Drug Interactions in Oncology

489

ReviewDrugdrug interactions

Oncology Vol 5 August 2004 http://oncology.thelancet.com

Drug interactions are an ongoing concern in treatment ofcancer, especially when cytotoxic drugs are being used.However, the clinical relevance of these interactions isnot always investigated. Drug interactions can bepharmaceutical, pharmacokinetic, or pharmacodynamic.They can also be wanted (eg, use of ciclosporin toenhance the oral bioavailability of paclitaxel); unwanted(eg, combination of the antiviral agent sorivudine andoral fluorouracil analogues can lead to fatalcomplications); between cytotoxic drugs, cytotoxicdrugs and non-cytotoxic drugs; or with pharmaceuticalvehicles. Potential interactions between anticancerdrugs and over-the-counter or alternative medicines andherbs should not be underestimated. More attentionshould be given to the recognition of potential druginteractions in the preclinical and early clinicaldevelopment phase of a new anticancer drug. Here, weprovide a comprehensive overview of drug interactions,with selected examples.

Lancet Oncol 2004; 5: 48996

Drug interactions are an ongoing concern in treatment.2030% of all adverse drug reactions are caused byinteractions between drugs, and these reactions are clinicallyrelevant in up to 80% of elderly patients.1,2 Relevant druginteractions, however, are not always recognised during theclinical development phase of a drug. Widespread use, aftermarketing approval, sometimes results in the discovery ofnew drug interactions. For several drugs, the lateidentification of such interactions has led to restrictionsbeing placed on the indications, or even withdrawal of thedrug from the market (eg, cisapride, astemizol, terfenadine,cerivastatin, mibefradil, and sorivudine).

Anticancer drugs are no exception. Cytotoxic anticancerdrugs are some of the strongest acting drugs. They have acomplex pharmacological profile, a narrow therapeuticwindow, a steep dose-toxicity curve, and manypharmacokinetic and pharmacodynamic differences bothwithin and between patients. In oncology, such drugs areoften used in combinations, especially in elderly patients,3

and are not only chemococktails, but can also include drugsthat reduce the toxic side-effects of chemotherapy andprovide palliation.4 The use of such combinations and thenumber of drugs involved increases the potential fordrugdrug interactions.

Many anticancer drugs are metabolised by the hepaticoxidative cytochrome P450 system, which can result in

formation of toxic products. Furthermore, some of thesedrugs are substrates for drug-transporting proteinseg, P-glycoprotein, the multidrug resistance proteins (MRPs),and breast cancer resistance protein (BCRP).5 Drugdruginteractions can occur at all levels, and failure to recognisethem can lead to overdosing or undertreatment, with far-reaching clinical consequences. Over-the-counterproducts, alternative medicines, herbs, and nutritionalsupplements can also interact (figure 1), and doctors arenot always aware that patients are also taking theseproducts.

Drug interactions can be categorised as pharmaceutical,pharmacokinetic, or pharmacodynamic. In this review, we

Drug interactions in oncology

Jos H Beijnen and Jan H M Schellens

JHB is a hospital pharmacist at the Department of Pharmacy andPharmacology, Slotervaart Hospital, The Netherlands CancerInstitute, Amsterdam, The Netherlands. JHB and JHMS are lecturersat the Department of Biomedical Analysis, Division of DrugToxicology, Faculty of Pharmaceutical Sciences, Utrecht University,The Netherlands. JHMS is medical oncologist in the Departments ofMedical Oncology and Experimental Therapy, Antoni vanLeeuwenhoek Hospital, The Netherlands Cancer Institute,Amsterdam, The Netherlands.

Correspondence: Prof Jos H Beijnen, Department of Pharmacy and Pharmacology, Slotervaart Hospital, The Netherlands CancerInstitute, Louwesweg 6, 1066 EC Amsterdam, The Netherlands.Tel: + 31 20 512 4481. Fax: + 31 20 512 4753. Email: [email protected]

Figure 1. Over-the-counter products can modify the effectiveness ofprescribed drugs.

490

present selected examples of drug interactions in oncologyand describe their potential clinical relevance. Moreinformation is available in other reviews of this topic.112

Pharmaceutical interactionsPharmaceutical interactions occur when two compoundsinteract because of they are incompatible either physically orchemically. An example is when admixtures for infusion areprepared: when the thiol compound mesna is added to acisplatin solution, it inactivates the platinum drug byforming a covalent mesnaplatinum adduct.13 Otherexamples include the rapid degradation of mitomycin intoinactive mitosenes when the drug is dissolved in a 5%dextrose infusion fluid (pH 45);14 and the precipitation of taxanes, epipodophyllotoxins (after dilution), andfluorouracil (at low pH) in infusion fluids.

During clinical development, recombinant interleukin 2(aldesleukin) was investigated as a continuous infusion onan outpatient basis. Patients received seven prefilled syringesto change once a day. The infusion device consisted of theplastic syringe in a driver, a polyethylene catheter, and acentral venous access system (titanium injection portal withpolyurethane catheter). Although the drug was chemicallystable and bioactivity was not lost when the solution passedquickly through the infusion device, patients reported notoxic effects.15 Further laboratory studies,15 showed thatbioactivity was almost completely lost when the drugsolution was pumped at a very low rate, as was the case in thepatients. The recommendation is now to dilute aldesleukinin 5% dextrose with 01% albumin, which prevents loss dueto adsorption during infusion. In vitro studies can, in mostcases, predict these interactions. This example suggests thatthe compatibilities of a drug should be investigated before itis entered into clinical trials, and in ways that mimic theexact clinical situation.16

Another example of a pharmaceutical interaction is themodulating effect of a vehicle on the pharmacokinetic andpharmacodynamic properties of a drug.17 Encapsulation ofdoxorubicin into pegylated liposomes results in a lowerincidence of cardiotoxicity,18 and this process has asubstantial effect on the pharmacokinetic profile of the drug.The area under the plasma concentration-time curve (AUC)of the total drug concentration in plasmaie, unbound plusliposomal encapsulatedis about 300 times greater,clearance is 250 times lower, and the distribution volume is60 times lower after this drug is encapsulated in theseliposomes compared with free doxorubicin. As aconsequence, the dose-limiting toxic-effects profile has alsochanged from bone-marrow suppression and cardiac toxic effects with free doxorubicin, to palmarplantarerythrodysaesthesia with pegylated liposomal doxorubicin.19

However, liposomal incorporation of cisplatin seems toprevent the drug from reaching its target efficiently and fromforming cytotoxic platinumDNA adducts. Total bodyclearance of pegylated liposomal cisplatin (as total platinumin plasma) was 1430 mL/h100 times lower than thatreported for cisplatin. Furthermore, concentrations ofplatinumDNA adducts in white blood cells and tumourtissue were 10100 times lower compared with

administration of comparable dose of non-liposomalcisplatin. Further disappointing clinical results have stoppedthis programme.20,21

When the cytotoxic active ingredient paclitaxel isdissolved in a mixture of polyoxyethylated castor oil andethanol (50/50, volume/volume), the solvent greatly affectsthe pharmacokinetic behaviour of the drug.22 In one study,mice were given 10 mg/kg intravenous paclitaxel dissolved ineither polyoxyethylated castor oil or in Tween 80,supplemented with ethanol. The AUC of paclitaxel in thepolyoxyethylated castor oil group was eight times higher,with lower clearance and distribution volume, than that inthe Tween 80 group.22 This difference is probably becausethe non-ionic polyoxyethylated castor oil forms micelles inthe blood stream, entrapping paclitaxel, and therebypreventing distribution of the drug into tissues. Thismechanism is also a plausible explanation for the non-linearpharmacokinetics of paclitaxel seen in several clinicalstudies.22,23

This effect caused by polyoxyethylated castor oil shouldbe taken into account when paclitaxel is combined withother drugs. Cardiotoxicity that is induced by anthracyclinesis enhanced by concomitant use of paclitaxel, possiblybecause doxorubicin is modified pharmacokinetically by thepolyoxyethylated castor oil in the paclitaxel solvent.24

Millward and colleagues24 investigated the pharmacokineticsof doxorubicin without or with coinfusion of 3060 mL/m2

polyoxyethylated castor oil. The presence of the castor oil ledto a significant increase of the AUC of doxorubicin and itsactive metabolite doxorubicinol, and could explain thehigher incidence of cardiotoxicity when paclitaxel iscombined with anthracyclines.2426 However, inclusion ofdoxorubicin in pegylated liposomes, which reducescardiotoxicity, seems to have the opposite effect (ie, morecardiotoxicity) when doxorubicin is combined withpaclitaxel with entrapment in polyoxyethylated castor oilmicelles. The role of paclitaxel itself in this interaction isunclear. Nevertheless, a vehicle is not always aphysiologically inert compound.

Pharmacokinetic interactionsPharmacokinetic interactions arise as a result of the foursimple, almost indistinguishable, kinetic principles:absorption, distribution, metabolism, and elimination.Metabolising enzymes or drug transporters are ofteninvolved in these processes.

AbsorptionThe oral bioavailability of mercaptopurine rises substantiallywhen the drug is combined with allopurinol. Allopurinolinhibits the enzyme xanthine oxidase in the intestinal tractand liver, which also converts mercaptopurine into theinactive thiouric acid. During combined use, this oxidativecatabolic pathway of mercaptopurine is inhibited, whichslows breakdown of the drug, making it more available foranabolic conversions. It is through these anabolicconversions that cytotoxic products are formed, in particulartioguanine. Such interaction can lead to serious side-effects(eg, bone-marrow suppression and liver damage) sometimes

Review Drugdrug interactions


491



with a fatal outcome.27 When the combination is still desired,despite these side-effects, mercaptopurine should be reducedto 2533% of the normal dose. This interaction also occurswith azathioprine.

For several reasons oral chemotherapy is preferred overother methods of administration.28 However, because adrugs bioavailability is limited and variable through thismethod of administration, development of oral anticancerdrugs has been hampered. New research into themechanisms behind this liability has opened new avenues oforal chemotherapy. Drug transporters and CYP isozymes(eg, CYP3A4 and CYP3A5) in the intestinal epitheliumseem to be major obstacles for efficient drug uptake. Thefirst knowledge about these transporters originated fromresearch into tumour resistance. Tumours sometimesbecome resistant to several drugs after exposure to just oneagent, a process known as multidrug resistance. One of themechanisms in multidrug resistance is overexpression of theATP-binding cassette-containing family of proteins, such asP-glycoprotein, BCRP, and MRPs. These proteins arelocated mainly in the plasma membrane and can activelyextrude substrates out of cells. They are, however, expressednot only in resistant tumour cells, but also in healthy tissueswith a barrier function, such as the gut epithelium,endothelial cells in the bloodbrain barrier, and theplacenta. P-glycoprotein, BCRP, and MRP2 are highlyexpressed in the apical membrane of the gut epitheliumie, towards the lumen of the gut. Their physiologicalfunction is probably to protect sensitive and critical tissues

against xenotoxins.5 Studies with knockout mice that do nothave Mdr1a/1b P-glycoprotein and their wildtype litter-mates with functional P-glycoprotein have shown that P-glycoprotein substantially impedes oral uptake of severalanticancer drugs, including paclitaxel: the AUC ofpaclitaxel after oral administration was six times higher inthe knockouts than in the wildtype mice.29,30 Inhibitors of P-glycoprotein such as valspodar, elacridar, and ciclosporineffectively block the function of P-glycoprotein in the gut,and thereby increase the oral bioavailability of paclitaxel toachieve therapeutically relevant drug concentrations inplasma.3035 Phase II studies with oral paclitaxel incombination with ciclosporin have shown that thecombination is clinically effective in lung and stomachcancer.32,33

Docetaxel is a weak P-glycoprotein substrate. Its limitedoral bioavailability is caused mainly by CYP3A4-mediatedfirst-pass metabolism in the gut wall and liver. Plasmaconcentrations of docetaxel are 50 times higher in micewhen oral docetaxel is combined with the potent CYP3A4,but weak P-glycoprotein inhibitor, ritonavir.36

Oral treatment with topotecan is hampered by a variablebioavailability of 3044%, resulting in higher incidences ofneutropenia when administered at the maximum tolerateddose than after standard intravenous treatment. Ourstudies37 have showed that topotecan is a high-affinitysubstrate drug for BCRP, transport of which can beeffectively inhibited by the P-glycoprotein and BCRPblocker elacridar. We used this strategy to improve oraluptake of topotecan. Topotecan was given to Mdr1a/1b(/)P-glycoprotein knockout and wildtype mice with or withoutelacridar.38 Transport was also investigated in cells thatoverexpress BCRP1, which might mediate apically-directeddrug transport and, through this mechanism, reduce thebioavailability of topotecan. In a clinical study,39 patientsreceived 10 mg/m2 oral topotecan with or without1 g elacridar. The oral bioavailability increased significantlyfrom 40% to 971% (figure 2A). The variability betweenpatients of the oral bioavailability diminished from 17%without elacridar, to 11% with this inhibitor.

Several studies that used P-glycoprotein inhibitors toreverse multidrug resistance in tumours resistant tochemotherapy have reported pharmacokinetic drugdruginteractions: the combination of valspodar and doxorubicinhad substantially higher AUC values for doxorubicin and itsmetabolite doxorubicinol than without valspodar.40 Despiteseveral studies, however, this finding has never been provedclinically relevant. On the other hand, modulation of P-glycoprotein, BCRP, and CYP3A4 in the gastrointestinaltract to facilitate oral drug uptake seems to be a promisingstrategy in the development of oral chemotherapy and is anexample of a beneficial drugdrug pharmacokineticinteraction.

DistributionAs mentioned above, entrapment of a drug in a vehicle suchas a liposome can substantially reduce the distributionvolume. In the case of doxorubicin, such encapsulationresulted in a change of its toxic-effects profile.18

0

25

50

75

100

125A

B

Topo

teca

n co

ncen

trat

ion

(g/

L)

With coinfusion of indisulam

Without coinfusion of indisulam

With 1000 mg elacridar

Without elacridar

045

040035

030

025

020

015

010

0050

Time after administration (h)

0 2 4 6 8 10 12 14 16 18 20 22 24 26

Acen

ocou

mar

ol c

once

ntra

tion

(m

ol/L

)

Figure 2. A beneficial drugdrug interaction: elacridar boosts the oraluptake and bioavailability of topotecan from 40% to almost 100% (A). Anunwanted drug-drug interaction: the investigational anticancer drugindisulam reduces systemic clearance of acenocoumarol (B).

492



Anticancer drugs can also bind to several bloodcomponents, including albumin, 1 acid glycoprotein,lipoproteins, immunoglobulins, and erythrocytes. Theunbound drug is regarded the biologically active fractionbecause it can extravasate to reach target tissues.Theoretically, drug displacement from blood components ortissue-binding sites increases the apparent distributionvolume. The net pharmacodynamic effect, however, isdifficult to predict because drug displacement with anincrease of the free fraction not only makes the drug moreavailable for its target, but also assists metabolic and renalelimination. The therapeutic implications of displacement of many anticancer drugs from their protein binding have yet to be defined.41 Cytotoxic drugs that are highlyprotein-boundeg, paclitaxel and etoposidehave thepotential to interact with other protein-bound drugs likewarfarin.

MetabolismThe hepatic CYP system is the major site of drugmetabolism, and most drugdrug interactions take place atthis site. For drugs that are administered orally, gut wallCYP3A is probably also of major importance in drugdrugand drug-xenobiotic interactions. Many anticancer drugsare cleared by the CYP3A4 system. There exists, therefore, anotorious potential for drugdrug interaction with bothcytotoxic and non-cytotoxic drugs that share the same CYPmachinery. Anticancer drugs that are (partly) metabolisedby CYP3A4 include the oxazaphosphorines (cyclophos-phamide, ifosfamide) and the taxanes (paclitaxel, docetaxel).Treatments that include these agents are thus at risk whencombined with other CYP3A4 substrates or inhibitors suchas benzodiazepines, antifungals, HIV protease inhibitors,antihistamines, immunosuppressants, and anticonvulsants.12

Cyclophosphamide is a prodrug that needs bioactivationbefore it becomes cytotoxic. The first activation step is thehydroxylation of the parent drug by CYP isozymes to form4-hydroxycyclophosphamide. Several isozymes are involvedin this reaction, including CYP2B6 and CYP3A4. A pharmacokinetic interaction was seen betweencyclophosphamide and thiotepa, which are frequentlycombined in high-dose chemotherapy regimens. Combinedadministration resulted in significantly lower maximumconcentration and AUC values of 4-hydroxycyclo-phosphamide than did individual administration ofcyclophosphamide. In human microsomes, inhibition of theconversion of cyclophosphamide into 4-hydroxycyclophos-phamide by thiotepa was seen at clinically relevantconcentrations, with an IC50 of 23 mol/L.

42,43 Clinicalrelevance remains to be established.

Doxorubicin and vinblastin are metabolised by CYP2D6.Potential interactions could occur with, for example,selective serotonin reuptake inhibitors, tricyclic anti-depressants, and antiarrhytmics.12 As far as we know, no datahave been published about any clinically relevant drugdruginteraction with these agents. Enhanced neurotoxicity,however, was noticed in two patients with acutelymphoblastic leukaemia when vincristine was given withitraconazole.44

In addition to the type of companion drug, the sequenceof their administration can also affect the pharmacokineticinteraction. In a phase I study,45 escalating doses and thesequence of administration of paclitaxel (110200 mg/m2)and cisplatin (5075 mg/m2) were tested. Myelosuppressionwas more pronounced when paclitaxel was given aftercisplatin compared with the alternate sequence. This findingwas explained by a 25% lower paclitaxel clearance whencisplatin preceded paclitaxel than when given after thistaxane, possibly because of its effect on paclitaxel-metabolising CYP enzymes.45

Most of the common CYP isozymes can be induced bycorticosteroids and anticonvulsants.46 Anticonvulsants canchange the pharmacokinetics of anticancer drugs such as theepipodophyllotoxins and topotecan by this mechanism.46,47

An example of how the enzyme-inducer dexamethasonereduces drug toxic effects has been published.48 Clinical useof the new, potent anticancer drug trabectedin is hamperedby its hepatoxicity, as shown by increases in plasmaconcentrations of alkaline phosphatase, aminotransferases,and bilirubin.48 The same effect is seen in rats, with femalerats having higher sensitivity of hepatotoxic effects thanmales. Pretreatment of rats with dexamethasone, however,ameliorates or abrogates the biochemical and histopatho-logical manifestations of trabectedin-induced liver changes,without interfering with the antitumor effectiveness. Thetiming was crucial: dexamethasone administration 24 hbefore trabectedin was effective, whereas coadministrationshowed no protection. It is noteworthy that trabectedinconcentrations were much lower in the liver, but not inplasma, after pretreatment with dexamethasone comparedwith coadministration. Dexamethasone has pleiotropicpharmacological actions, including induction of CYPenzymes, but the exact mechanism of this drugdruginteraction, also tested with other modulators, remains to beelucidated.49,50 Furthermore, studies in humans are needed tosubstantiate the usefulness of this finding in the clinic.

Autoinduction is a mechanism by which a drug inducesits own metabolising enzymes (eg, oxazaphosphorines andthiotepa51), and could thus be regarded as single-druginteractions. Autoinduction becomes apparent by a increasein clearance with time. However, when given together,thiotepa inhibits cyclophosphamide (an oxazaphosphorine)conversion into 4-hydroxycyclophosphamide, turning thiscombination into a complex pharmacology.42 Huitema andcolleagues52 developed an integrated kinetic model with bothinducible and and non-inducible breakdown pathways todescribe the pharmacokinetics both of the parentcyclophosphamide and its active metabolites 4-hydroxy-cyclophosphamide and phosphoramide mustard. Enzymeinduction was represented in terms of rates of formation andelimination of the metabolising enzyme.

Understandably, drugdrug interactions with oralanticoagulants are always of concern, especially when theyare combined with anticancer drugs. Several interactionsbetween anticancer drugs and anticoagulants have been reported, including warfarin and fluorouracil,53

capecitabine,54 paclitaxel,55 ifosfamide and mesna,56 andetoposide and carboplatin.57 Even a low dose (1 mg/day) of

493



warfarin prophylaxis for catheter-associated thrombosis wasaccompanied with a high incidence of INR (internationalnormalised ratio) abnormalities, especially in patientsreceiving fluorouracil, folinic acid, and oxaliplatin.58 Wehave identified a interaction between acenocoumarol andthe investigational, sulphonamide anticancer drugindisulam. Three patients receiving the combinationdeveloped bleeding and high INR values. Indisulam inhibitsCYP2C9, which is the major enzyme involved inacenocoumarol metabolism and which leads to higher AUCvalues of acenocoumarol (figure 2B).59 In general, closemonitoring of coagulation variables is recommended forpatients receiving concomitant anticoagulant andchemotherapy.

In Japan, 15 patients with cancer and herpes zoster diedafter combined use of oral fluorouracil prodrugs (oraltegafur) and the oral antiviral agent sorivudine. Patients diedwith a typical picture of fluorouracil overdose withdiarrhoea, mucositis, leucopenia, and thrombocytopenia.Follow-up toxicological investigations in rats given the combination showed very high concentrations of fluorouracil in plasma and tissues, including bone marrow,liver, and small intestine. All animals died within 10 days. Rats who received tegafur or sorivudine alone werestill alive after 20 days, without notable toxic symptoms.Further studies suggest that sorivudine is converted into (E)-5-(2-bromovinyl)uracil by the gut flora. This compoundforms a reactive intermediate in the presence of NADPH,which irreversibly inhibits dihydropyrimidine dehydro-genase. This process explains the high concentrations offluorouracil, because dihydropyrimidine dehydrogenase is akey enzyme in the catabolism of this drug. Okuda andcolleagues60 comment that this fatal outcome could havebeen prevented if assessments of safety and risk of druginteractions had been considered more carefully duringdevelopment of the antiviral drug

EliminationMost anticancer drugs are eliminated through metabolism.Platinum compounds and methotrexate, however, areeliminated mainly by the kidneys through glomerularfiltration and active tubular secretion. Thus, most concernfor drug interactions relates to the handling of thesecompounds in the kidney. Drugdrug interactionsgenerally involve renal impairment, either by the drug

itself or the concomitant (nephrotoxic) agent. Probenecid,salicylates, and trimethoprim and sulphamethoxazol canincrease plasma concentrations of methotrexate to toxiclevels.61 Non-steroidal anti-inflammatory drugs (NSAIDs)have caused (lethal) toxic effects when given withmethotrexate or cisplatin.8 With low-dose methotrexate(15 mg intramuscularly, once a week) in combination withpantoprazole (20 mg per day, orally) one patient hadsevere myalgia and bone pain.62 After replacement ofpantoprazole by ranitidine the symptoms disappeared, butreappeared when the patient was rechallenged withpantoprazole. Methotrexate concentrations did notchange, but 7-hydroxymethotrexate plasma concentrationsincreased 70% when pantoprazol was given. Themechanism is not clear, although studies from ourinstitute63 suggest that benzimidazoles, such as panto-prazole, interfere with methotrexate transport mediated byBCRP and MRP2. Cisplatin changes the renal clearance oflithium64 and topotecan, which enhanced the toxic effects(myelosuppression).65

Pharmacodynamic interactionsPharmacokinetic drugdrug interactions do not always haverelevant clinical consequences. However, when two drugsshow no pharmacokinetic interactions, they might stillinteract with each other pharmacodynamically (toxic effectsor antitumour activity) in an additive, synergistic, orantagonistic manner. Anticancer drugs are given mostly incombination regimens. Examples are: MOPP (chlormethine,vincristine, procarbazine, and prednisone) for Hodgkinslymphomas and BEP (bleomycin, etoposide, and cisplatin)for testicular cancer. Combination chemotherapy is oftenpreferred to circumvent resistance, to reduce non-overlapping toxic effects, and to benefit from any synergisticantitumour action.

The synergistic cytotoxicity of cisplatin and gemcitabinehas been shown in both in vitro and animal studies, andcombination studies have now started in the clinic; nopharmacokinetic interactions have been noted. The effect ofDNA repair mechanisms has been investigated by use of apanel of cell lines, each of which is deficient in one of the known repair pathways. In the most synergisticcombination, cisplatin followed by gemcitabine, we foundloss of synergy in cell lines deficient for NER (nucleotideexcision repair) and HR (homologous recombination).66

Potential pharmaceutical, pharmacokinetic, and pharmacodynamic interactions in treatment regimens containingcarboplatin and taxol for patients with non-small-cell lung cancer

Drug Dose Action Interaction

Paclitaxel 300 mg CYP3A4 and CYP2C8 substrate, P-glycoprotein on BCRP substrate Pharmacokinetic

Ethanol 25 mL Irreversible CYP inhibition and induction Pharmacokinetic

Polyoxyethylated castor oil 25 mL Emulgator, formation of micelles, P-glycoprotein inhibition Pharmaceutical

Dexamethasone 220 mg CYP induction, CYP3A4 substrate Pharmacokinetic

Clemastine 2 mg Sedating ( ethanol) Pharmacodynamic

Cimetidine 50 mg Inhibition CYP3A4 and gastric alcohol dehydrogenase Pharmacokinetic

Carboplatin 550 mg Thrombocytopenia ( taxol) Pharmacodynamic

Granisetron 1 mg CYP3A3 and CYP3A4 substrate Pharmacokinetic

Specific interaction.

494

Synergism between cisplatin and topotecan could also beexplained at the level of DNA repair.67

That patients with colon cancer have increased responserates when given the combination of fluorouracil andleucovorin compared with fluorouracil alone, suggests thatthe cytotoxic effects of fluorouracil are potentiated bybiochemical modulation with leucovorin. The anabolite 5-fluoro-2deoxyuridine monophosphate inhibits theenzyme thymidylate synthase, which catalyses conversions of5-fluoro-2deoxyuridine monophosphate into thymidine-5-monophosphatea mechanism by which the cofactorN5,N10-methylenetetrahydrofolate donates a methyl group.The stability of the complex between thymidylate synthaseand 5-fluoro-2-deoxyuridine-monophosphate depends onintracellular concentrations of reduced folate. Highconcentrations stabilise the complex and thus reduceenzyme activity. Intracellular concentrations of N5,N10-methylenetetrahydrofolate increase after administration ofleucovorin, which explains the synergism in cytotoxicitywhen fluorouracil and leucovorin are combined. Fluorouracil combined with leucovorin is now part ofstandard care for colorectal cancers.68

When carboplatin and paclitaxel are combined, theincidence and seriousness of thrombocytopenia are less thanexpected on the basis of the carboplatin dose and exposure.69

The mechanism behind this platelet-sparing effect has notbeen elucidated; it cannot be explained pharmacokinetically.Theoretically, this combination has even more interactions.To illustrate, a patient with lung cancer given this standardcombination receives not only carboplatin and paclitaxel,but also 25 mL ethanol, and 25 mL polyoxyethylated castoroil. To prevent allergic reactions, dexamethasone,clemastine, and cimetidine are also given, with granisetronas an antiemetic, which yields several potential interactions(see table).

Over-the-counter and alternative medicinesThe risks associated with alternative (herbal) medicines,over-the-counter products (eg, vitamins, NSAIDs),nutritional supplements, and foodstuffs (eg, grapefruit juice)when used in combination with chemotherapy are of mostconcern. Most of these interactions however are probablygrossly under-reported. Widespread use of these productsand a perceived lack of awareness of risk could confront thepatient and their doctor with sudden, unexpected toxiceffects. High doses of vitamin C acidifies urine, which canlead to acute renal insufficiency when combined, inparticular, with high-dose methotrexate.70 The methotrexatemetabolite, 7-hydroxymethotrexate, is water insoluble andprecipitates in the renal tubules at low pH, leading to renalcomplications. As a result, methotrexate cannot be excretedrenally and will evoke severe, life-threatening toxic effectsthat will need specialist treatment.71

Mathijssen and colleagues72 noted that St Johns Wort(Hypericum perforatum), a popular herbal product used asan antidepressant, interacts with irinotecan. Five patientswith various types of cancer were given 350 mg/m2 irinotecanintravenously with or without 900 mg St Johns Wort once aday, orally, for 18 days. The researchers found that in the

presence of St Johns Wort, the plasma concentrations of theactive metabolite of irinotecan (SN-38) decreased by 42%,and myelosuppression was worse in the absence of St JohnsWort. They conclude that patients on irinotecan should nottake this herb because of the deleterious effects it could haveon treatment outcome.72 Extracts of St Johns Wort containpotent inducers of hepatic enzymes and P-glycoprotein, andinteractions with other drugs have also been seeneg, withthe antiretroviral drug nevirapine.73 Such issues need to becarefully considered.74

Prediction of drug interactionsDrug interactions can cause many clinical problems. Ideally,all this knowledge is available before a new drug entersclinical testing: although translation of preclinical data to theclinic remains cumbersome and will never be perfect, weshould always aim for the maximum attainable therapeuticeffect. It is therefore important to continue the collection ofmore mechanistic and theoretical knowledge about druginteractions. New in vitro and in vivo techniques are alsovery useful in this respect.75 The enzymes that are the maincontributors to the metabolism of a drug can be identifiedeg, from in vitro experiments by use of selective inhibitorsand isolated, purified CYPs or cDNA-expressed CYPs.Transgenic mice expressing human CYPs are good modelsto investigate drugdrug interactions at the level of selectedhuman CYPs.76,77 Computerised methods to make bothqualitative and quantitative predictions have beendesigned.78 These developments will certainly help to makebetter predictions.

Conflict of interestNone declared.

References1 Khler GI, Bode-Bger SM, Busse R, et al. Drugdrug interactions

in medical patients: effects on in-hospital treatment and relation to multiple drug use. Int J Clin Pharmacol Ther 2000; 38:50413.

2 Kuhlmann J, Mueck W. Clinical pharmacological strategies to assess drug interaction potential during drug development. Drug Saf 2001; 24: 71525.

3 Corcoran ME. Polypharmacy in the older patient with cancer.Cancer Control 1997; 4: 41928.

4 Bernard SA, Bruera E. Drug interactions in palliative care. J ClinOncol 2000; 18: 178099.

5 Schinkel AH, Jonker JW. Mammalian drug efflux transporters ofthe ATP binding cassette (ABC) family: an overview. Adv DrugDeliv Rev 2003; 55: 329.

6 Loadman PM, Bibby MC. Pharmacokinetic drug interactions withanticancer drugs. Clin Pharmacokinet 1994; 26: 486500.

7 Van Meerten E, Verweij J, Schellens JHM. Antineoplastic agents:drug interactions of clinical significance. Drug Safety 1995; 12:16882.

8 Balis F. Pharmacokinetic drug interactions of commonly usedanticancer drugs. Clin Pharmacokinet 1986; 11: 22335.



Search strategy and selection criteriaData for this review were identified by searches in PubMed andreferences cited in relevant articles. Search items included:drug interactions, drugdrug interactions, and oncology.Only papers published in English were included. Radiopharma-ceuticals, hormones, immunotherapeutics used in oncologywere considered to be beyond the scope of this report.

495

9 McLeod HL. Clinically relevant drugdrug interactions in oncology.Br J Clin Pharmacol 1998; 45: 53944.

10 Lam MSH, Ignoffo RJ. A guide to clinically relevant drug interactionsin oncology. J Oncol Pharm Pract 2003; 9: 4585.

11 Moosa A, Dobish R, Watts C. Interacting with drugs used inoncology: an Alberta cancer board initiative. J Oncol Pharm Pract2003; 9: 87107.

12 Levy RH, Thummel KE, Trager WF, et al (eds). Metabolic druginteractions. Philadelphia: Lippincott, Williams, and Wilkins, 2000:793.

13 Verschraagen M, Kedde MA, Hausheer FH, Van der Vijgh WJF. The chemical reactivity of BNP7787 and its metabolite mesna withthe cytostatic agent cisplatin: comparsion with the nucleophiledthiosulfate, DDTC, glutathione and its disulfide GSSG. CancerChemother Pharmacol 2003; 51: 499504.

14 Beijnen JH, Lingeman H, Van Munster HA, Underberg WJM.Mitomycin antitumour agents: a review of their physico-chemicaland analytical properties and stability. J Pharm Biomed Anal 1986;4: 27595.

15 Vlasveld LTh, Rankin EM, Rodenhuis S, et al. Reconstitution ofinterleukin-2. Lancet 1990; 336: 446.

16 Nuijen B, Bouma M, Manada C, et al. Compatibility and stability ofthe investigational polypetide marine anticancer agentr kahalalide Fin infusion devices. Invest New Drugs 2001; 19: 27381.

17 Ten Tije AJ, Verweij J, Loos WJ, Sparreboom A. Pharmacologicaleffects of formulation vehicles: implications for cancer chemotherapy.Clin Pharmacokinet 2003; 42: 66585.

18 Safra T. Cardiac safety of liposomal anthracyclines. Oncologist 2003;8 (suppl 2): 1724.

19 Gabison A, Shmeeda H, Barenholz Y. Pharmacokinetics of pegylatedliposomal doxorubicin: review of animal and human studies. ClinPharmacokinet 2003; 42: 41936.

20 Meerum Terwogt JM, Groenewegen G, Pluim D, et al. Phase I and pharmacokinetic study of SPI-77, a liposomal encapsulateddosage form of cisplatin. Cancer Chemother Pharmacol 2002; 49:20110.

21 Kim ES, Lu C, Khuri FR, et al. A phase II study of STEALTH cisplatin(SPI-77) in patients with advanced non-small cell lung cancer. LungCancer 2001; 34: 42732.

22 Sparreboom A, Van Tellingen O, Nooijen WJ, Beijnen JH. Non-linearpharmacokinetics of paclitaxel in mice results from thepharmaceutical vehicle cremophor EL. Cancer Res 1996; 56: 211215.

23 Vaishampayan U, Parchment RE, Jasti BR, Hussain M. Taxanes: anoverview of the pharmacokinetics and pharmacodynamics. Urology1999; 54 (suppl 6A): 2229.

24 Millward MJ, Webster LK, Rischin D, et al.. Phase I trial ofcremophor EL with bolus doxorubicin. Clin Cancer Res 1998;4: 232129.

25 Gennari A, Salvadori B, Donati S, et al. Cardiotoxicity ofepirubicin/paclitaxel-containg regimens: role of cardiac risk factors.J Clin Oncol 1999; 17: 3596602.

26 Danesi R, Innocenti F, Fogli S, et al. Pharmacokinetics andpharmacodynamics of combination chemotherapy with paclitaxeland epirubicin in breast cancer patients. Br J Clin Pharmacol 2002;53: 50818.

27 Kennedy DT, Haynay MS, Lake KD. Azathioprine and allopurinol:The price of an avoidable drug-interaction. Ann Pharmacother 1996;30: 95154.

28 Kruijtzer CMF, Beijnen JH, Schellens JHM. Improvement of oraldrug treatment by temporary inhibition of drug transporters and/orcytochrome P450 in the gastrointestinal tract and liver: an overview.Oncologist 2002; 7: 51630.

29 Sparreboom A, Van Asperen J, Mayer U, et al. Limited oralbioavailability and active epithelial excretion of paclitaxel (taxol)caused by P-glycoproetin in the intestine. Proc Natl Acad Sci USA1997; 94: 203135.

30 Bardelmeijer HA, Van Tellingen O, Schellens JHM, Beijnen JH. The oral route for the administration of cytotoxic drugs: strategies toincrease the efficiency and consistency of drug delivery. Invest NewDrugs 2000; 18: 23140.

31 Malingr MM, Meerum Terwogt JM, Beijnen JH, et al. Phase I andpharmacokinetic study of oral paclitaxel. J Clin Oncol 2000; 18:246875.

32 Kruijtzer CMF, Schellens JHM, Mezger J, et al. Phase II andpharmacologic study of weekly oral paclitaxel plus cyclosporine inpatients with advanced non-small lung cancer. J Clin Oncol 2002;20: 450816.

33 Kruijtzer CMF, Boot H, Beijnen JH, et al. Weekly oral paclitaxel asfirst-line treatment in patienst with advanced cancer. Ann Oncol2003; 14: 197204.

34 Van Asperen J, Van Tellingen O, Sparreboom A, et al Enhancedoral bioavailability of paclitaxel in mice treated with the P-glycoprotein blocker SDZ PSC 833. Br J Cancer 1997; 76: 118183.

35 Bardelmeijer HA, Beijnen JH, Brouwer KR, et al. Increased oralbioavailability of paclitaxel by GF 120918 in mice through selectivemodulation of P-glycoprotein. Clin Cancer Res 2000; 6: 441621.

36 Bardelmeijer HA, Ouwehand M, Buckle T, et al. Low systemicexposure of oral docetaxel in mice resulting from extensive first-pass metabolism is boosted by ritonavir. Cancer Res 2002; 62:615864.

37 Maliepaard M, van Gastelen MA, Tohgo A, et al. Circumvention ofbreast cancer resistance protein (BCRP)-mediated resistance tocamptothecins in vitro using non-substrate drugs or the BCRPinhibitor GF120918. Clin Cancer Res 2001; 7: 93541.

38 Jonker JW, Smit JW, Brinkhuis RF, et al. The multidrug resistanceprotein BCRP restricts the oral bioavailablity and fetal penetrationof topotecan. J Natl Cancer Inst 2000; 92: 165156.

39 Kruijtzer CMF, Beijnen JH, Rosing H, et al. Increased oral bioavail-ability of topotecan in combination with the breast cancerresistance protein and P-glycoprotein inhibitor GF120918. J ClinOncol 2002; 20: 294350.

40 Advani R, Fisher GA, Lum BL, et al. A phase I trial of doxorubicin,paclitaxel and valspodar (PSC833), a modulator of multidrugresistance. Clin Cancer Res 2001; 7: 122129.

41 Stewart CF, Zamboni WC. Plasma protein binding of chemothera-peutic agents. In: A clinicians guide to chemotherapy pharmaco-kinetics and pharmacodynamics. Grochow LB, Ames MM (eds).Baltimore: Williams and Wilkins, 1998: 5566.

42 Huitema ADR, Kerbusch T, Tibben MM, et al. Reduction ofcyclophosphamide-bioactivation of thioTEPA: critical sequence-dependency in high-dose chemotherapy regimens. CancerChemother Pharmacol 2000; 46: 11927.

43 Chen TL, Passos-Coelho JL, Noe DA, et al. Nonlinear pharmaco-kinetics of cyclophosphamide in patients with metastatic breastcancer receiving high-dose chemotherapy followed by autologousbone marrow transplantation. Cancer Res 1995; 55: 81016.

44 Gillies J, Hung KA, Fitzsimons E, Soutar R. Severe vincristinetoxicity in combination with itraconazole. Clin Lab Haematol 1998;20: 12324.

45 Rowinsky EK, Gilbert MR, McGuire WP, et al. Sequences of taxoland cisplatin: a phase I and pharmacologic study. J Clin Oncol 1991;9: 1692703.

46 Vecht CJ, Wagner GL, Wilms EB. Interactions betweenantiepileptic and chemotherapeutic drugs. Lancet Neurol 2003; 2:40409.

47 Zamboni WC, Gajjar AJ, Heideman RL, et al. Phenytoin alters thedisposition of topotecan and N-desmethyl topotecan in a patientwith medulloblastoma. Clin Cancer Res 1998; 4: 78389.

48 Van Kesteren Ch, De Vooght MM, Lopez-Lazaro L, et al. Yondelis(trabectedin, ET-743): the development of an anticancer agent ofmarine origin. Anti-Cancer Drugs 2003; 14: 487502.

49 Donald S, Verschoyle RD, Greaves P, et al. Complete protection byhigh dose dexamethasone against the hepatotoxicity of the novelantitumor drug yondelis (ET-743) in the rat. Cancer Res 2003;63: 590208.

50 Donald S, Vreschoyle RD, Greaves P, et al. Comparison of fourmodulators of drug metabolism as protectants against the hepato-toxicity of the novel antitumor drug yondelis (ET-743) in thefemale rat and in hepatocytes in vitro. Cancer Chemother Pharmacol2004; 53: 30512.

51 Kaijser GP, Beijnen JH. Oxazaphosphorines: cyclophosphamideand ifosfamide. In: Grochow LB, Ames MM (eds). A cliniciansguide to chemotherapy pharmacokinetics and pharmacodynamics.Baltimore: Williams and Wilkins, 1998: 22958.

52 Huitema ADR, Matht RAA, Tibben MM, et al. A mechanism-based pharmacokinetic model for the cytochrome P450 drugdruginteraction between cyclophosphamide and thioTEPA and theautoinduction of cyclophosphamide. J Pharmacokinet Pharmacodyn2001; 28: 21130.

53 Brown MC. An adverse interaction between warfarin and 5-fluoro-uracil: a case report and review of the literature. Chemotherapy1999; 45: 39295.

54 Copur MS, Ledakis P, Bolton M, et al. An adverse interactionbetween warfarin and capecitabine: a case report and review of theliterature. Clin Colorectal Cancer 2001; 1: 18284.



496

55 Thompson ME, Highley MS. Interaction between paclitaxel andwarfarin. Ann Oncol 2003; 14: 500.

56 Hall G, Lind MJ, Huang M, et al. Intravenous infusions ofifosfamide/mesna and perturbation of warfarin anticoagulantcontrol. Postgrad Med J 1990; 66: 86061.

57 Le AT, Hasson NK, Lum BL. Enhancement of warfarin response in apatient receiving etoposide and carboplatin chemotherapy. Ann Pharmacother 1997; 31: 100608.

58 Masci G, Magagnoli M, Zucali PA, et al. Minidose warfarinprophylaxis for catheter-associated thrombosis in cancer patients :can it be safely associated with fluorouracil-based chemotherapy? J Clin Oncol 2003; 21: 73639.

59 Van den Bongard HJGD, Sparidans RW, Critchley DJP, et al.Pharmacokinetic drugdrug interaction of the novel anticanceragent E7070 and acenocoumarol. Invest New Drugs 2004; 22:15158.

60 Okuda H, Nishiyama T, Ogura Y, et al. Lethal drug interactions ofsorivudine, a new antiviral drug, with oral 5-fluorouracil prodrugs.Drug Metab Dispos 1997; 25: 27073.

61 Bannwarth B, Pehourcq F, Schaeverbeke T, Dehais J. Clinicalpharmacokinetics of low-dose pulse methotrexate in rheumatoidarthritis. Clin Pharmacokinet 1996; 30: 194210

62 Trger U, Sttzel B, Martens-Lobenhoffer J, et al. Severe myalgiafrom an interaction between treatments with pantoprazole andmethotrexate. BMJ 2002; 324: 1497.

63 Breedveld P, Zelcer N, Pluim D, et al. Mechanism of thepharmacokinetic interaction between methotrexate andbenzimidazoles: potential role for BCRP in clinical drugdruginteractions. Cancer Res (in press).

64 Beijnen JH, Bais EM, Ten Bokkel Huinink WW. Lithiumpharmacokinetics during cisplatin based chemotherapy. CancerChemother Pharmacol 1994; 33: 52326.

65 Rowinsky EK, Kaufmann SH, Baker SD, et al. Sequences oftopotecan and cisplatin: phase I, pharmacologic, and in vitro studies to examine sequence dependence. J Clin Oncol 1996;14: 307484.

66 Crul M, Van Waardenburg RC, Bocxe S, et al. DNA repairmecahnisms involved in gemcitabine cytotoxicity and in the

interaction between gemcitabine and cisplatin. Biochem Pharmacol2003; 65: 27582.

67 Crul M, Van Waardenburg RC, Beijnen JH, Schellens JHM. DNA-based drug interactions of cisplatin. Cancer Treat Rev 2002; 28:291303.

68 Grogan L, Sotos GA, Allegra CJ. Leucovorin modulation offluorouracil. Oncology 1993; 7: 6372.

69 Huizing MT, Giaccone G, Van Warmerdam LJC, et al.Pharmacokinetics of paclitaxel and carboplatin in a dose escalatingand sequencing study in patients with non-small cell lung cancer. J Clin Oncol 1997; 15: 31729.

70 Sketris IS, Farmer PS, Fraser A. Effect of vitamin C on the excretionof methotrexate. Cancer Treat Rep 1984; 68: 44647.

71 Van den Bongard HJGD, Matht RAA, Boogerd W, et al. Successfulrescue with leucovorin and thymidine in a patient with high-dosemethotrexate induced acute renal failure. Cancer ChemotherPharmacol 2001; 12: 53740.

72 Mathijssen RHJ, Verweij J, De Bruijn P, et al. Effects of St JohnsWort on irinotecan metabolism. J Natl Cancer Inst 2002; 94:124749.

73 De Maat MMR, Hoetelmans RMW, Matht RAA, et al. Drug inter-action between St Johns Wort and nevirapine. AIDS 2001; 15: 42021.

74 Block KI, Gyllenhaal C. Clinical corner: herb-drug interactions incancer chemotherapy: theoretical concerns regarding drugmetabolizing enzymes. Integrative Cancer Ther 2002; 1: 8389.

75 Brandon EF, Raap CD, Meijerman I, et al. An update on in vitro testmethods in human hepatic drug biotransformation research: prosand cons. Toxicol Appl Pharmacol 2003; 189: 23346.

76 Granvil CP, Yu AM, Elizondo G, et al. Expression of the humanCYP3A4 gene in the small intestine of transgeneic mice: in vitrometabolism and pharmacokinetics of midazolam. Drug Metab Disp2003; 31: 54858.

77 Imaoka S, Hayashi K, Hiroi T, et al. A transgenic mouse expressinghuman CYP4B1 in the liver. Biochem Biophys Res Commun 2001;284: 75762.

78 Bonnabry P, Sievering J, Leemann, Dayer P. Quantitative druginteractions prediction system (Q-DIPS). Clin Pharmacokinet 2001;40: 63140.



Drug interactions in oncologyPharmaceutical interactionsPharmacokinetic interactionsAbsorptionDistributionMetabolismEliminationPharmacodynamic interactionsOver-the-counter and alternative medicines

Prediction of drug interactionsReferences

Documents

Drug Interactions in Oncology