-p
regn
ant w
omen
mat
ched
for h
isto
ry o
f fev
er,
tem
p. >
37.
5°C
, sm
okin
g st
atus
and
leve
l of p
aras
itaem
ia.
AL
(80/
480
mg
p.o.
b.i.d
. for
3da
ys) +
200
mL
milk
tea
21 p
regn
ant
wom
enEs
timat
ed e
xpos
ure
to a
rtem
ethe
r and
DH
A w
as si
mila
r to
that
pre
viou
sly
repo
rted
in p
regn
ant T
hai p
atie
nts a
ndlo
wer
than
repo
rted
in a
dult
non-
preg
nant
Tha
i pat
ient
s.
Tarn
ing
(201
2-2)
Uga
nda
(Mar
ch20
08–
Sept
2008
)
Preg
nant
wom
en in
seco
nd a
ndth
ird tr
imes
ter o
f pre
gnan
cy(E
GA
>13w
ks) w
ithun
com
plic
ated
P. fa
lcip
arum
mal
aria
.
AL
(80/
480
mg
p.o.
b.i.d
. for
3da
ys) +
200
mL
milk
tea
21 p
regn
ant
wom
enN
o st
atis
tical
ly si
gnifi
cant
diff
eren
ces i
n ph
arm
acok
inet
icpr
oper
ties b
etw
een
seco
nd a
nd th
ird tr
imes
ter.
McG
read
y(2
006-
2)Th
aila
nd
(Apr
il20
04-
Preg
nant
wom
en in
the
seco
ndan
d th
ird tr
imes
ter o
f pre
gnan
cyw
ith re
crud
esce
nt
AL
(80/
480
mg
p.o.
13 p
regn
ant
wom
enN
o si
gnifi
cant
diff
eren
ces i
n th
e ph
arm
acok
inet
icpa
ram
eter
s of a
rtem
ethe
r and
DH
A b
etw
een
the
seco
ndan
d th
ird tr
imes
ter.
Com
paris
on w
ith d
ata
from
lite
ratu
re
Processed on: 19-1-2017Processed on: 19-1-2017Processed on: 19-1-2017Processed on: 19-1-2017
507377-L-bw-Visser507377-L-bw-Visser507377-L-bw-Visser507377-L-bw-Visser
5
Aut
hor
(yea
r)C
ount
ry(t
ime
peri
od)
Typ
e of
stud
yPo
pula
tion
Dru
g (d
ose)
Num
ber
ofw
omen
Phar
mac
okin
etic
anal
ytic
met
hodo
log
y
Phar
mac
okin
etic
vari
able
s
Rem
arks
P. fa
lcip
arum
mal
aria
&he
alth
y ad
ult m
ale
volu
ntee
rsw
ithou
tP. f
alci
paru
mm
alar
ia*.
patie
nts*
Nos
ten
(199
0)Th
aila
nd(n
otre
port
ed)
Clin
ical
trial
Preg
nant
wom
en in
third
trim
este
r of p
regn
ancy
.G
roup
1:
Mef
loqu
ine
(250
mg
per
wee
k)
Gro
up 2
:M
eflo
quin
e(1
25 m
g pe
rw
eek)
20 p
regn
ant
wom
enC
ompa
rtme
ntal
ana
lysi
sC
max
, Tm
ax,
CL/
F, t 1
/2,
AU
C.
q.d.
= o
nce
a da
y; b
.i.d.
= tw
ice
ada
y; t.
i.d. =
thre
e tim
es a
day
; p.o
. = p
er o
s (or
al);
i.v. (
intra
veno
us);
AL
= ar
tem
ethe
r-lu
mef
antri
ne; D
HA
-PPQ
=di
hydr
oarte
mis
inin
-pip
eraq
uine
; SP
= Su
lfado
xine
-Pyr
imet
ham
ine;
AP
= at
ovaq
uone
-pro
guan
il; P
G =
pro
guan
il; C
G =
cyc
logu
anil;
Cm
ax=
max
imum
conc
entra
tion
afte
r adm
inis
tratio
n; T
max
= tim
e to
max
imum
con
cent
ratio
n af
ter a
dmin
istra
tion;
CL/
F =
oral
cle
aran
ce; V
/F =
app
aren
t vol
ume
ofdi
strib
utio
n; t 1
/2=
half-
life;
AU
C =
are
a un
der t
he c
urve
(exp
osur
e); H
b =
haem
oglo
bin;
Ht =
hae
mat
ocrit
; wks
= w
eeks
;*
Dat
a fo
r mal
e su
bjec
ts w
ere
incl
uded
from
a pr
evio
us st
udy
for c
ompa
rison
.
Tab
le 2
.Prim
ary
stud
y ou
tcom
es p
er c
ompo
und
Art
emet
her
Aut
hor
(yea
r)C
ount
ry (t
ime
peri
od)
Popu
latio
nD
rug
(dos
e)N
umbe
r of
wom
enR
esul
t
Tarn
ing
(201
3)U
gand
a(O
ct20
06–
May
2009
)
Preg
nant
wom
en w
ithun
com
plic
ated
P. fa
lcip
arum
infe
ctio
n w
ith a
n EG
A>1
3wks
& n
on-p
regn
ant w
omen
mat
ched
for h
isto
ry o
f fev
er,
tem
p. >
37.
5°C
, sm
okin
g st
atus
and
leve
l of p
aras
itaem
ia.
AL
(80/
480
mg
p.o.
b.i.d
. for
3da
ys) +
200
mL
milk
tea
21 p
regn
ant
wom
enEs
timat
ed e
xpos
ure
to a
rtem
ethe
r and
DH
A w
as si
mila
r to
that
pre
viou
sly
repo
rted
in p
regn
ant T
hai p
atie
nts a
ndlo
wer
than
repo
rted
in a
dult
non-
preg
nant
Tha
i pat
ient
s.
Tarn
ing
(201
2-2)
Uga
nda
(Mar
ch20
08–
Sept
2008
)
Preg
nant
wom
en in
seco
nd a
ndth
ird tr
imes
ter o
f pre
gnan
cy(E
GA
>13w
ks) w
ithun
com
plic
ated
P. fa
lcip
arum
mal
aria
.
AL
(80/
480
mg
p.o.
b.i.d
. for
3da
ys) +
200
mL
milk
tea
21 p
regn
ant
wom
enN
o st
atis
tical
ly si
gnifi
cant
diff
eren
ces i
n ph
arm
acok
inet
icpr
oper
ties b
etw
een
seco
nd a
nd th
ird tr
imes
ter.
McG
read
y(2
006-
2)Th
aila
nd
(Apr
il20
04-
Preg
nant
wom
en in
the
seco
ndan
d th
ird tr
imes
ter o
f pre
gnan
cyw
ith re
crud
esce
nt
AL
(80/
480
mg
p.o.
13 p
regn
ant
wom
enN
o si
gnifi
cant
diff
eren
ces i
n th
e ph
arm
acok
inet
icpa
ram
eter
s of a
rtem
ethe
r and
DH
A b
etw
een
the
seco
ndan
d th
ird tr
imes
ter.
Com
paris
on w
ith d
ata
from
lite
ratu
re
Processed on: 19-1-2017Processed on: 19-1-2017Processed on: 19-1-2017Processed on: 19-1-2017
507377-L-bw-Visser507377-L-bw-Visser507377-L-bw-Visser507377-L-bw-Visser
Aug
2004
)un
com
plic
ated
mul
ti-dr
ugre
sist
antP
. fal
cipa
rum
mal
aria
afte
r 7-d
ay q
uini
ne tr
eatm
ent.
b.i.d
. for
3da
ys) +
250
ml
choc
olat
em
ilk (7
gfa
t)
show
ed a
low
er A
UC
and
Cm
ax o
f arte
met
her c
ompa
red
to m
ale
Thai
pat
ient
s and
of D
HA
com
pare
d to
non
-pr
egna
nt p
atie
nts.
Art
esun
ate
Aut
hor
(yea
r)C
ount
ry(t
ime
peri
od)
Typ
e of
stud
yPo
pula
tion
Dru
g (d
ose)
Num
ber
ofw
omen
Phar
mac
okin
etic
anal
ytic
met
hodo
log
y
Phar
mac
okin
etic
vari
able
s
Rem
arks
Klo
prog
ge(2
015)
Thai
land
(Apr
il 20
08–
Mar
ch20
09)
Clin
ical
trial
Preg
nant
wom
en in
seco
ndan
d th
ird tr
imes
ter o
fpr
egna
ncy
(Ht>
25%
) with
unco
mpl
icat
edP.
falc
ipar
umm
alar
ia &
the
sam
e w
omen
post
par
tum
(3 m
onth
s)w
ithou
t mal
aria
.
Gro
up 1
Arte
suna
te(4
mg/
kg)
i.v. q
.d. o
nda
y 0;
arte
suna
te(4
mg/
kg)
p.o
q.d.
on
day
1-6
Gro
up 2
20 p
regn
ant
wom
enG
roup
1: 1
0w
omen
Gro
up 2
: 10
wom
en14
pos
tpar
tum
wom
en
Com
partm
ent
al a
naly
sis
AU
C0-
12,
Cm
ax, T
max
,t 1/
2, C
L/F,
Vd/
F.
Bas
ed o
n th
esa
me
clin
ical
stud
y as
McG
read
y(2
012)
.
Arte
suna
te(4
mg/
kg)
p.o.
q.d
. on
day
0;ar
tesu
nate
(4m
g/kg
) i.v
.q.
d. o
n da
y1,
arte
suna
te(4
mg/
kg)
p.o.
q.d
. on
day
2-6)
Val
ea(2
014)
Bur
kina
Faso
(Sep
t20
08-J
an20
09)
Clin
ical
trial
Preg
nant
wom
en in
seco
ndan
d th
ird tr
imes
ter o
fpr
egna
ncy
with
unco
mpl
icat
edP.
falc
ipar
umm
onoi
nfec
tion
& m
atch
edno
n-pr
egna
nt w
omen
with
P.fa
lcip
arum
infe
ctio
n.
Mef
loqu
ine
+ A
rtesu
nate
(8/3
.6m
g/kg
q.d
.fo
r 3 d
ays)
24 p
regn
ant
wom
en23
non
-pr
egna
ntw
omen
Non
com
part
men
tal
anal
ysis
Tota
l dos
e,C
max
,C
max
/dos
e,T m
ax, C
L/F,
V/F
, t1/
2,A
UC
0-la
st,
AU
C0-
∞,
AU
C-
∞/d
ose.
McG
read
y(2
012)
Thai
land
(Apr
il 20
08–
Mar
ch20
09)
Clin
ical
trial
Preg
nant
wom
en in
seco
ndan
d th
ird tr
imes
ter o
fpr
egna
ncy
(Ht>
25%
) with
unco
mpl
icat
edP.
falc
ipar
umm
alar
ia &
the
sam
e w
omen
post
par
tum
(3 m
onth
s)
Gro
up 1
Arte
suna
te(4
mg/
kg)
i.v. q
.d. o
nda
y 0;
arte
suna
te
20 p
regn
ant
wom
enG
roup
1: 1
0w
omen
Gro
up 2
: 10
wom
en
Non
com
part
men
tal
anal
ysis
Tota
l dos
e,C
max
,C
max
/dos
e,T m
ax, C
L/F,
V/F
, t1/
2,A
UC
0-∞
,
Bas
ed o
n th
esa
me
clin
ical
stud
y as
Klo
prog
ge(2
015)
.
Processed on: 19-1-2017Processed on: 19-1-2017Processed on: 19-1-2017Processed on: 19-1-2017
507377-L-bw-Visser507377-L-bw-Visser507377-L-bw-Visser507377-L-bw-Visser
5
Aug
2004
)un
com
plic
ated
mul
ti-dr
ugre
sist
antP
. fal
cipa
rum
mal
aria
afte
r 7-d
ay q
uini
ne tr
eatm
ent.
b.i.d
. for
3da
ys) +
250
ml
choc
olat
em
ilk (7
gfa
t)
show
ed a
low
er A
UC
and
Cm
ax o
f arte
met
her c
ompa
red
to m
ale
Thai
pat
ient
s and
of D
HA
com
pare
d to
non
-pr
egna
nt p
atie
nts.
Art
esun
ate
Aut
hor
(yea
r)C
ount
ry(t
ime
peri
od)
Typ
e of
stud
yPo
pula
tion
Dru
g (d
ose)
Num
ber
ofw
omen
Phar
mac
okin
etic
anal
ytic
met
hodo
log
y
Phar
mac
okin
etic
vari
able
s
Rem
arks
Klo
prog
ge(2
015)
Thai
land
(Apr
il 20
08–
Mar
ch20
09)
Clin
ical
trial
Preg
nant
wom
en in
seco
ndan
d th
ird tr
imes
ter o
fpr
egna
ncy
(Ht>
25%
) with
unco
mpl
icat
edP.
falc
ipar
umm
alar
ia &
the
sam
e w
omen
post
par
tum
(3 m
onth
s)w
ithou
t mal
aria
.
Gro
up 1
Arte
suna
te(4
mg/
kg)
i.v. q
.d. o
nda
y 0;
arte
suna
te(4
mg/
kg)
p.o
q.d.
on
day
1-6
Gro
up 2
20 p
regn
ant
wom
enG
roup
1: 1
0w
omen
Gro
up 2
: 10
wom
en14
pos
tpar
tum
wom
en
Com
partm
ent
al a
naly
sis
AU
C0-
12,
Cm
ax, T
max
,t 1/
2, C
L/F,
Vd/
F.
Bas
ed o
n th
esa
me
clin
ical
stud
y as
McG
read
y(2
012)
.
Arte
suna
te(4
mg/
kg)
p.o.
q.d
. on
day
0;ar
tesu
nate
(4m
g/kg
) i.v
.q.
d. o
n da
y1,
arte
suna
te(4
mg/
kg)
p.o.
q.d
. on
day
2-6)
Val
ea(2
014)
Bur
kina
Faso
(Sep
t20
08-J
an20
09)
Clin
ical
trial
Preg
nant
wom
en in
seco
ndan
d th
ird tr
imes
ter o
fpr
egna
ncy
with
unco
mpl
icat
edP.
falc
ipar
umm
onoi
nfec
tion
& m
atch
edno
n-pr
egna
nt w
omen
with
P.fa
lcip
arum
infe
ctio
n.
Mef
loqu
ine
+ A
rtesu
nate
(8/3
.6m
g/kg
q.d
.fo
r 3 d
ays)
24 p
regn
ant
wom
en23
non
-pr
egna
ntw
omen
Non
com
part
men
tal
anal
ysis
Tota
l dos
e,C
max
,C
max
/dos
e,T m
ax, C
L/F,
V/F
, t1/
2,A
UC
0-la
st,
AU
C0-
∞,
AU
C-
∞/d
ose.
McG
read
y(2
012)
Thai
land
(Apr
il 20
08–
Mar
ch20
09)
Clin
ical
trial
Preg
nant
wom
en in
seco
ndan
d th
ird tr
imes
ter o
fpr
egna
ncy
(Ht>
25%
) with
unco
mpl
icat
edP.
falc
ipar
umm
alar
ia &
the
sam
e w
omen
post
par
tum
(3 m
onth
s)
Gro
up 1
Arte
suna
te(4
mg/
kg)
i.v. q
.d. o
nda
y 0;
arte
suna
te
20 p
regn
ant
wom
enG
roup
1: 1
0w
omen
Gro
up 2
: 10
wom
en
Non
com
part
men
tal
anal
ysis
Tota
l dos
e,C
max
,C
max
/dos
e,T m
ax, C
L/F,
V/F
, t1/
2,A
UC
0-∞
,
Bas
ed o
n th
esa
me
clin
ical
stud
y as
Klo
prog
ge(2
015)
.
Processed on: 19-1-2017Processed on: 19-1-2017Processed on: 19-1-2017Processed on: 19-1-2017
507377-L-bw-Visser507377-L-bw-Visser507377-L-bw-Visser507377-L-bw-Visser
with
out m
alar
ia.
(4m
g/kg
)p.
o q.
d. o
nda
y 1-
6G
roup
2A
rtesu
nate
(4 m
g/kg
)p.
o. q
.d. o
nda
y 0;
arte
suna
te (4
mg/
kg) i
.v.
q.d.
on
day
1, a
rtesu
nate
(4 m
g/kg
)p.
o.q.
d. o
nda
y 2-
6)
14 p
ostp
artu
mw
omen
AU
C0-
∞/d
ose.
Mor
ris(2
011)
DR
C(M
ay20
07-N
ov20
08)
Clin
ical
trial
Preg
nant
wom
en in
seco
nd(2
2-26
wks
) and
third
(32-
36w
ks) t
rimes
ter o
fpr
egna
ncy
with
asym
ptom
atic
P. fa
lcip
arum
para
sita
emia
(200
-300
,000
p/µL
; Ht>
30%
) & sa
me
wom
en p
ost p
artu
m (3
mon
ths)
with
(n=2
) or
with
out (
n=24
)P. f
alci
paru
mpa
rasi
taem
ia &
non
-pre
gnan
t
Arte
suna
te(2
00 m
g)p.
o. q
.d. o
nda
y 0
+ SP
(172
5 m
g)p.
o. q
.d. o
nda
y 1
26 p
regn
ant
wom
en26
pos
tpar
tum
wom
en25
non
-pr
egna
ntw
omen
Com
partm
ent
al a
naly
sis
T 1/2, C
L/F,
V/F
.B
ased
on
the
sam
e cl
inic
alst
udy
asO
nyam
boko
(201
1).
fem
ale
volu
ntee
rs w
ithas
ympt
omat
icP.
falc
ipar
umpa
rasi
taem
ia (2
00-3
00,0
00p/
µL).
Ony
ambo
ko(2
011)
DR
C(M
ay20
07-N
ov20
08)
Clin
ical
trial
Preg
nant
wom
enin
seco
nd(2
2-26
wks
) and
third
(32-
36w
ks) t
rimes
ter o
fpr
egna
ncy
with
asym
ptom
atic
P. fa
lcip
arum
para
sita
emia
(200
-300
,000
p/µL
; Ht>
30%
) & sa
me
wom
en p
ost p
artu
m (3
mon
ths)
with
(n=2
) or
with
out (
n=24
)P. f
alci
paru
mpa
rasi
taem
ia &
non
-pre
gnan
tfe
mal
e vo
lunt
eers
with
asym
ptom
atic
P. fa
lcip
arum
para
sita
emia
(200
-300
,000
p/µL
).
Arte
suna
te(2
00 m
g)p.
o. q
.d. o
nda
y 0
+ SP
(172
5 m
g)p.
o. q
.d. o
nda
y 1
26 p
regn
ant
wom
en26
pos
tpar
tum
wom
en25
non
-pr
egna
ntw
omen
Non
com
part
men
tal
anal
ysis
Tota
l dos
e,C
max
, Tm
ax,
CL/
F, V
/F,
t 1/2,
AU
C0-
∞.
Bas
ed o
n th
esa
me
clin
ical
stud
y as
Mor
ris(2
011)
.
McG
read
y(2
006-
1)Th
aila
nd(O
ct 2
000-
July
200
1)
Clin
ical
trial
Preg
nant
wom
en in
seco
ndor
third
trim
este
r of
preg
nanc
y w
ith re
crud
esce
ntun
com
plic
ated
P. fa
lcip
arum
mal
aria
afte
r 7-d
ay q
uini
netre
atm
ent a
nd H
t>25
%.
Arte
suna
te-
AP
(4/2
0/8
mg/
kg p
.o.
q.d.
for 3
days
) + 2
00m
Lch
ocol
ate
24N
onco
mpa
rtm
enta
l &co
mpa
rtmen
tal a
naly
sis
Tota
l dos
e,C
max
, Tm
ax,
CL/
F, V
/F,
t 1/2,
AU
C48
-72
.
Processed on: 19-1-2017Processed on: 19-1-2017Processed on: 19-1-2017Processed on: 19-1-2017
507377-L-bw-Visser507377-L-bw-Visser507377-L-bw-Visser507377-L-bw-Visser
5
with
out m
alar
ia.
(4m
g/kg
)p.
o q.
d. o
nda
y 1-
6G
roup
2A
rtesu
nate
(4 m
g/kg
)p.
o. q
.d. o
nda
y 0;
arte
suna
te (4
mg/
kg) i
.v.
q.d.
on
day
1, a
rtesu
nate
(4 m
g/kg
)p.
o.q.
d. o
nda
y 2-
6)
14 p
ostp
artu
mw
omen
AU
C0-
∞/d
ose.
Mor
ris(2
011)
DR
C(M
ay20
07-N
ov20
08)
Clin
ical
trial
Preg
nant
wom
en in
seco
nd(2
2-26
wks
) and
third
(32-
36w
ks) t
rimes
ter o
fpr
egna
ncy
with
asym
ptom
atic
P. fa
lcip
arum
para
sita
emia
(200
-300
,000
p/µL
; Ht>
30%
) & sa
me
wom
en p
ost p
artu
m (3
mon
ths)
with
(n=2
) or
with
out (
n=24
)P. f
alci
paru
mpa
rasi
taem
ia &
non
-pre
gnan
t
Arte
suna
te(2
00 m
g)p.
o. q
.d. o
nda
y 0
+ SP
(172
5 m
g)p.
o. q
.d. o
nda
y 1
26 p
regn
ant
wom
en26
pos
tpar
tum
wom
en25
non
-pr
egna
ntw
omen
Com
partm
ent
al a
naly
sis
T 1/2, C
L/F,
V/F
.B
ased
on
the
sam
e cl
inic
alst
udy
asO
nyam
boko
(201
1).
fem
ale
volu
ntee
rs w
ithas
ympt
omat
icP.
falc
ipar
umpa
rasi
taem
ia (2
00-3
00,0
00p/
µL).
Ony
ambo
ko(2
011)
DR
C(M
ay20
07-N
ov20
08)
Clin
ical
trial
Preg
nant
wom
enin
seco
nd(2
2-26
wks
) and
third
(32-
36w
ks) t
rimes
ter o
fpr
egna
ncy
with
asym
ptom
atic
P. fa
lcip
arum
para
sita
emia
(200
-300
,000
p/µL
; Ht>
30%
) & sa
me
wom
en p
ost p
artu
m (3
mon
ths)
with
(n=2
) or
with
out (
n=24
)P. f
alci
paru
mpa
rasi
taem
ia &
non
-pre
gnan
tfe
mal
e vo
lunt
eers
with
asym
ptom
atic
P. fa
lcip
arum
para
sita
emia
(200
-300
,000
p/µL
).
Arte
suna
te(2
00 m
g)p.
o. q
.d. o
nda
y 0
+ SP
(172
5 m
g)p.
o. q
.d. o
nda
y 1
26 p
regn
ant
wom
en26
pos
tpar
tum
wom
en25
non
-pr
egna
ntw
omen
Non
com
part
men
tal
anal
ysis
Tota
l dos
e,C
max
, Tm
ax,
CL/
F, V
/F,
t 1/2,
AU
C0-
∞.
Bas
ed o
n th
esa
me
clin
ical
stud
y as
Mor
ris(2
011)
.
McG
read
y(2
006-
1)Th
aila
nd(O
ct 2
000-
July
200
1)
Clin
ical
trial
Preg
nant
wom
en in
seco
ndor
third
trim
este
r of
preg
nanc
y w
ith re
crud
esce
ntun
com
plic
ated
P. fa
lcip
arum
mal
aria
afte
r 7-d
ay q
uini
netre
atm
ent a
nd H
t>25
%.
Arte
suna
te-
AP
(4/2
0/8
mg/
kg p
.o.
q.d.
for 3
days
) + 2
00m
Lch
ocol
ate
24N
onco
mpa
rtm
enta
l &co
mpa
rtmen
tal a
naly
sis
Tota
l dos
e,C
max
, Tm
ax,
CL/
F, V
/F,
t 1/2,
AU
C48
-72
.
Processed on: 19-1-2017Processed on: 19-1-2017Processed on: 19-1-2017Processed on: 19-1-2017
507377-L-bw-Visser507377-L-bw-Visser507377-L-bw-Visser507377-L-bw-Visser
milk
(8%
fat)
Dih
ydro
arte
mis
inin
Aut
hor
(yea
r)C
ount
ry(t
ime
peri
od)
Typ
e of
stud
yPo
pula
tion
Dru
g (d
ose)
Num
ber
ofw
omen
Phar
mac
okin
etic
anal
ytic
met
hodo
log
y
Phar
mac
okin
etic
vari
able
s
Rem
arks
Ben
jam
in(2
015)
Papu
a N
ewG
uine
e (…
)C
linic
altri
alPr
egna
nt w
omen
in se
cond
and
third
trim
este
r of
preg
nanc
y(E
GA
>14w
ks)
and
age-
mat
ched
non
-pr
egna
nt w
omen
with
unco
mpl
icat
ed w
ith m
alar
iain
fect
ion.
Gro
up 1
DH
A-P
PQ(7
/58
mg/
kgp.
o. q
.d. f
or3
days
)
Gro
up 2
PPQ
(128
0mg
p.o.
q.d
. for
3 da
ys) +
SP
(25m
g/kg
once
)
32 p
regn
ant
wom
en33
non
-pr
egna
ntw
omen
Com
partm
ent
alan
alys
isM
TT, N
N,
CL/
F, V
c/F,
Q/F
, Vp/
F,t 1/
2, A
UC
0-∞
.
Val
ea(2
014)
Bur
kina
Faso
(Sep
t20
08-J
an20
09)
Clin
ical
trial
Preg
nant
wom
en in
seco
ndan
d th
ird tr
imes
ter o
fpr
egna
ncy
with
unco
mpl
icat
edP.
falc
ipar
umm
onoi
nfec
tion
& m
atch
ed
Mef
loqu
ine
+ A
rtesu
nate
(8/3
.6m
g/kg
q.d
.fo
r 3 d
ays)
24 p
regn
ant
wom
en23
non
-pr
egna
ntw
omen
Non
com
part
men
tal
anal
ysis
Tota
l dos
e,C
max
,C
max
/dos
e,T m
ax, C
L/F,
V/F
, t1/
2,
non-
preg
nant
wom
en w
ithP.
falc
ipar
umin
fect
ion.
AU
C0-
last
,A
UC
0-∞
,A
UC
-∞
/dos
e.M
cGre
ady
(201
2)Th
aila
nd(A
pril
2008
–M
arch
2009
)
Clin
ical
trial
Preg
nant
wom
en in
seco
ndan
d th
ird tr
imes
ter o
fpr
egna
ncy
(Ht>
25%
) with
unco
mpl
icat
edP.
falc
ipar
umm
alar
ia &
the
sam
e w
omen
post
par
tum
(3 m
onth
s)w
ithou
t mal
aria
.
Gro
up 1
Arte
suna
te(4
mg/
kg)
i.v. q
.d. o
nda
y 0;
arte
suna
te(4
mg/
kg)
p.o
q.d.
on
day
1-6
Gro
up 2
Arte
suna
te(4
mg/
kg)
p.o.
q.d
. on
day
0;ar
tesu
nate
(4m
g/kg
) i.v
.q.
d. o
n da
y1,
arte
suna
te(4
mg/
kg)
p.o.
q.d
. on
day
2-6)
20 p
regn
ant
wom
enG
roup
1: 1
0w
omen Gro
up 2
: 10
wom
en14
pos
tpar
tum
wom
en
Non
com
part
men
tal
anal
ysis
Tota
l dos
e,C
max
,C
max
/dos
e,T m
ax, C
L/F,
V/F
, t1/
2,A
UC
0-∞
,A
UC
0-∞
/dos
e.
Bas
ed o
n th
esa
me
clin
ical
stud
y as
Klo
prog
ge(2
015)
.
Processed on: 19-1-2017Processed on: 19-1-2017Processed on: 19-1-2017Processed on: 19-1-2017
507377-L-bw-Visser507377-L-bw-Visser507377-L-bw-Visser507377-L-bw-Visser
5
milk
(8%
fat)
Dih
ydro
arte
mis
inin
Aut
hor
(yea
r)C
ount
ry(t
ime
peri
od)
Typ
e of
stud
yPo
pula
tion
Dru
g (d
ose)
Num
ber
ofw
omen
Phar
mac
okin
etic
anal
ytic
met
hodo
log
y
Phar
mac
okin
etic
vari
able
s
Rem
arks
Ben
jam
in(2
015)
Papu
a N
ewG
uine
e (…
)C
linic
altri
alPr
egna
nt w
omen
in se
cond
and
third
trim
este
r of
preg
nanc
y(E
GA
>14w
ks)
and
age-
mat
ched
non
-pr
egna
nt w
omen
with
unco
mpl
icat
ed w
ith m
alar
iain
fect
ion.
Gro
up 1
DH
A-P
PQ(7
/58
mg/
kgp.
o. q
.d. f
or3
days
)
Gro
up 2
PPQ
(128
0mg
p.o.
q.d
. for
3 da
ys) +
SP
(25m
g/kg
once
)
32 p
regn
ant
wom
en33
non
-pr
egna
ntw
omen
Com
partm
ent
alan
alys
isM
TT, N
N,
CL/
F, V
c/F,
Q/F
, Vp/
F,t 1/
2, A
UC
0-∞
.
Val
ea(2
014)
Bur
kina
Faso
(Sep
t20
08-J
an20
09)
Clin
ical
trial
Preg
nant
wom
en in
seco
ndan
d th
ird tr
imes
ter o
fpr
egna
ncy
with
unco
mpl
icat
edP.
falc
ipar
umm
onoi
nfec
tion
& m
atch
ed
Mef
loqu
ine
+ A
rtesu
nate
(8/3
.6m
g/kg
q.d
.fo
r 3 d
ays)
24 p
regn
ant
wom
en23
non
-pr
egna
ntw
omen
Non
com
part
men
tal
anal
ysis
Tota
l dos
e,C
max
,C
max
/dos
e,T m
ax, C
L/F,
V/F
, t1/
2,
non-
preg
nant
wom
en w
ithP.
falc
ipar
umin
fect
ion.
AU
C0-
last
,A
UC
0-∞
,A
UC
-∞
/dos
e.M
cGre
ady
(201
2)Th
aila
nd(A
pril
2008
–M
arch
2009
)
Clin
ical
trial
Preg
nant
wom
en in
seco
ndan
d th
ird tr
imes
ter o
fpr
egna
ncy
(Ht>
25%
) with
unco
mpl
icat
edP.
falc
ipar
umm
alar
ia &
the
sam
e w
omen
post
par
tum
(3 m
onth
s)w
ithou
t mal
aria
.
Gro
up 1
Arte
suna
te(4
mg/
kg)
i.v. q
.d. o
nda
y 0;
arte
suna
te(4
mg/
kg)
p.o
q.d.
on
day
1-6
Gro
up 2
Arte
suna
te(4
mg/
kg)
p.o.
q.d
. on
day
0;ar
tesu
nate
(4m
g/kg
) i.v
.q.
d. o
n da
y1,
arte
suna
te(4
mg/
kg)
p.o.
q.d
. on
day
2-6)
20 p
regn
ant
wom
enG
roup
1: 1
0w
omen Gro
up 2
: 10
wom
en14
pos
tpar
tum
wom
en
Non
com
part
men
tal
anal
ysis
Tota
l dos
e,C
max
,C
max
/dos
e,T m
ax, C
L/F,
V/F
, t1/
2,A
UC
0-∞
,A
UC
0-∞
/dos
e.
Bas
ed o
n th
esa
me
clin
ical
stud
y as
Klo
prog
ge(2
015)
.
Processed on: 19-1-2017Processed on: 19-1-2017Processed on: 19-1-2017Processed on: 19-1-2017
507377-L-bw-Visser507377-L-bw-Visser507377-L-bw-Visser507377-L-bw-Visser
Tarn
ing
(201
2-1)
Thai
land
(Jun
e 20
08-
Dec
200
8)
Clin
ical
trial
Preg
nant
wom
en in
seco
ndan
d th
ird tr
imes
ter o
fpr
egna
ncy
(Ht>
25%
) with
unco
mpl
icat
edP.
falc
ipar
umm
alar
ia &
mat
ched
non
-pr
egna
nt w
omen
with
P.fa
lcip
arum
mal
aria
.
DH
A-P
PQ(6
.4/5
1.2
mg/
kg p
.o.
q.d.
for 3
days
)
24 p
regn
ant
wom
en24
non
-pr
egna
ntw
omen
Com
partm
ent
al a
naly
sis
Cm
ax, T
max
,C
L/F,
V/F
,t 1/
2, A
UC
0-24
, AU
C0-
92, d
ay 7
and
28co
ncen
tratio
n.
Bas
ed o
n th
esa
me
clin
ical
stud
y as
Rijk
en (2
011-
2).
Tarn
ing
(201
2-2)
Uga
nda
(Mar
ch20
08–
Sept
2008
)
Clin
ical
trial
Preg
nant
wom
en in
seco
ndan
d th
ird tr
imes
ter o
fpr
egna
ncy
(EG
A>1
3wks
)w
ith u
ncom
plic
ated
P.fa
lcip
arum
mal
aria
.
AL
(80/
480
mg
p.o.
b.i.d
. for
3da
ys) +
200
mL
milk
tea
21 p
regn
ant
wom
enC
ompa
rtme
ntal
ana
lysi
sTo
tal d
ose,
Cm
ax, T
max
,C
L/F,
V/F
,t 1/
2, A
UC
60-
last
,A
UC
/dos
e.
Nes
ted
inla
rger
effic
acy
stud
yby
Pio
la(2
010)
.
Mor
ris(2
011)
DR
C(M
ay20
07-N
ov20
08)
Clin
ical
trial
Preg
nant
wom
en in
seco
nd(2
2-26
wks
) and
third
(32-
36w
ks) t
rimes
ter o
fpr
egna
ncy
with
asym
ptom
atic
P. fa
lcip
arum
para
sita
emia
(200
-300
,000
p/µL
; Ht>
30%
) & sa
me
wom
en p
ost p
artu
m (3
mon
ths)
with
(n=2
) or
with
out (
n=24
)P. f
alci
paru
mpa
rasi
taem
ia &
non
-pre
gnan
t
Arte
suna
te(2
00 m
g)p.
o. q
.d. o
nda
y 0
+ SP
(172
5 m
g)p.
o. q
.d. o
nda
y 1
26 p
regn
ant
wom
en26
pos
tpar
tum
wom
en25
non
-pr
egna
ntw
omen
Com
partm
ent
al a
naly
sis
T 1/2, C
L/F,
V/F
.B
ased
on
the
sam
e cl
inic
alst
udy
asO
nyam
boko
(201
1).
fem
ale
volu
ntee
rs w
ithas
ympt
omat
icP.
falc
ipar
umpa
rasi
taem
ia (2
00-3
00,0
00p/
µL).
Ony
ambo
ko(2
011)
DR
C(M
ay20
07-N
ov20
08)
Clin
ical
trial
Preg
nant
wom
en in
seco
nd(2
2-26
wks
) and
third
(32-
36w
ks) t
rimes
ter o
fpr
egna
ncy
with
asym
ptom
atic
P. fa
lcip
arum
para
sita
emia
(200
-300
,000
p/µL
; Ht>
30%
) & sa
me
wom
en p
ost p
artu
m (3
mon
ths)
with
(n=2
) or
with
out (
n=24
)P. f
alci
paru
mpa
rasi
taem
ia &
non
-pre
gnan
tfe
mal
e vo
lunt
eers
with
asym
ptom
atic
P. fa
lcip
arum
para
sita
emia
(200
-300
,000
p/µL
).
Arte
suna
te(2
00 m
g)p.
o. q
.d. o
nda
y 0
+ SP
(172
5 m
g)p.
o.q.
d. o
nda
y 1
26 p
regn
ant
wom
en26
pos
tpar
tum
wom
en25
non
-pr
egna
ntw
omen
Non
com
part
men
tal
anal
ysis
Tota
l dos
e,C
max
, Tm
ax,
CL/
F, V
/F,
t 1/2,
AU
C0-
∞.
Bas
ed o
n th
esa
me
clin
ical
stud
y as
Mor
ris(2
011)
.
Rijk
en(2
011-
2)Th
aila
nd(J
une
2008
-D
ec 2
008)
Clin
ical
trial
Preg
nant
wom
en in
seco
ndan
d th
ird tr
imes
ter o
fpr
egna
ncy
(Ht<
25%
) with
unco
mpl
icat
edP.
falc
ipar
umm
alar
ia &
mat
ched
non
-pr
egna
nt w
omen
with
P.fa
lcip
arum
mal
aria
.
DH
A-P
PQ(6
.4/5
1.2
mg/
kg p
.o.
q.d.
for 3
days
)
24 p
regn
ant
wom
en24
non
-pr
egna
ntw
omen
Non
com
part
men
tal
anal
ysis
Tota
l dos
e,C
max
,C
max
/dos
e,C
L/F,
V/F
,t 1/
2, A
UC
0-la
st, A
UC
0-∞
, AU
C0-
Bas
ed o
n th
esa
me
clin
ical
stud
y as
Tarn
ing
2012
-1.
Processed on: 19-1-2017Processed on: 19-1-2017Processed on: 19-1-2017Processed on: 19-1-2017
507377-L-bw-Visser507377-L-bw-Visser507377-L-bw-Visser507377-L-bw-Visser
5
Tarn
ing
(201
2-1)
Thai
land
(Jun
e 20
08-
Dec
200
8)
Clin
ical
trial
Preg
nant
wom
en in
seco
ndan
d th
ird tr
imes
ter o
fpr
egna
ncy
(Ht>
25%
) with
unco
mpl
icat
edP.
falc
ipar
umm
alar
ia &
mat
ched
non
-pr
egna
nt w
omen
with
P.fa
lcip
arum
mal
aria
.
DH
A-P
PQ(6
.4/5
1.2
mg/
kg p
.o.
q.d.
for 3
days
)
24 p
regn
ant
wom
en24
non
-pr
egna
ntw
omen
Com
partm
ent
al a
naly
sis
Cm
ax, T
max
,C
L/F,
V/F
,t 1/
2, A
UC
0-24
, AU
C0-
92, d
ay 7
and
28co
ncen
tratio
n.
Bas
ed o
n th
esa
me
clin
ical
stud
y as
Rijk
en (2
011-
2).
Tarn
ing
(201
2-2)
Uga
nda
(Mar
ch20
08–
Sept
2008
)
Clin
ical
trial
Preg
nant
wom
en in
seco
ndan
d th
ird tr
imes
ter o
fpr
egna
ncy
(EG
A>1
3wks
)w
ith u
ncom
plic
ated
P.fa
lcip
arum
mal
aria
.
AL
(80/
480
mg
p.o.
b.i.d
. for
3da
ys) +
200
mL
milk
tea
21 p
regn
ant
wom
enC
ompa
rtme
ntal
ana
lysi
sTo
tal d
ose,
Cm
ax, T
max
,C
L/F,
V/F
,t 1/
2, A
UC
60-
last
,A
UC
/dos
e.
Nes
ted
inla
rger
effic
acy
stud
yby
Pio
la(2
010)
.
Mor
ris(2
011)
DR
C(M
ay20
07-N
ov20
08)
Clin
ical
trial
Preg
nant
wom
en in
seco
nd(2
2-26
wks
) and
third
(32-
36w
ks) t
rimes
ter o
fpr
egna
ncy
with
asym
ptom
atic
P. fa
lcip
arum
para
sita
emia
(200
-300
,000
p/µL
; Ht>
30%
) & sa
me
wom
en p
ost p
artu
m (3
mon
ths)
with
(n=2
) or
with
out (
n=24
)P. f
alci
paru
mpa
rasi
taem
ia &
non
-pre
gnan
t
Arte
suna
te(2
00 m
g)p.
o. q
.d. o
nda
y 0
+ SP
(172
5 m
g)p.
o. q
.d. o
nda
y 1
26 p
regn
ant
wom
en26
pos
tpar
tum
wom
en25
non
-pr
egna
ntw
omen
Com
partm
ent
al a
naly
sis
T 1/2, C
L/F,
V/F
.B
ased
on
the
sam
e cl
inic
alst
udy
asO
nyam
boko
(201
1).
fem
ale
volu
ntee
rs w
ithas
ympt
omat
icP.
falc
ipar
umpa
rasi
taem
ia (2
00-3
00,0
00p/
µL).
Ony
ambo
ko(2
011)
DR
C(M
ay20
07-N
ov20
08)
Clin
ical
trial
Preg
nant
wom
en in
seco
nd(2
2-26
wks
) and
third
(32-
36w
ks) t
rimes
ter o
fpr
egna
ncy
with
asym
ptom
atic
P. fa
lcip
arum
para
sita
emia
(200
-300
,000
p/µL
; Ht>
30%
) & sa
me
wom
en p
ost p
artu
m (3
mon
ths)
with
(n=2
) or
with
out (
n=24
)P. f
alci
paru
mpa
rasi
taem
ia &
non
-pre
gnan
tfe
mal
e vo
lunt
eers
with
asym
ptom
atic
P. fa
lcip
arum
para
sita
emia
(200
-300
,000
p/µL
).
Arte
suna
te(2
00 m
g)p.
o. q
.d. o
nda
y 0
+ SP
(172
5 m
g)p.
o.q.
d. o
nda
y 1
26 p
regn
ant
wom
en26
pos
tpar
tum
wom
en25
non
-pr
egna
ntw
omen
Non
com
part
men
tal
anal
ysis
Tota
l dos
e,C
max
, Tm
ax,
CL/
F, V
/F,
t 1/2,
AU
C0-
∞.
Bas
ed o
n th
esa
me
clin
ical
stud
y as
Mor
ris(2
011)
.
Rijk
en(2
011-
2)Th
aila
nd(J
une
2008
-D
ec 2
008)
Clin
ical
trial
Preg
nant
wom
en in
seco
ndan
d th
ird tr
imes
ter o
fpr
egna
ncy
(Ht<
25%
) with
unco
mpl
icat
edP.
falc
ipar
umm
alar
ia &
mat
ched
non
-pr
egna
nt w
omen
with
P.fa
lcip
arum
mal
aria
.
DH
A-P
PQ(6
.4/5
1.2
mg/
kg p
.o.
q.d.
for 3
days
)
24 p
regn
ant
wom
en24
non
-pr
egna
ntw
omen
Non
com
part
men
tal
anal
ysis
Tota
l dos
e,C
max
,C
max
/dos
e,C
L/F,
V/F
,t 1/
2, A
UC
0-la
st, A
UC
0-∞
, AU
C0-
Bas
ed o
n th
esa
me
clin
ical
stud
y as
Tarn
ing
2012
-1.
Processed on: 19-1-2017Processed on: 19-1-2017Processed on: 19-1-2017Processed on: 19-1-2017
507377-L-bw-Visser507377-L-bw-Visser507377-L-bw-Visser507377-L-bw-Visser
∞/d
ose,
AU
C0-
24,
AU
C24
-48,
AU
C48
-72,
AU
C72
-∞,
d ay
7, 1
4an
d 28
conc
entra
tion.
McG
read
y(2
006-
1)Th
aila
nd(O
ct 2
000-
July
200
1)
Clin
ical
trial
Preg
nant
wom
en in
seco
ndor
third
trim
este
r of
preg
nanc
y w
ith re
crud
esce
ntun
com
plic
ated
P. fa
lcip
arum
mal
aria
afte
r 7-d
ay q
uini
netre
atm
ent a
nd H
t>25
%.
Arte
suna
te-
AP
(4/2
0/8
mg/
kg p
.o.
q.d.
for 3
days
) + 2
00m
Lch
ocol
ate
milk
(8%
fat)
24N
onco
mpa
rtm
enta
l &co
mpa
rtmen
tal a
naly
sis
Tota
l dos
e,C
max
, Tm
ax,
CL/
F, V
/F,
t 1/2,
AU
C48
-72
.
McG
read
y(2
006-
2)Th
aila
nd(A
pril
2004
-Au
g 20
04)
Clin
ical
trial
Preg
nant
wom
en in
the
seco
nd a
nd th
ird tr
imes
ter o
fpr
egna
ncy
with
recr
udes
cent
unco
mpl
icat
ed m
ulti-
drug
resi
stan
tP. f
alci
paru
mm
alar
ia a
fter 7
-day
qui
nine
treat
men
t.
AL
(80/
480
mg
p.o.
b.i.d
. for
3da
ys) +
250
ml c
hoco
late
milk
(7g
fat)
13 p
regn
ant
wom
enN
onco
mpa
rtm
enta
l &co
mpa
rtmen
tal a
naly
sis
Tota
l dos
e,C
max
, Tm
ax,
CL/
F, V
/F,
t 1/2,
AU
C0-
24, A
UC
60-8
4,A
UC
/dos
e.
Lum
efan
trin
eA
utho
r(y
ear)
Cou
ntry
(tim
epe
riod
)
Typ
e of
stud
yPo
pula
tion
Dru
g (d
ose)
Num
ber
ofw
omen
Phar
mac
okin
etic
anal
ytic
met
hodo
log
y
Phar
mac
okin
etic
vari
able
s
Rem
arks
Klo
prog
ge(2
013)
Uga
nda
(Mar
ch20
08–
Sept
2008
)
Clin
ical
trial
Preg
nant
wom
en in
seco
ndan
d th
ird tr
imes
ter o
fpr
egna
ncy
(EG
A>1
3wks
)w
ith u
ncom
plic
ated
P.fa
lcip
arum
mal
aria
.
AL
(80/
480
mg
p.o.
b.i.d
. for
3da
ys) +
200
mL
milk
tea
115
preg
nant
wom
en26
ven
ous
sam
ples
89 c
apill
ary
sam
ples
17 n
on-
preg
nant
wom
en(a
ll ve
nous
sam
ples
)
Com
partm
ent
al a
naly
sis
AU
C0-
∞,
Cm
ax, T
1/2,
day
7co
ncen
tratio
n.
Nes
ted
inla
rger
effic
acy
/sa
fety
stud
yby
Pio
la(2
010)
.
Tarn
ing
(201
3)U
gand
a(O
ct20
06–
May
2009
)
Clin
ical
trial
Preg
nant
wom
en w
ithun
com
plic
ated
P. fa
lcip
arum
infe
ctio
n w
ith a
nEG
A>1
3wks
& n
on-
preg
nant
wom
en m
atch
ed fo
r
AL
(80/
480
mg
p.o.
b.i.d
. for
3da
ys) +
200
mL
milk
tea
AL:
21 p
regn
ant
wom
en
Lum
efan
trine
:
Non
com
part
men
tal
anal
ysis
Tota
l dos
e,C
max
,C
max
/dos
e,T m
ax, C
L/F,
V/F
, t1/
2,
Res
ults
for
arte
met
her
and
dihy
droa
rtem
isi
nin
are
Processed on: 19-1-2017Processed on: 19-1-2017Processed on: 19-1-2017Processed on: 19-1-2017
507377-L-bw-Visser507377-L-bw-Visser507377-L-bw-Visser507377-L-bw-Visser
5
∞/d
ose,
AU
C0-
24,
AU
C24
-48,
AU
C48
-72,
AU
C72
-∞,
day
7, 1
4an
d 28
conc
entra
tion.
McG
read
y(2
006-
1)Th
aila
nd(O
ct 2
000-
July
200
1)
Clin
ical
trial
Preg
nant
wom
en in
seco
ndor
third
trim
este
r of
preg
nanc
y w
ith re
crud
esce
ntun
com
plic
ated
P. fa
lcip
arum
mal
aria
afte
r 7-d
ay q
uini
netre
atm
ent a
nd H
t>25
%.
Arte
suna
te-
AP
(4/2
0/8
mg/
kg p
.o.
q.d.
for 3
days
) + 2
00m
Lch
ocol
ate
milk
(8%
fat)
24N
onco
mpa
rtm
enta
l &co
mpa
rtmen
tal a
naly
sis
Tota
l dos
e,C
max
, Tm
ax,
CL/
F, V
/F,
t 1/2,
AU
C48
-72
.
McG
read
y(2
006-
2)Th
aila
nd(A
pril
2004
-Au
g 20
04)
Clin
ical
trial
Preg
nant
wom
en in
the
seco
nd a
nd th
ird tr
imes
ter o
fpr
egna
ncy
with
recr
udes
cent
unco
mpl
icat
ed m
ulti-
drug
resi
stan
tP. f
alci
paru
mm
alar
ia a
fter 7
-day
qui
nine
treat
men
t.
AL
(80/
480
mg
p.o.
b.i.d
. for
3da
ys) +
250
ml c
hoco
late
milk
(7g
fat)
13 p
regn
ant
wom
enN
onco
mpa
rtm
enta
l &co
mpa
rtmen
tal a
naly
sis
Tota
l dos
e,C
max
, Tm
ax,
CL/
F, V
/F,
t 1/2,
AU
C0-
24, A
UC
60-8
4,A
UC
/dos
e.
Lum
efan
trin
eA
utho
r(y
ear)
Cou
ntry
(tim
epe
riod
)
Typ
e of
stud
yPo
pula
tion
Dru
g (d
ose)
Num
ber
ofw
omen
Phar
mac
okin
etic
anal
ytic
met
hodo
log
y
Phar
mac
okin
etic
vari
able
s
Rem
arks
Klo
prog
ge(2
013)
Uga
nda
(Mar
ch20
08–
Sept
2008
)
Clin
ical
trial
Preg
nant
wom
en in
seco
ndan
d th
ird tr
imes
ter o
fpr
egna
ncy
(EG
A>1
3wks
)w
ith u
ncom
plic
ated
P.fa
lcip
arum
mal
aria
.
AL
(80/
480
mg
p.o.
b.i.d
. for
3da
ys) +
200
mL
milk
tea
115
preg
nant
wom
en26
ven
ous
sam
ples
89 c
apill
ary
sam
ples
17 n
on-
preg
nant
wom
en(a
ll ve
nous
sam
ples
)
Com
partm
ent
al a
naly
sis
AU
C0-
∞,
Cm
ax, T
1/2,
day
7co
ncen
tratio
n.
Nes
ted
inla
rger
effic
acy
/sa
fety
stud
yby
Pio
la(2
010)
.
Tarn
ing
(201
3)U
gand
a(O
ct20
06–
May
2009
)
Clin
ical
trial
Preg
nant
wom
en w
ithun
com
plic
ated
P. fa
lcip
arum
infe
ctio
n w
ith a
nEG
A>1
3wks
& n
on-
preg
nant
wom
en m
atch
ed fo
r
AL
(80/
480
mg
p.o.
b.i.d
. for
3da
ys) +
200
mL
milk
tea
AL:
21 p
regn
ant
wom
en
Lum
efan
trine
:
Non
com
part
men
tal
anal
ysis
Tota
l dos
e,C
max
,C
max
/dos
e,T m
ax, C
L/F,
V/F
, t1/
2,
Res
ults
for
arte
met
her
and
dihy
droa
rtem
isi
nin
are
Processed on: 19-1-2017Processed on: 19-1-2017Processed on: 19-1-2017Processed on: 19-1-2017
507377-L-bw-Visser507377-L-bw-Visser507377-L-bw-Visser507377-L-bw-Visser
hist
ory
of fe
ver,
tem
p. >
37.5
°C, s
mok
ing
stat
us a
ndle
vel o
f par
asita
emia
.
OR
Qui
nine
(10
mg/
kg p
.o.
t.i.d
. for
7da
ys)
26 p
regn
ant
wom
en17
non
-pr
egna
ntw
omen
Qui
nine
:21
pre
gnan
tw
omen
AU
C0-
last
,A
UC
0-∞
,A
UC
-∞
/dos
e,A
UC
72-la
st,
AU
C72
-∞,
day
7co
ncen
tratio
n.
repo
rted
byTa
rnin
g(2
012-
2).
Nes
ted
inla
rger
effic
acy
/sa
fety
stud
yby
Pio
la(2
010)
.Pi
ola
(201
0)U
gand
a(O
ct20
06-M
ay20
09)
Clin
ical
trial
Preg
nant
wom
en w
ithun
com
plic
ated
P. fa
lcip
arum
infe
ctio
n (<
250,
000
p/µL
)w
ith a
n EG
A>1
3wks
and
Hb
> 7g
/dL.
AL
(80/
480
mg
p.o.
b.i.d
. for
3da
ys) +
200
mL
milk
97 p
regn
ant
wom
enN
onco
mpa
rtm
enta
lan
alys
is
Day
7co
ncen
tratio
n.
Bas
ed o
n th
esa
me
clin
ical
stud
y as
Tarn
ing
(201
2-2)
and
Tarn
ing
(201
3).
Tarn
ing
(200
9)Th
aila
nd(n
otre
port
ed)
Clin
ical
trial
Preg
nant
wom
en in
seco
ndor
third
trim
este
r of
preg
nanc
y w
ithun
com
plic
ated
sym
ptom
atic
P. fa
lcip
arum
mal
aria
.
AL
(80/
480
mg
p.o.
b.i.d
. for
3da
ys) +
200
-25
0 m
lch
ocol
ate
milk
(6-7
gfa
t)
103
preg
nant
wom
enC
ompa
rtme
ntal
ana
lysi
sTo
tal d
ose,
CL/
F, V
/F,
day
7co
ncen
tratio
n.
Nes
ted
inla
rger
effic
acy
/sa
fety
stud
yby
McG
read
y(2
008)
.
McG
read
y(2
008)
Thai
land
(Apr
il 20
04-
Clin
ical
trial
Preg
nant
wom
en in
seco
ndor
third
trim
este
r of
AL
(80/
480
mg
p.o.
85 p
regn
ant
wom
enN
onco
mpa
rtm
enta
lD
ay 7
conc
entra
tioB
ased
on
the
sam
e cl
inic
al
Aug
2006
)pr
egna
ncy
with
acu
teun
com
plic
ated
P. fa
lcip
arum
mal
aria
.
b.i.d
. for
3da
ys) +
250
ml c
hoco
late
milk
(7g
fat)
anal
ysis
n.st
udy
asM
cGre
ady
(200
6-2)
and
Tarn
ing
(200
9).
McG
read
y(2
006-
2)Th
aila
nd(A
pril
2004
-Au
g 20
04)
Clin
ical
trial
Preg
nant
wom
en in
the
seco
nd a
nd th
ird tr
imes
ter o
fpr
egna
ncy
with
recr
udes
cent
unco
mpl
icat
ed m
ulti-
drug
resi
stan
tP. f
alci
paru
mm
alar
ia a
fter 7
-day
qui
nine
treat
men
t.
AL
(80/
480
mg
p.o.
b.i.d
. for
3da
ys) +
250
ml c
hoco
late
milk
(7g
fat)
13 p
regn
ant
wom
enN
onco
mpa
rtm
enta
l &co
mpa
rtmen
tal a
naly
sis
Tota
l dos
e,C
max
, Tm
ax,
CL/
F, V
/F,
t 1/2,
AU
C0-
24, A
UC
60-8
4,A
UC
/dos
e.
Am
odia
quin
eA
utho
r(y
ear)
Cou
ntry
(tim
epe
riod
)
Typ
e of
stud
yPo
pula
tion
Dru
g (d
ose)
Num
ber
ofw
omen
Phar
mac
okin
etic
anal
ytic
met
hodo
log
y
Phar
mac
okin
etic
vari
able
s
Rem
arks
Tarn
ing
(201
2-3)
Thai
land
(Oct
200
7-M
ay20
08)
Clin
ical
trial
Preg
nant
wom
en in
seco
ndan
d th
ird tr
imes
ters
of
preg
nanc
y w
ith a
cute
P.vi
vax
mon
oinf
ectio
n &
sam
ew
omen
pos
t par
tum
(84-
173
days
) with
(n=7
) or w
ithou
t
Am
odia
quin
e (1
0 m
g/kg
p.o.
q.d
. for
3 da
ys)
27 p
regn
ant
wom
en19
pos
tpar
tum
wom
en
Com
partm
ent
al a
naly
sis
Cm
ax, T
max
,t 1/
2, A
UC
-la
st.
Bas
ed o
n th
esa
me
clin
ical
stud
y as
Rijk
en (2
011-
1).
Processed on: 19-1-2017Processed on: 19-1-2017Processed on: 19-1-2017Processed on: 19-1-2017
507377-L-bw-Visser507377-L-bw-Visser507377-L-bw-Visser507377-L-bw-Visser
5
hist
ory
of fe
ver,
tem
p. >
37.5
°C, s
mok
ing
stat
us a
ndle
vel o
f par
asita
emia
.
OR
Qui
nine
(10
mg/
kg p
.o.
t.i.d
. for
7da
ys)
26 p
regn
ant
wom
en17
non
-pr
egna
ntw
omen
Qui
nine
:21
pre
gnan
tw
omen
AU
C0-
last
,A
UC
0-∞
,A
UC
-∞
/dos
e,A
UC
72-la
st,
AU
C72
-∞,
day
7co
ncen
tratio
n.
repo
rted
byTa
rnin
g(2
012-
2).
Nes
ted
inla
rger
effic
acy
/sa
fety
stud
yby
Pio
la(2
010)
.Pi
ola
(201
0)U
gand
a(O
ct20
06-M
ay20
09)
Clin
ical
trial
Preg
nant
wom
en w
ithun
com
plic
ated
P. fa
lcip
arum
infe
ctio
n (<
250,
000
p/µL
)w
ith a
n EG
A>1
3wks
and
Hb
> 7g
/dL.
AL
(80/
480
mg
p.o.
b.i.d
. for
3da
ys) +
200
mL
milk
97 p
regn
ant
wom
enN
onco
mpa
rtm
enta
lan
alys
is
Day
7co
ncen
tratio
n.
Bas
ed o
n th
esa
me
clin
ical
stud
y as
Tarn
ing
(201
2-2)
and
Tarn
ing
(201
3).
Tarn
ing
(200
9)Th
aila
nd(n
otre
port
ed)
Clin
ical
trial
Preg
nant
wom
en in
seco
ndor
third
trim
este
r of
preg
nanc
y w
ithun
com
plic
ated
sym
ptom
atic
P. fa
lcip
arum
mal
aria
.
AL
(80/
480
mg
p.o.
b.i.d
. for
3da
ys) +
200
-25
0 m
lch
ocol
ate
milk
(6-7
gfa
t)
103
preg
nant
wom
enC
ompa
rtme
ntal
ana
lysi
sTo
tal d
ose,
CL/
F, V
/F,
day
7co
ncen
tratio
n.
Nes
ted
inla
rger
effic
acy
/sa
fety
stud
yby
McG
read
y(2
008)
.
McG
read
y(2
008)
Thai
land
(Apr
il 20
04-
Clin
ical
trial
Preg
nant
wom
en in
seco
ndor
third
trim
este
r of
AL
(80/
480
mg
p.o.
85 p
regn
ant
wom
enN
onco
mpa
rtm
enta
lD
ay 7
conc
entra
tioB
ased
on
the
sam
e cl
inic
al
Aug
2006
)pr
egna
ncy
with
acu
teun
com
plic
ated
P. fa
lcip
arum
mal
aria
.
b.i.d
. for
3da
ys) +
250
ml c
hoco
late
milk
(7g
fat)
anal
ysis
n.st
udy
asM
cGre
ady
(200
6-2)
and
Tarn
ing
(200
9).
McG
read
y(2
006-
2)Th
aila
nd(A
pril
2004
-Au
g 20
04)
Clin
ical
trial
Preg
nant
wom
en in
the
seco
nd a
nd th
ird tr
imes
ter o
fpr
egna
ncy
with
recr
udes
cent
unco
mpl
icat
ed m
ulti-
drug
resi
stan
tP. f
alci
paru
mm
alar
ia a
fter 7
-day
qui
nine
treat
men
t.
AL
(80/
480
mg
p.o.
b.i.d
. for
3da
ys) +
250
ml c
hoco
late
milk
(7g
fat)
13 p
regn
ant
wom
enN
onco
mpa
rtm
enta
l &co
mpa
rtmen
tal a
naly
sis
Tota
l dos
e,C
max
, Tm
ax,
CL/
F, V
/F,
t 1/2,
AU
C0-
24, A
UC
60-8
4,A
UC
/dos
e.
Am
odia
quin
eA
utho
r(y
ear)
Cou
ntry
(tim
epe
riod
)
Typ
e of
stud
yPo
pula
tion
Dru
g (d
ose)
Num
ber
ofw
omen
Phar
mac
okin
etic
anal
ytic
met
hodo
log
y
Phar
mac
okin
etic
vari
able
s
Rem
arks
Tarn
ing
(201
2-3)
Thai
land
(Oct
200
7-M
ay20
08)
Clin
ical
trial
Preg
nant
wom
en in
seco
ndan
d th
ird tr
imes
ters
of
preg
nanc
y w
ith a
cute
P.vi
vax
mon
oinf
ectio
n &
sam
ew
omen
pos
t par
tum
(84-
173
days
) with
(n=7
) or w
ithou
t
Am
odia
quin
e (1
0 m
g/kg
p.o.
q.d
. for
3 da
ys)
27 p
regn
ant
wom
en19
pos
tpar
tum
wom
en
Com
partm
ent
al a
naly
sis
Cm
ax, T
max
,t 1/
2, A
UC
-la
st.
Bas
ed o
n th
esa
me
clin
ical
stud
y as
Rijk
en (2
011-
1).
Processed on: 19-1-2017Processed on: 19-1-2017Processed on: 19-1-2017Processed on: 19-1-2017
507377-L-bw-Visser507377-L-bw-Visser507377-L-bw-Visser507377-L-bw-Visser
(n=1
2)P.
viv
axm
alar
ia.
Rijk
en(2
011-
1)Th
aila
nd(O
ct 2
007-
May
200
8)
Clin
ical
trial
Preg
nant
wom
en in
seco
ndan
d th
ird tr
imes
ters
of
preg
nanc
y w
ith a
cute
P.vi
vax
mon
oinf
ectio
n &
sam
ew
omen
pos
t par
tum
(84-
173
days
) with
(n=7
) or w
ithou
t(n
=12)
P. v
ivax
mal
aria
.
Am
odia
quin
e (1
0 m
g/kg
p.o.
q.d
. for
3 da
ys)
24 p
regn
ant
wom
en18
pos
tpar
tum
wom
en
Non
com
part
men
tal
anal
ysis
Tota
l dos
e,C
max
,C
max
/dos
e,T m
ax,C
L/F,
V/F
, t1/
2,A
UC
0-la
st,
AU
C0-
∞,
AU
C0-
∞/d
ose,
day
7 conc
entra
tion.
Bas
ed o
n th
esa
me
clin
ical
stud
y as
Tarn
ing
(201
2-3)
Mef
loqu
ine
Aut
hor
(yea
r)C
ount
ry(t
ime
peri
od)
Typ
e of
stud
yPo
pula
tion
Dru
g (d
ose)
Num
ber
ofw
omen
Phar
mac
okin
etic
anal
ytic
met
hodo
log
y
Phar
mac
okin
etic
vari
able
s
Rem
arks
Val
ea(2
014)
Bur
kina
Faso
(Sep
t20
08-J
an20
09)
Clin
ical
trial
Preg
nant
wom
en in
seco
ndan
d th
ird tr
imes
ter o
fpr
egna
ncy
with
unco
mpl
icat
edP.
falc
ipar
umm
onoi
nfec
tion
& m
atch
ed
Mef
loqu
ine
+ A
rtesu
nate
(8/3
.6m
g/kg
q.d
.fo
r 3 d
ays)
24 p
regn
ant
wom
en23
non
-pr
egna
ntw
omen
Non
com
part
men
tal
anal
ysis
Tota
l dos
e,C
max
,C
max
/dos
e,T m
ax, C
L/F,
V/F
, t1/
2,
non-
preg
nant
wom
en w
ithP.
falc
ipar
umin
fect
ion.
AU
C0-
last
,A
UC
0-∞
,A
UC
-∞
/dos
e.N
aB
angc
hang
(199
4)
Thai
land
(Sep
t 198
6-Ju
ne 1
988)
Clin
ical
trial
Preg
nant
wom
en in
firs
t(n
=2) a
nd th
ird (n
=7)
trim
este
r of p
regn
ancy
with
P. fa
lcip
arum
para
sita
emia
& n
on-p
regn
ant w
omen
mat
ched
for a
ge w
ithP.
falc
ipar
umpa
rasi
taem
ia.
Mef
loqu
ine
(15
mg/
kg)
9 pr
egna
ntw
omen
8 no
n-pr
egna
ntw
omen
Com
partm
ent
al a
naly
sis
Tota
l dos
e,C
max
, Tm
ax,
CL/
F, V
/F,
t 1/2.
Nos
ten
(199
0)Th
aila
nd(n
otre
port
ed)
Clin
ical
trial
Preg
nant
wom
en in
third
trim
este
r of p
regn
ancy
.G
roup
1:
Mef
loqu
ine
(250
mg
per
wee
k)
Gro
up 2
:M
eflo
quin
e(1
25 m
g pe
rw
eek)
20 p
regn
ant
wom
enC
ompa
rtme
ntal
ana
lysi
sC
max
, Tm
ax,
CL/
F, t 1
/2,
AU
C.
Sulfa
doxi
ne-p
yrim
etha
min
eA
utho
r(y
ear)
Cou
ntry
(tim
epe
riod
)
Typ
e of
stud
yPo
pula
tion
Dru
g (d
ose)
Num
ber
ofw
omen
Phar
mac
okin
etic
anal
ytic
Phar
mac
okin
etic
vari
able
s
Rem
arks
Processed on: 19-1-2017Processed on: 19-1-2017Processed on: 19-1-2017Processed on: 19-1-2017
507377-L-bw-Visser507377-L-bw-Visser507377-L-bw-Visser507377-L-bw-Visser
5
(n=1
2)P.
viv
axm
alar
ia.
Rijk
en(2
011-
1)Th
aila
nd(O
ct 2
007-
May
200
8)
Clin
ical
trial
Preg
nant
wom
en in
seco
ndan
d th
ird tr
imes
ters
of
preg
nanc
y w
ith a
cute
P.vi
vax
mon
oinf
ectio
n &
sam
ew
omen
pos
t par
tum
(84-
173
days
) with
(n=7
) or w
ithou
t(n
=12)
P. v
ivax
mal
aria
.
Am
odia
quin
e (1
0 m
g/kg
p.o.
q.d
. for
3 da
ys)
24 p
regn
ant
wom
en18
pos
tpar
tum
wom
en
Non
com
part
men
tal
anal
ysis
Tota
l dos
e,C
max
,C
max
/dos
e,T m
ax,C
L/F,
V/F
, t1/
2,A
UC
0-la
st,
AU
C0-
∞,
AU
C0-
∞/d
ose,
day
7 conc
entra
tion.
Bas
ed o
n th
esa
me
clin
ical
stud
y as
Tarn
ing
(201
2-3)
Mef
loqu
ine
Aut
hor
(yea
r)C
ount
ry(t
ime
peri
od)
Typ
e of
stud
yPo
pula
tion
Dru
g (d
ose)
Num
ber
ofw
omen
Phar
mac
okin
etic
anal
ytic
met
hodo
log
y
Phar
mac
okin
etic
vari
able
s
Rem
arks
Val
ea(2
014)
Bur
kina
Faso
(Sep
t20
08-J
an20
09)
Clin
ical
trial
Preg
nant
wom
en in
seco
ndan
d th
ird tr
imes
ter o
fpr
egna
ncy
with
unco
mpl
icat
edP.
falc
ipar
umm
onoi
nfec
tion
& m
atch
ed
Mef
loqu
ine
+ A
rtesu
nate
(8/3
.6m
g/kg
q.d
.fo
r 3 d
ays)
24 p
regn
ant
wom
en23
non
-pr
egna
ntw
omen
Non
com
part
men
tal
anal
ysis
Tota
l dos
e,C
max
,C
max
/dos
e,T m
ax, C
L/F,
V/F
, t1/
2,
non-
preg
nant
wom
en w
ithP.
falc
ipar
umin
fect
ion.
AU
C0-
last
,A
UC
0-∞
,A
UC
-∞
/dos
e.N
aB
angc
hang
(199
4)
Thai
land
(Sep
t 198
6-Ju
ne 1
988)
Clin
ical
trial
Preg
nant
wom
en in
firs
t(n
=2) a
nd th
ird (n
=7)
trim
este
r of p
regn
ancy
with
P. fa
lcip
arum
para
sita
emia
& n
on-p
regn
ant w
omen
mat
ched
for a
ge w
ithP.
falc
ipar
umpa
rasi
taem
ia.
Mef
loqu
ine
(15
mg/
kg)
9 pr
egna
ntw
omen
8 no
n-pr
egna
ntw
omen
Com
partm
ent
al a
naly
sis
Tota
l dos
e,C
max
, Tm
ax,
CL/
F, V
/F,
t 1/2.
Nos
ten
(199
0)Th
aila
nd(n
otre
port
ed)
Clin
ical
trial
Preg
nant
wom
en in
third
trim
este
r of p
regn
ancy
.G
roup
1:
Mef
loqu
ine
(250
mg
per
wee
k)
Gro
up 2
:M
eflo
quin
e(1
25 m
g pe
rw
eek)
20 p
regn
ant
wom
enC
ompa
rtme
ntal
ana
lysi
sC
max
, Tm
ax,
CL/
F, t 1
/2,
AU
C.
Sulfa
doxi
ne-p
yrim
etha
min
eA
utho
r(y
ear)
Cou
ntry
(tim
epe
riod
)
Typ
e of
stud
yPo
pula
tion
Dru
g (d
ose)
Num
ber
ofw
omen
Phar
mac
okin
etic
anal
ytic
Phar
mac
okin
etic
vari
able
s
Rem
arks
Processed on: 19-1-2017Processed on: 19-1-2017Processed on: 19-1-2017Processed on: 19-1-2017
507377-L-bw-Visser507377-L-bw-Visser507377-L-bw-Visser507377-L-bw-Visser
met
hodo
log
yN
yunt
(201
0)M
ali,
Moz
ambi
que,
Sud
an &
Zam
bia
(not
repo
rted
)
Clin
ical
trial
Preg
nant
wom
en w
ith a
nEG
A 1
5-36
wks
with
outP
.fa
lcip
arum
para
sita
emia
(Hb>
8g/d
L) &
sam
e w
omen
post
par
tum
(6-4
3wks
)w
ithou
tP. f
alci
paru
mpa
rasi
taem
ia a
nd w
ithH
b>8g
/dL
(Mal
i & Z
ambi
a)/ p
ostp
artu
m w
omen
(> 6
mon
ths)
with
outP
.fa
lcip
arum
para
sitae
mia
and
with
Hb>
8g/d
L(M
ozam
biqu
e &
Sud
an) &
mat
ched
non
-pre
gnan
tw
omen
with
acu
teun
com
plic
ated
falc
ipar
umm
alar
ia (M
ozam
biqu
e).
SP (1
500/
75m
g p.
o.on
ce)
97 p
regn
ant
wom
en77
pos
tpar
tum
wom
en
Com
partm
ent
al a
naly
sis
Tota
l dos
e,C
max
, CL/
F,V
/F, t
1/2,
AU
C0-
∞,
day
7co
ncen
tratio
n.
Kar
unaj
eew
a (2
009)
Papu
a N
ewG
uine
e(F
eb20
06-J
uly
2006
)
Clin
ical
trial
Preg
nant
wom
en in
seco
ndor
third
trim
este
r of
preg
nanc
y w
ithou
t sev
ere
mal
aria
(n=1
7:P.
falc
ipar
um/ v
ivax
/m
alar
iae
para
sita
emia
; n=1
3: n
opa
rasi
taem
ia) &
mat
ched
SP (1
500/
75m
g p.
o.on
ce)+
Chl
oroq
uine
(135
0 m
gp.
o. q
.d. f
or3
days
)
30 p
regn
ant
wom
en30
non
-pr
egna
ntw
omen
Com
partm
ent
al a
naly
sis
CL/
F, V
/F,
t 1/2,
AU
C0-
∞.
non-
preg
nant
wom
en (n
=9:
falc
ipar
um /
viva
x /m
alar
iae
para
sita
emia
; n=2
1: n
opa
rasi
taem
ia).
Gre
en(2
007)
Ken
ya(1
999-
2000
)C
linic
altri
alPr
imi-
and
secu
ndig
ravi
dw
omen
with
unc
ompl
icat
edsi
ngle
ton
preg
nanc
ies w
ithEG
A 1
6-28
wks
and
Hb>
8g/d
L w
ithou
tsy
mpt
omat
ic m
alar
ia (n
=11:
para
sita
emic
; n=2
2:ap
aras
itaem
ic) &
sam
ew
omen
pos
t par
tum
(2-3
mon
ths)
with
out
sym
ptom
atic
mal
aria
(n=1
:pa
rasi
taem
ic; n
=10:
apar
asita
emic
).
SP (1
500/
75m
g p.
o.on
ce)
33 p
regn
ant
wom
en16
HIV
-po
sitiv
e17
HIV
-ne
gativ
e11
pos
tpar
tum
wom
en6
HIV
-po
sitiv
e5
HIV
-ne
gativ
e
Com
partm
ent
al a
naly
sis
CL/
F, V
/F,
t 1/2,
AU
C0-
∞.
Pipe
raqu
ine
Aut
hor
(yea
r)C
ount
ry(t
ime
peri
od)
Typ
e of
stud
yPo
pula
tion
Dru
g (d
ose)
Num
ber
ofw
omen
Phar
mac
okin
etic
anal
ytic
met
hodo
log
y
Phar
mac
okin
etic
vari
able
s
Rem
arks
Processed on: 19-1-2017Processed on: 19-1-2017Processed on: 19-1-2017Processed on: 19-1-2017
507377-L-bw-Visser507377-L-bw-Visser507377-L-bw-Visser507377-L-bw-Visser
5
met
hodo
log
yN
yunt
(201
0)M
ali,
Moz
ambi
que,
Sud
an &
Zam
bia
(not
repo
rted
)
Clin
ical
trial
Preg
nant
wom
en w
ith a
nEG
A 1
5-36
wks
with
outP
.fa
lcip
arum
para
sita
emia
(Hb>
8g/d
L) &
sam
e w
omen
post
par
tum
(6-4
3wks
)w
ithou
tP. f
alci
paru
mpa
rasi
taem
ia a
nd w
ithH
b>8g
/dL
(Mal
i & Z
ambi
a)/ p
ostp
artu
m w
omen
(> 6
mon
ths)
with
outP
.fa
lcip
arum
para
sitae
mia
and
with
Hb>
8g/d
L(M
ozam
biqu
e &
Sud
an) &
mat
ched
non
-pre
gnan
tw
omen
with
acu
teun
com
plic
ated
falc
ipar
umm
alar
ia (M
ozam
biqu
e).
SP (1
500/
75m
g p.
o.on
ce)
97 p
regn
ant
wom
en77
pos
tpar
tum
wom
en
Com
partm
ent
al a
naly
sis
Tota
l dos
e,C
max
, CL/
F,V
/F, t
1/2,
AU
C0-
∞,
day
7co
ncen
tratio
n.
Kar
unaj
eew
a (2
009)
Papu
a N
ewG
uine
e(F
eb20
06-J
uly
2006
)
Clin
ical
trial
Preg
nant
wom
en in
seco
ndor
third
trim
este
r of
preg
nanc
y w
ithou
t sev
ere
mal
aria
(n=1
7:P.
falc
ipar
um/ v
ivax
/m
alar
iae
para
sita
emia
; n=1
3: n
opa
rasi
taem
ia) &
mat
ched
SP (1
500/
75m
g p.
o.on
ce)+
Chl
oroq
uine
(135
0 m
gp.
o. q
.d. f
or3
days
)
30 p
regn
ant
wom
en30
non
-pr
egna
ntw
omen
Com
partm
ent
al a
naly
sis
CL/
F, V
/F,
t 1/2,
AU
C0-
∞.
non-
preg
nant
wom
en (n
=9:
falc
ipar
um /
viva
x /m
alar
iae
para
sita
emia
; n=2
1: n
opa
rasi
taem
ia).
Gre
en(2
007)
Ken
ya(1
999-
2000
)C
linic
altri
alPr
imi-
and
secu
ndig
ravi
dw
omen
with
unc
ompl
icat
edsi
ngle
ton
preg
nanc
ies w
ithEG
A 1
6-28
wks
and
Hb>
8g/d
L w
ithou
tsy
mpt
omat
ic m
alar
ia (n
=11:
para
sita
emic
; n=2
2:ap
aras
itaem
ic) &
sam
ew
omen
pos
t par
tum
(2-3
mo n
ths)
with
out
sym
ptom
atic
mal
aria
(n=1
:pa
rasi
taem
ic; n
=10:
apar
asita
emic
).
SP (1
500/
75m
g p.
o.on
ce)
33 p
regn
ant
wom
en16
HIV
-po
sitiv
e17
HIV
-ne
gativ
e11
pos
tpar
tum
wom
en6
HIV
-po
sitiv
e5
HIV
-ne
gativ
e
Com
partm
ent
al a
naly
sis
CL/
F, V
/F,
t 1/2,
AU
C0-
∞.
Pipe
raqu
ine
Aut
hor
(yea
r)C
ount
ry(t
ime
peri
od)
Typ
e of
stud
yPo
pula
tion
Dru
g (d
ose)
Num
ber
ofw
omen
Phar
mac
okin
etic
anal
ytic
met
hodo
log
y
Phar
mac
okin
etic
vari
able
s
Rem
arks
Processed on: 19-1-2017Processed on: 19-1-2017Processed on: 19-1-2017Processed on: 19-1-2017
507377-L-bw-Visser507377-L-bw-Visser507377-L-bw-Visser507377-L-bw-Visser
Ben
jam
in(2
015)
Papu
a N
ewG
uine
e (n
otre
port
ed)
Clin
ical
trial
Preg
nant
wom
en in
seco
ndan
d th
ird tr
imes
ter o
fpr
egna
ncy
(EG
A>1
4wks
)an
d ag
e-m
atch
ed n
on-
preg
nant
wom
en w
ithun
com
plic
ated
with
mal
aria
infe
ctio
n.
Gro
up 1
DH
A-P
PQ(7
/58
mg/
kgp.
o. q
.d. f
or3
days
)
Gro
up 2
PPQ
(128
0mg
p.o.
q.d
. for
3 da
ys) +
SP
(25m
g/kg
once
)
32 p
regn
ant
wom
en33
non
-pr
egna
ntw
omen
Com
partm
ent
al a
naly
sis
MTT
, NN
,C
L/F,
Vc/
F,Q
/F, V
p/F,
t 1/2,
AU
C0-
∞.
Ada
m(2
012)
Suda
n(A
ug20
07-F
eb20
08)
Clin
ical
trail
Preg
nant
wom
en in
seco
ndan
d th
ird tr
imes
ter o
fpr
egna
ncy
(EG
A 1
5-40
wks
)w
ith u
ncom
plic
ated
P.fa
lcip
arum
mal
aria
and
Hb>
7g/d
L. &
age
-and
wei
ght-m
atch
ed n
on-
preg
nant
wom
en w
ithun
com
plic
ated
P. fa
lcip
arum
mal
aria
.
DH
A-P
PQ(2
.4/2
0m
g/kg
q.d
.fo
r 3 d
ays)
12 p
regn
ant
wom
en12
non
-pr
egna
ntw
omen
Non
com
part
men
tal
anal
ysis
Tota
l dos
e,C
max
(afte
rdo
se 1
, 2an
d 3)
, Tm
ax
(afte
r dos
e1,
2 a
nd 3
),C
L/F,
V/F
,T 1
/2, A
UC
0-la
st, A
UC
0-∞
, AU
C-
∞/d
ose,
AU
C0-
24,
AU
C24
-48,
Bas
ed o
n th
esa
me
clin
ical
stud
y as
Hog
lund
(201
2).
AU
C48
-72,
AU
C72
-∞,
day
7 an
d 14
conc
entra
tion.
Hog
lund
(201
2)Su
dan
(Aug
2007
-Feb
2008
)
Clin
ical
trial
Preg
nant
wom
en in
seco
ndan
d th
ird tr
imes
ter o
fpr
egna
ncy
(EG
A 1
5-40
wks
)w
ith u
ncom
plic
ated
P.fa
lcip
arum
mal
aria
and
Hb>
7g/d
L. &
age
-and
wei
ght-m
atch
ed n
on-
preg
nant
wom
en w
ithun
com
plic
ated
P. fa
lcip
arum
mal
aria
.
DH
A-P
PQ(2
.4/2
0m
g/kg
q.d
.fo
r 3 d
ays)
12 p
regn
ant
wom
en12
non
-pr
egna
ntw
omen
Com
partm
ent
al a
naly
sis
Cm
ax, T
max
,t 1/
2, A
UC
48-9
0,A
UC
0-90
,da
y 7
and
28co
ncen
tratio
n.
Bas
ed o
n th
esa
me
clin
ical
stud
y as
Ada
m (2
012)
.
Tarn
ing
(201
2-1)
Thai
land
(Jun
e 20
08-
Dec
200
8)
Clin
ical
trial
Preg
nant
wom
en in
seco
ndan
d th
ird tr
imes
ter o
fpr
egna
ncy
(Ht>
25%
) with
unco
mpl
icat
edP.
falc
ipar
umm
alar
ia &
mat
ched
non
-pr
egna
nt w
omen
with
P.fa
lcip
arum
mal
aria
.
DH
A-P
PQ(6
.4/5
1.2
mg/
kg p
.o.
q.d.
for 3
days
)
24 p
regn
ant
wom
en24
non
-pr
egna
ntw
omen
Com
partm
ent
al a
naly
sis
Cm
ax, T
max
,C
L/F,
V/F
,t1
/2, A
UC
0-24
, AU
C0-
92, d
ay 7
and
28co
ncen
tratio
n.
Bas
ed o
n th
esa
me
clin
ical
stud
y as
Rijk
en (2
011-
2).
Rijk
en(2
011-
2)Th
aila
nd(J
une
2008
-D
ec 2
008)
Clin
ical
trial
Preg
nant
wom
en in
seco
ndan
d th
ird tr
imes
ter o
fpr
egna
ncy
(Ht<
25%
) with
DH
A-P
PQ(6
.4/5
1.2
mg/
kg p
.o.
24 p
regn
ant
wom
en24
non
-
Non
com
part
men
tal
anal
ysis
Tota
l dos
e,C
max
,C
max
/dos
e,
Bas
ed o
n th
esa
me
clin
ical
stud
y as
Processed on: 19-1-2017Processed on: 19-1-2017Processed on: 19-1-2017Processed on: 19-1-2017
507377-L-bw-Visser507377-L-bw-Visser507377-L-bw-Visser507377-L-bw-Visser
5
Ben
jam
in(2
015)
Papu
a N
ewG
uine
e (n
otre
port
ed)
Clin
ical
trial
Preg
nant
wom
en in
seco
ndan
d th
ird tr
imes
ter o
fpr
egna
ncy
(EG
A>1
4wks
)an
d ag
e-m
atch
ed n
on-
preg
nant
wom
en w
ithun
com
plic
ated
with
mal
aria
infe
ctio
n.
Gro
up 1
DH
A-P
PQ(7
/58
mg/
kgp.
o. q
.d. f
or3
days
)
Gro
up 2
PPQ
(128
0mg
p.o.
q.d
. for
3 da
ys) +
SP
(25m
g/kg
once
)
32 p
regn
ant
wom
en33
non
-pr
egna
ntw
omen
Com
partm
ent
al a
naly
sis
MTT
, NN
,C
L/F,
Vc/
F,Q
/F, V
p/F,
t 1/2,
AU
C0-
∞.
Ada
m(2
012)
Suda
n(A
ug20
07-F
eb20
08)
Clin
ical
trail
Preg
nant
wom
en in
seco
ndan
d th
ird tr
imes
ter o
fpr
egna
ncy
(EG
A 1
5-40
wks
)w
ith u
ncom
plic
ated
P.fa
lcip
arum
mal
aria
and
Hb>
7g/d
L. &
age
-and
wei
ght-m
atch
ed n
on-
preg
nant
wom
en w
ithun
com
plic
ated
P. fa
lcip
arum
mal
aria
.
DH
A-P
PQ(2
.4/2
0m
g/kg
q.d
.fo
r 3 d
ays)
12 p
regn
ant
wom
en12
non
-pr
egna
ntw
omen
Non
com
part
men
tal
anal
ysis
Tota
l dos
e,C
max
(afte
rdo
se 1
, 2an
d 3)
, Tm
ax
(afte
r dos
e1,
2 a
nd 3
),C
L/F,
V/F
,T 1
/2, A
UC
0-la
st, A
UC
0-∞
, AU
C-
∞/d
ose,
AU
C0-
24,
AU
C24
-48,
Bas
ed o
n th
esa
me
clin
ical
stud
y as
Hog
lund
(201
2).
AU
C48
-72,
AU
C72
-∞,
day
7 an
d 14
conc
entra
tion.
Hog
lund
(201
2)Su
dan
(Aug
2007
-Feb
2008
)
Clin
ical
trial
Preg
nant
wom
en in
seco
ndan
d th
ird tr
imes
ter o
fpr
egna
ncy
(EG
A 1
5-40
wks
)w
ith u
ncom
plic
ated
P.fa
lcip
arum
mal
aria
and
Hb>
7g/d
L. &
age
-and
wei
ght-m
atch
ed n
on-
preg
nant
wom
en w
ithun
com
plic
ated
P. fa
lcip
arum
mal
aria
.
DH
A-P
PQ(2
.4/2
0m
g/kg
q.d
.fo
r 3 d
ays)
12 p
regn
ant
wom
en12
non
-pr
egna
ntw
omen
Com
partm
ent
al a
naly
sis
Cm
ax, T
max
,t 1/
2, A
UC
48-9
0,A
UC
0-90
,da
y 7
and
28co
ncen
tratio
n.
Bas
ed o
n th
esa
me
clin
ical
stud
y as
Ada
m (2
012)
.
Tarn
ing
(201
2-1)
Thai
land
(Jun
e 20
08-
Dec
200
8)
Clin
ical
trial
Preg
nant
wom
en in
seco
ndan
d th
ird tr
imes
ter o
fpr
egna
ncy
(Ht>
25%
) with
unco
mpl
icat
edP.
falc
ipar
umm
alar
ia &
mat
ched
non
-pr
egna
nt w
omen
with
P.fa
lcip
arum
mal
aria
.
DH
A-P
PQ(6
.4/5
1.2
mg/
kg p
.o.
q.d.
for 3
days
)
24 p
regn
ant
wom
en24
non
-pr
egna
ntw
omen
Com
partm
ent
al a
naly
sis
Cm
ax, T
max
,C
L/F,
V/F
,t1
/2, A
UC
0-24
, AU
C0-
92, d
ay 7
and
28co
ncen
tratio
n.
Bas
ed o
n th
esa
me
clin
ical
stud
y as
Rijk
en (2
011-
2).
Rijk
en(2
011-
2)Th
aila
nd(J
une
2008
-D
ec 2
008)
Clin
ical
trial
Preg
nant
wom
en in
seco
ndan
d th
ird tr
imes
ter o
fpr
egna
ncy
(Ht<
25%
) with
DH
A-P
PQ(6
.4/5
1.2
mg/
kg p
.o.
24 p
regn
ant
wom
en24
non
-
Non
com
part
men
tal
anal
ysis
Tota
l dos
e,C
max
,C
max
/dos
e,
Bas
ed o
n th
esa
me
clin
ical
stud
y as
Processed on: 19-1-2017Processed on: 19-1-2017Processed on: 19-1-2017Processed on: 19-1-2017
507377-L-bw-Visser507377-L-bw-Visser507377-L-bw-Visser507377-L-bw-Visser
unco
mpl
icat
edP.
falc
ipar
umm
alar
ia &
mat
ched
non
-pr
egna
nt w
omen
with
P.fa
lcip
arum
mal
aria
.
q.d.
for 3
days
)pr
egna
ntw
omen
CL/
F, V
/F,
t 1/2,
AU
C0-
last
, AU
C0-
∞, A
UC
0-∞
/dos
e,A
UC
0-24
,A
UC
24-4
8,A
UC
48-7
2,A
UC
72-∞
,da
y 7,
14
and
28co
ncen
tratio
n.
Tarn
ing
2012
-1.
173
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