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Blackwell Science, Ltd

Oxford, UK

BCPBritish Journal of Clinical Pharmacology

0306-5251Blackwell Publishing 2003

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?464468

Original Article

Malaria chemotherapyP. Winstanley

Correspondence:

Professor P. Winstanley, Department of Pharmacology &Therapeutics and Director, Wellcome Trust Centre for Research in ClinicalTropical Medicine, University of Liverpool, Liverpool L69 3GE. Tel.:

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44 151 794 5544 or 4221; Fax:

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44 151 794 5540 or 4222; E-mail:peterwin@liv.ac.uk

Received 16 December 2002, accepted 27 January 2003.

The contribution of clinical pharmacology to antimalarial drug discovery and development

Peter Winstanley

Professor, Department of Pharmacology & Therapeutics, University of Liverpool, L69 3GE, UK, and Director, Wellcome Trust Centre for Research in Clinical Tropical Medicine, University of Liverpool, Liverpool L69 3GE, UK

Unlike human immunodeficiency virus (HIV) disease or tuberculosis, both of whichare also major threats to public health throughout the tropics, uncomplicated falci-parum malaria is relatively cheaply and rapidly cured, usually in Outpatients. How-ever, in common with both HIV and TB (but to varying degrees), control of malariais threatened by inadequate resources and drug resistance. Worldwide, it is Africathat carries the greatest burden of falciparum malaria mortality and morbidity; byno coincidence, it is also Africa that is most resource-limited. The drugs for severedisease (quinine and the artemisinins) are largely unaffected by resistance so far, butthe ‘first-line’ drugs, mostly used by outpatients (mainly chloroquine and sulfadox-ine-pyrimethamine) are a major cause for concern. Although effective drugs areavailable, they are largely too expensive for routine use. The present article reviewsthe ways in which clinical pharmacology has contributed to the identification ofnew drugs and strategies for malaria.

Introduction

Malaria has always been a major killer of populationsthroughout the tropics. During the last century, it wasmarked out as a problem by colonial authorities andmilitary strategists, and great advances were made inunderstanding its biology and developing methods ofcontrol. Indeed, in the latter half of the 20th century thecombination of potent insecticides and cheap drugsoffered the possibility of global eradication, for a fleetingmoment. However, malaria still remains one of the larg-est global health care problems of the 21st century. Ofthe four species of human malarial parasite,

Plasmodiumfalciparum

is remarkable for its high case–fatality rate andalarming development of resistance to antimalarial drugs.This parasite will be the focus of the present article.

Sub-Saharan Africa bears the brunt of malarial mor-tality. There is a wide range of transmission conditions,from stable, endemic areas (where most of the populationlives) to areas of infrequent parasite exposure [1]. Inendemic conditions, functional immunity is acquired

early in life and over 75% of mortality affects childrenless than 5 years of age. The ‘cost’ of developing popu-lation immunity is enormous: there were about 765 000annual malaria deaths among children living in stable,endemic areas of Africa in 1995 [1]. In addition, pregnantmothers exposed to malaria infection suffer increased risksof severe anaemia, while the unborn child, if it survives,is often born with low birth weight; about 25% of allneonatal mortality is mediated through low birth weightconsequent upon malaria infection during pregnancy [2].Africa includes the majority of the world’s poorest coun-tries, and these are often unable to finance basic servicesand sustainable infrastructure. In global terms, malaria,poverty and development are intrinsically linked [3], andsub-Saharan Africa epitomises this vicious cycle. At a timewhen conflicts, displaced populations, human immuno-deficiency virus (HIV) and global economics threaten thefragile livelihoods of most rural population,s there isgrowing evidence that, since the mid-1980s, the burdenfrom malaria has been increasing [4].

The drugs used for severe malaria syndromes (quinineand the artemisinin group) largely retain efficacy inAfrica. In sharp contrast, there is an impending disasterbecause of resistance to those inexpensive drugs tradi-tionally employed for ‘outpatient malaria’. Clinical failureafter a course of chloroquine (CQ) now exceeds 25% bya wide margin in much of East Africa, and the situationis worsening in parts of West Africa too. Critically, resis-

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tance to sulfadoxine-pyrimethamine (SP), which severalcountries now use as first-line, is developing apace; itseems likely that this drug will be redundant within5 years in parts of East Africa. Many effective drugs areruled out because of their high cost (for example atova-quone–proguanil), and alternative first-line drugs (suchas amodiaquine or oral quinine) present difficulties.Artemisinin combination therapy (ACT) has beenstrongly suggested as the correct strategy for Africa, butimmense hurdles (of cost, access and political will)remain.

Current drugs for uncomplicated malariain Africa

Chloroquine and amodiaquine

Chloroquine (CQ) remains the treatment of choice for

P. vivax, P. ovale, P. malariae

and uncomplicated falciparummalaria in those few geographical areas where this drugcan still be relied on. Even in areas of high-level resis-tance, such as East Africa, CQ is often still the mostwidely used treatment and still produces a clinicalresponse (albeit with recrudescence in a majority ofpatients). CQ is cheap, safe and well-tolerated but itsfailure to eliminate parasitaemia may eventually lead tothe development of profound anaemia. The efficacy ofamodiaquine is greater than that of CQ, and it remainsa common second-line drug in many national malariacontrol programmes in Africa [5]. The combination ofamodiaquine with anti-retroviral therapies (ARTs) is cur-rently being examined under the auspices of the WorldHealth Organization (WHO).

Sulfadoxine–pyrimethamine

In many parts of Africa a decision must soon be madeto replace CQ as the first-line treatment for falciparummalaria. The switch to sulfadoxine-pyrimethamine (SP)has already been made in many countries (Malawi, theforerunner, having done so in 1993). This has the greatadvantages of being (i) a single dose treatment, and (ii)inexpensive. Unfortunately, resistance usually developswithin a few years [6], facilitated by the slow eliminationof SP from the body. Folate supplements, which oftenaccompany malaria treatment for anaemic children, prob-ably reduce the efficacy of SP [7]. Uganda has recentlyopted to use a combination of CQ

+

SP as its first-linetreatment. It will be interesting to see what success thisregimen achieves, for although there are few data tosupport this move, there is a logical basis:

1 despite a high prevalence of CQ resistance, the drugretains some clinical efficacy in a high proportion ofpatients;

2 even in the face of extensive resistance, CQ can causea rapid fall in peripheral parasitaemia;

3 the likelihood of encountering a parasite isolate resis-tant to both SP and CQ is lower than that for eitherdrug alone;

4 the cost of CQ

+

SP, although higher than for eitherdrug alone, is still readily affordable in an Africansetting;

5 the toxicity profiles of CQ and SP differ widely, andcombined use is unlikely to increase the risk ofadverse drug reactions in anything other than an addi-tive manner.

Quinine

Quinine is an effective replacement for CQ and is a drugof choice for nonimmune patients with falciparummalaria. However, it has the disadvantage that it must betaken three times a day for 7 days, tastes bitter, andpredictably causes unpleasant symptoms at normal ther-apeutic dose, thus compliance is a major problem. Inthose parts of South-east Asia where parasite sensitivityto quinine is declining, and where few alternatives areavailable, cure rates are improved if the drug is combinedwith tetracycline or clindamycin.

Mefloquine

This is given as a single dose (or in divided doses 6–8 hapart to reduce the risk of vomiting), and was initiallyhighly effective against multiresistant strains of falciparummalaria throughout the world. However, in some areas,notably in the border regions of Thailand, mefloquineresistance has developed rapidly and a combination ofmelfoquine with artesunate is currently used. The rela-tively high cost of mefloquine limits its usefulness inAfrica.

Artemisinin combination therapy

During treatment with two (or more) drugs, the chanceof a mutant resistant to both drugs emerging can becalculated from the product of the individual per-parasitemutation rates (assuming that the resistance mutations arenot ‘linked’). The artemisinin derivatives reduce the par-asite biomass by around 4 logs for each asexual cycle; thismakes them the most rapidly efficacious antimalarialdrugs in use [8, 9]. This rapid reduction of the parasitebiomass has a major theoretical role when artemisininderivatives are combined with another antimalarial drug;the parasite population available to develop mutations tothe second drug is reduced by several log orders. Thus,when mefloquine was used in combination with ARTsin Thailand, that rate of development of mefloquine

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resistance was reduced. WHO recommends ACT as partof the ‘ideal’ strategy for malaria control in Africa, butthere are practical concerns:

1 ACT will be relatively expensive. There is only onefixed-ratio combination, lumefantrine with artemether(coartem; Riamet), and this will be made available forUS$ 2.50 per adult treatment course. While this isgenerous of the manufacturer (in Switzerland, the drugis selling at SFr 78.50 [US$ 57.00] for a 3-day adultcourse), there are still problems. Firstly, US$ 2.50 isstill probably too costly. Secondly, there is concernabout the stability of this price. It represents an awe-some commitment by the manufacturer, unless theGlobal Fund can contribute large revenue costs.

2 ACT has been shown to work in an experimentalsetting in Thailand, but it is not clear that the samewill apply in an operational African setting.

3 The artemisinins are embryotoxic in rats and rabbits,and the reproductive safety of the drug class remainsunder scrutiny.

The biggest current problem: case management of uncomplicated falciparum malaria in Africa

Sustainable vector control has proved an elusive toolunder most endemic conditions of Africa, and a malariavaccine is unlikely to be available for some years. Insec-ticide-treated bed nets do offer enormous potential tohouseholds with enough resources to buy/maintainthem, but case management is likely to remain the prin-cipal means of malaria ‘control’ in Africa for some timeto come. Although severe falciparum malaria is a majorproblem throughout Africa, it is largely unaffected bydrug resistance, and quinine or the artemisinin derivativeswork reliably. Perhaps paradoxically, the greatest threat atthe moment is the inability of poor people to accesseffective and affordable therapy early in the course of anuncomplicated clinical attack (thereby hopefully prevent-ing severe disease).

The challenge can be appreciated by realizing that themajority of countries with extensive clinical CQ resis-tance are still using this drug because of the severe con-straints faced by national malaria control programmes(NMCPs): (i) CQ is affordable, whereas most alternativesare not; (ii) SP is also affordable but resistance developsvery quickly (as discussed above); and (iii) NMCP man-agers are wary of committing themselves to policychanges that may prove short-lived.

Academia has a role in the search for antimalarialdrugs. One such example is chlorproguanil–dapsone(CPG-DDS; Lapdap

TM

), the result of 15 years of labora-tory and clinical research by the Department of Pharma-cology and Therapeutics at Liverpool. CPG-DDS is not

yet commercially available, but a dossier was submittedto the Medicines Control Agency (by GlaxoSmithKlinePharmaceuticals in partnership with WHO and DFID)in October 2002. Daily CPG-DDS for 3 days (CPG2.0 mg kg

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1

and DDS 2.5 mg kg

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1

daily) is an effectivetreatment for uncomplicated falciparum malaria in semi-immune patients, and seems to be well-tolerated. CPG-DDS will cost less than US$ 0–0.5 for a 3-day adulttreatment course in the public sector. There is evidencethat SP treatment of parasite strains with

dhfr

mutationsat positions 108, 51 and 59 often results in clinical failure;in contrast, the risk of clinical failure seems lower withCPG-DDS [10]. It is also probable that CPG-DDS exertsa smaller degree of ‘selection pressure for resistance’ thanSP. In line with the reasoning underpinning ACT, (dis-cussed above), work has started on the manufactureof a chlorproguanil-dapsone-artesunate (CDA) triple-combination tablet.

There have been few examples to guide us on thethinking of national ‘decision-makers’ faced with theproblem of changing first-line antimalarial drugs. It seemslikely that, in the case of a new drug (such as CPG-DDS)or treatment strategy, any such decision to change policywould take several years before final implementation. Thefirst stage of assessment would comprise submission of thedossier to the national drug regulatory authority, whichwould establish that the drug met agreed standards ofquality, efficacy and safety. However, these efficacy andsafety data are usually severely limited: (ai) the drug hasbeen studied in the artificial setting of controlled trials (sothat real-world efficacy (effectiveness) may be overesti-mated) and (ii) only around 2000 people will usually havetaken the drug (so the safety profile will be incomplete).

Furthermore, the majority of malaria case managementin Africa occurs through self-medication (using drugs onthe ‘General Sales List’). This is because: (i) clinical attacksare very common; (ii) most communities regard fever assynonymous with malaria; and (iii) formal health servicesare often distant and resource-limited. Effective use ofinformal services requires an informed patient/providerpopulation; this is rarely achieved, but there is a growingrecognition that the informal sector must be included asa partner in the delivery of malaria therapeutic services.Thus the final stage in assessment of a new drug orstrategy would need to demonstrate its safety and robust-ness as a home treatment. This would require a combi-nation of Phase IV postmarketing surveillance with anattempt to address the following logistic realities

.

The practicability of the drug regimen for unsupervisedout-patient use

Treatment regimens that are either protracted (beyond3 days treatment) or complicated (e.g. treatment with

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two or more separately formulated drugs) would be dif-ficult to implement.

The cost of the drug

This is a major factor; people need to remember thatCQ costs around US$ 0–0.1 for a treatment course, soeven a US$ 0–0.5 drug – inexpensive by any definition– still represents a significant extra burden. Further-more, national authorities need to be convinced thatthe price is going to be stable. Drugs offered at a sub-stantially subsidized price carry the risk of future pricerises if the manufacturer finds that it can not maintainthe subsidy.

Stability of supply

Clearly, an NMCP would need to be convinced that anadequate drug supply would always be available (this cansurface as a concern over the ART drugs that, becausethe source material is extracted from plants, are depen-dent on the many determinants of crop yield).

Safety

The safety data in a standard regulatory dossier is suffi-cient to visualize Type A adverse drug reactions(ADRs); these are dose–concentration-related, and usu-ally predictable from the drug’s pharmacological prop-erties). However, such Type A ADRs are rarely asource of major clinical concern (with the exception ofoverdose and patient subgroups in whom pharmacoki-netics are perturbed, e.g. renal or hepatic impairment).Much more worrying are TypeB ADRs, which areusually/often: (i) unrelated to dose/concentration; (ii)unpredictable from the drug’s pharmacological proper-ties; (iii) immune-mediated; (iv) more severe than TypeA; and critically (v) too rare to have been assessedbefore market authorization (a prevalence of 1 : 10 000users is not unusual). Large Phase IV studies areneeded, in which ADR-reporting systems would beestablished

.

Pregnancy

The risks of giving a new drug to pregnant women aredaunting and so: (i) drug use in pregnancy usually hap-pens by chance; and (ii) tentative conclusions about safetytake years to evolve. We do not have the time for thisserendipitous process; the failure of SP ‘intermittent pre-sumptive treatment’ will mean increased perinatal mor-tality for large numbers of women. Further, for a drugto be useful for malaria control, it must be usable by bothchildren and adults, and women are often unaware of

their condition during early pregnancy, when the fetusis most vulnerable. Thus new antimalarial drugs (or strat-egies) must address the matter of safety in pregnancyprospectively.

Effectiveness in the real world

In general, the shorter and simpler the regimen, thebetter. However, even the simplest regimen can bedogged by problems: (i) if a drug frequently causes atrivial but irritating ADR, e.g. chloroquine-induced pru-ritus, then compliance with the ideal dose regimen maybe poo; (ii) if packaging allows a 3-day regimen to besold in smaller quantities, even though the drug may bevery inexpensive, savings will often be made at theexpense of efficacy; (iii) if people are confused about theregimen, then a 3-day course may be taken as a singledose, perhaps causing toxicity; and (iv) compliance withthe dose regimen may be good but, if the drug causesvomiting (e.g. mefloquine), then its effectiveness will beimpaired.

Stability of drug sensitivity

If selection of drug resistance is facile, as it is with theantifolate compounds, NMCP managers would needreassurance that efficacy and/or effectiveness (in the ‘realworld’) is likely to be stable.

Conclusions

Falciparum malaria remains a major threat to globalhealth, especially in Africa where drug resistance threat-ens a major increase in mortality and morbidity. Althougheffective drugs are available, there are too few examples,and they are too expensive. Furthermore, the difficultiesof effecting change in national antimalarial drug policy(and implementing that policy) cannot be underesti-mated. To hold our ground against malaria there willneed to be continued collaboration between scientists,the pharmaceutical industry and malaria control pro-gramme personnel.

References

1 Snow RW, Craig MH, Deichmann U, Marsh K. Estimating mortality, morbidity and disability due to malaria among Africa’s non-pregnant population.

Bulletin of World Health Organisation

1999;

77

: 624–640.2 Brabin BJ, Hakimi M, Pelletier D. An analysis of anemia and

pregnancy–related maternal mortality.

J Nutr

2001;

131

(2S

-

2): 604S–614S; discussion 614S–615S.3 Sachs J. Helping the world’s poorest.

The Economist

August 14, 1999; 17–20.

P. Winstanley

468

© 2003 Blackwell Publishing Ltd

Br J Clin Pharmacol

,

55

, 464–468

4 Trape JF, Pison G, Preziosi MP,

et al.

Impact of chloroquine resistance on malaria mortality.

Comples Rendus l’Academie Des Sci Series 3, Sci la Vie

1998;

321

: 689–697.5 Olliaro P, Mussano P. Amodiaquine for treating malaria.

Cochrane Database Syst Rev

2000; CD000016.6 Mutabingwa T, Nzila A, Mberu E,

et al.

Drug resistant falciparum malaria in Tanzania: chlorproguanil-dapsone is effective treatment for infections resistant to pyrimethamine-sulfadoxine.

Lancet

2003; in press.7 van Hensbroek MB, Morris-Jones S, Meisner S,

et al.

Iron but not folic acid, combined with effective antimalarial therapy promotes haematological recovery in African children after

acute falciparum malaria.

Trans R Soc Trop Med Hyg

1995;

89

: 672–676.

8 Meshnick SR. Artemisinin antimalarials: mechanisms of action and resistance.

Med Trop (Mars)

1998;

58

(

3

Suppl): 13–17.9 http://www.foundation.novartis.com/

malaria_riamet_china.htm.10 Nzila A, Nduati E, Mberu E,

et al.

Molecular evidence of greater selective pressure for drug resistance exerted by the long acting antifolate pyrimethamine/sulfadoxine compared with the shorter acting chlorproguanil-dapsone on Kenyan

Plasmodium falciparum

.

J Inf Dis

2000;

181

: 2023–2028.