Clin Pharmacokinet 2003; 42 (3): 223-282 DRUG INTERACTIONS 0312-5963/03/0003-0223/$30.00/0 © Adis International Limited. All rights reserved. Drug Interactions Between Antiretroviral Drugs and Comedicated Agents Monique M.R. de Maat,1 G. Corine Ekhart,1 Alwin D.R. Huitema,1 Cornelis H.W. Koks,1 Jan W. Mulder2 and Jos H. Beijnen1,3 1 Department of Pharmacy and Pharmacology, Slotervaart Hospital, Amsterdam, The Netherlands 2 Department of Internal Medicine, Slotervaart Hospital, Amsterdam, The Netherlands 3 Faculty of Pharmaceutical Sciences, University of Utrecht, Utrecht, The Netherlands Contents Abstract . 223 1. Methods . 224 2. Pharmacokinetics of Antiretroviral Drugs . 225 2.1 Nucleoside Reverse Transcriptase Inhibitors . 225 2.2 Non-Nucleoside Reverse Transcriptase Inhibitors . 225 2.3 Protease Inhibitors . 225 3. Mechanisms of Drug Interaction . 225 3.1 Pharmacokinetic Interactions . 227 3.1.1 Drug Absorption . 227 3.1.2 Metabolism and P-Glycoprotein . 227 3.1.3 Protein Binding . 273 3.1.4 Excretion . 274 3.2 Pharmacodynamic Interactions . 274 3.2.1 Efficacy . 274 3.2.2 Toxicity . 274 4. Practical Issues for Use of Interactions Table . 274 5. Conclusions . 275 Abstract HIV-infected individuals usually receive a wide variety of drugs in addition to their antiretroviral drug regimen. Since both non-nucleoside reverse trans- criptase inhibitors and protease inhibitors are extensively metabolised by the cytochrome P450 system, there is a considerable potential for pharmacokinetic drug interactions when they are administered concomitantly with other drugs metabolised via the same pathway. In addition, protease inhibitors are substrates as well as inhibitors of the drug transporter P-glycoprotein, which also can result in pharmacokinetic drug interactions. The nucleoside reverse transcriptase inhib- itors are predominantly excreted by the renal system and may also give rise to interactions. This review will discuss the pharmacokinetics of the different classes of anti- retroviral drugs and the mechanisms by which drug interactions can occur. Fur- 224 de Maat et al. thermore, a literature overview of drug interactions is given, including the fol- lowing items when available: coadministered agent and dosage, type of study that is performed to study the drug interaction, the subjects involved and, if specified, the type of subjects (healthy volunteers, HIV-infected individuals, sex), anti- retroviral drug(s) and dosage, interaction mechanism, the effect and if possible the magnitude of interaction, comments, advice on what to do when the interac- tion occurs or how to avoid it, and references. This discussion of the different mechanisms of drug interactions, and the ac- companying overview of data, will assist in providing optimal care to HIV- infected patients. The treatment of HIV-1 infection has been im- same pathway. Awareness, recognition and man- proved markedly during recent years by the intro- agement of drug interactions are important in duction of new classes of antiretroviral drugs, re- the optimisation of pharmaceutical care to HIV- sulting in decreased morbidity and mortality.[1-3] infected patients, helping to prevent adverse Antiretroviral therapy generally involves combi- events and/or loss in efficacy of the drugs admin- nation therapy and consists typically of three or istered.[8-11] This review presents a tabulated over- four drugs, in most cases from different drug view of interactions of antiretroviral drugs and classes.[4] Although regimens have recently be- comedicated agents based on drug-drug interaction come more convenient after the reduction in di- studies, case reports, population pharmacokinetic etary restrictions and pill burden due to (i) the im- data, in vitro studies and theoretical grounds. Fur- plementation of boosting protease inhibitors (PIs) thermore, a concise review is presented of the phar- with ritonavir[4,5] and (ii) the introduction of co- macokinetics and mechanisms of interaction of formulations (lopinavir and ritonavir [Kaletra1]; antiretroviral drugs. lamivudine, zidovudine, and abacavir [Trizivir®]; lamivudine and zidovudine [Combivir®]), the treat- 1. Methods ment still requires much attention. HIV-infected individuals usually have an im- A Medline search was performed using the key- paired immune response. Therefore, they are fre- words ‘human immunodeficiency virus’, ‘pharma- quently confronted with opportunistic infections cokinetics’, ‘metabolism’, ‘drug interactions’ and and malignancies. In addition, comorbidity such as the names of the individual antiretroviral drugs. drug dependence, psychiatric disorders, neurolog- Information gathered from a review of the litera- ical manifestations of HIV disease (HIV-1 demen- ture, including peer-reviewed journals, abstracts tia complex) or hepatic disease may also be pres- from large congresses, review articles and package ent. Due to this comorbidity, a wide variety of inserts, has been incorporated in the overview. The drugs (e.g. antidepressives or antibacterials) is drug interactions were tabulated with the com- used in addition to the antiretroviral regimen. edicated agent (as a single drug or as a specific Since both non-nucleoside reverse transcriptase in- drug class) in alphabetical order. The following hibitors (NNRTIs) and PIs are extensively metabo- items were described in as much detail as possible: lised by the cytochrome P450 (CYP) system,[6,7] coadministered agent and dosage, type of study there is a considerable potential for pharmacoki- that was performed to study the specific drug inter- netic interactions when these drugs are adminis- action, the subjects involved and, if specified, the kind of subjects (healthy volunteers, HIV-infected tered concomitantly with drugs metabolised via the individuals, sex), antiretroviral drug and dosage, 1 Use of tradenames is for product identification only and mechanism of interaction, the effect, comments, does not imply endorsement. advice on what to do when the interaction occurs Adis International Limited. All rights reserved. Clin Pharmacokinet 2003; 42 (3) Drug Interactions with Antiretrovirals 225 or how to avoid the interaction, and references are extensively metabolised by the liver via the used to assemble the information. Advice on how CYP enzyme system. Besides substrates, NVP and to cope with specific interactions will be given as EFV are both inducers of CYP3A4, whereas DLV completely and clearly as possible. This review acts as a potent inhibitor of CYP3A4.[50] In addi- will only focus on drug interactions between anti- tion, in vitro studies showed that EFV inhibits retroviral drugs and comedicated agents, and not CYP2C9, 2C19 and 3A4.[30] Therefore, drug inter- on drug interactions among antiretroviral drugs. actions can be anticipated if the NNRTIs are For information on this subject, we refer to earlier coadministered with other drugs that are metabo- published reviews.[12-15] lised via the same metabolic pathway. Table I sum- marises the pharmacokinetic parameters of the dif- 2. Pharmacokinetics of ferent NNRTIs, including the specific enzymes Antiretroviral Drugs involved in their metabolism. 2.1 Nucleoside Reverse 2.3 Protease Inhibitors Transcriptase Inhibitors Six PIs are currently commercially available At this moment, six representatives of this class for the treatment of HIV-1-infection: amprenavir are licensed: zidovudine (AZT), didanosine (DDI), (AMP), indinavir (IDV), ritonavir (RTV), lop- zalcitabine (DDC), stavudine (D4T), lamivudine inavir (LPV) [coformulated with a low dose of (3TC), and abacavir (ABC). The NRTIs are pro- RTV], nelfinavir (NFV), and saquinavir (SQV) drugs that require intracellular phosphorylation to [formulated as hard or soft gelatin capsules]. The the active dideoxynucleoside triphosphates, which target of these drugs is the viral protease that is a compete with the natural substrates for HIV re- key enzyme in the synthesis of structural proteins verse transcriptase (deoxynucleoside triphos- and replicative enzymes. Inhibition of the viral phates) for incorporation into newly synthesised protease leads to production of noninfectious virus proviral DNA. The NRTIs lack a 3′-hydroxyl particles.[51,52] Pharmacokinetic parameters and group, thereby preventing growth of the DNA and metabolic pathways of each PI are listed in table I. resulting in termination of virus replication.[16] As As can be observed, CYP3A isoenzymes are pre- a class, the NRTIs are predominantly excreted by dominantly responsible for the metabolism of the the renal system (tubular secretion) and interac- PIs. In addition, all PIs are inhibitors of CYP3A. tions based upon CYP are not regularly encoun- Both RTV and LPV have also CYP-inducing prop- tered.[17] However, drugs influencing renal clear- erties. Besides being substrates of CYP, PIs are ance or intracellular phosphorylation may cause also substrates and can act as inhibitors of P- drug interactions with the NRTIs. Table I presents glycoprotein, a transmembrane glycoprotein that an overview of the pharmacokinetic parameters of functions as an energy-dependent efflux pump each NRTI. for a wide variety of structurally unrelated com- pounds.[53-55] Furthermore, the multidrug resis- 2.2 Non-Nucleoside Reverse tance associated proteins, MRP1 and possibly Transcriptase Inhibitors MRP2, are known to be involved in the disposition of the PIs.[53] These transporter proteins are also Currently, three drugs from this class are avail- involved in drug efflux. able: nevirapine (NVP), efavirenz (EFV) and delavirdine