Clin Pharmacokinet 2003; 42 (3): 223-282 DRUG INTERACTIONS 0312-5963/03/0003-0223/$30.00/0

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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 [Kaletra1]; 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

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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), (EFV) and delavirdine (DLV). In contrast to the NRTIs, the 3. Mechanisms of Drug Interaction NNRTIs are not incorporated in the proviral DNA, but bind directly to the viral reverse transcriptase Drug interactions are of pharmacokinetic or to block polymerase activity by causing a disrup- pharmacodynamic nature or consist of a combina- tion of the enzyme catalytic site.[6] The NNRTIs tion of both. Generally, pharmacokinetic interac-

 Adis International Limited. All rights reserved. Clin Pharmacokinet 2003; 42 (3) 226 de Maat et al. 3A, 2D6 Inhibition of CYP 3A4 3A4 = soft gel capsules; SGC 3A, 2C9 of CYP = minimum drug concentration; min C = once daily; = once 3A4, 2D6, 2C9/19 3A4, 2B6 3A43A4, 2B6 2B6 3A4, 2C9/19, 3A4 3A43A43A4 GT3A, 2D6 3A4 3A4 GT, 1A2, 3A4 2D6 3A4, 3A4 3A4, 2C9 /19, 2D6 qd e e b b (morning) (evening) f b b b b b 0.13 0.03 ± 4.6 4.0 2.6 ± 0.4 1.3 (mg/L) Metabolism Induction ± ± ± ± ± min <0.1 GT ADH, <0.026.8 1.55 GT (0.93–2.04) 3.72 (3.07–4.91) 0.32 (77) 0.18 5.5 2.2 3.7 0.04 0.7 = data not available; NA e e b b b b = maximum drug concentration; f

b b 9.1 2.87 3.6 max ± ± 4.4 0.89 1.6 ± (mg/L) C C ± ± ± c max 1.2 16.0 3.63 (2.61–5.37) 5.86 (5.52–7.22) 7.55 (54) 8.98 9.6 0.2 2.2 0.07 3A4 3A4 C 3.0 3.0 11.2 e e b b b b b b = hard gel capsules; = twice daily; 45.7 6.1 7.8 44.5 h/L) ± 6.2 ± ± ± 0.5 a • ± ± c bid HGC (mg 82.2 7.2 (33.3–66.6) (48.0–72.0) 18.9 20.2 82.8 0.9 (h) AUC β 2 ⁄ 1 t binding (%) 98 2–11 97 1.5 = glucuronosyltransferase; GT h d F (%) Protein = area under the concentration-time curve; AUC dosage (mg) 300 bid200 bid150 bid 8340 bid 420.75 tid 86 50300 bid 86 5 >80 <36%400 tid 1.5 65 5 5 5–7 1.5600 qd 6.02 85 34–38 12200 bid 1.2 1.4 NA 2 1 90 1.91200 bid >99 0.07 2.0 1.5 0.9800 tid 60 35–90400 bid 18–51750 tid 0.85 90 70 54.8 0.03 NA 0.1 12–22 <0.01 600 bid 70–80 54.5 60 2–10 0.02 98–99600 tid >98 <0.005 60–801200 tid 5–6 1–2 98–99 4 3.5–5 331 3–5 15.5 98 78 1.5 = oral bioavailability; F = elimination half-life.

β 2 ⁄ 1 t [45-47] [46,48,49] [17,22] [36] [17,20,21] [6,28,29] standard deviation. [17,25-27] [24] [33-35] [39,40] [17,23] ± [30-32] [41,42] g [43,44] [17-19] [37,38] Steady-state pharmacokinetics of the antiretroviral drugs = dehydrogenase; = cytochrome P450; = thrice daily; tid Saquinavir HGC Nucleoside reverse transcriptase inhibitors Abacavir Didanosine Non-nucleoside reverse transcriptase inhibitors Delavirdine c 200mg single dose. After d Relative to oral solution. e Median (interquartile range). f Mean (% coefficient of variation). g In combination with ritonavir 100mg bid. h Relative to saquinavir HGC. ADH a During one administration interval of a typical adult dose. b Mean CYP Table I. Drug Typical adult Efavirenz Nevirapine Protease inhibitors Amprenavir Indinavir Lopinavir Nelfinavir Saquinavir SGC Lamivudine Stavudine Zalcitabine Zidovudine Ritonavir

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tions involve alterations in absorption, transport, ation of the quinolone with the cations in the DDI distribution, metabolism or excretion of a drug. formulation, leading to a significant decrease in The results of these interactions can be a decreased the AUC of the quinolone (table III).[76] This type or an increased exposure, which in turn can lead to of drug interaction can easily be avoided by sepa- reduced efficacy or increased toxicity, respec- ration of drug administration. Alternatively, the tively. Pharmacodynamic interactions are those new, enteric-coated formulation of DDI,[21,126] where the pharmacological response to a drug is which lacks the buffer, could be used. directly altered. This can lead to potentiation of Change in gastrointestinal motility can also in- effect (including toxicity) in either an additive or fluence drug absorption. For instance, methadone synergistic manner, or antagonism. decreases D4T absorption by decreasing gastroin- Table II presents the comedicated drugs (with testinal motility, which results in a 25% reduction abbreviations) that are involved in the drug inter- in the AUC of D4T (table III).[144] actions that are displayed in table III. Mechanisms that may be involved in these drug interactions are 3.1.2 Metabolism and P-Glycoprotein outlined in the following sections. Metabolism of most drugs occurs by the liver via phase I reactions (involving oxidation, reduc- 3.1 Pharmacokinetic Interactions tion and hydrolysis) into more polar compounds. In addition, phase II reactions involve conjugation 3.1.1 Drug Absorption of the drugs. The metabolites formed are usually All currently available antiretroviral drugs are pharmacologically inactive. Both types of reac- given orally and require absorption through the tions result in more water-soluble compounds that mucous membranes of the gastrointestinal tract. A are more easily excreted by the kidneys. The most dramatic change in plasma concentrations can be important enzymes involved in phase I reactions the result of incomplete drug absorption. A clear are the CYP enzymes,[228] a family of mixed func- distinction must be made between an effect on the tion oxidases that account for the majority of oxi- rate of absorption or the total amount absorbed. For dative biotransformations of xenobiotics and drugs used long-term, which is the case in the treat- endogenous biochemicals.[229] These metabolic ment of HIV-1-infection, the rate of absorption is enzymes can both be induced and inhibited. It may usually of less importance, provided that the total take days to up to 2–3 weeks, depending on the amount absorbed is not markedly changed. A va- drug and its dosage, to fully develop enzyme in- riety of mechanisms could lead to reduced or in- duction. Enzyme induction can lead to an in- creased absorption from the gastrointestinal tract. creased (in case of the use of a prodrug) as well as Both DLV and IDV need normal gastric (acidic) a decreased drug effect. Another process involves pH for optimum absorption.[28,37] The concomitant enzyme inhibition, which unlike enzyme induc- administration of DLV with antacids led to im- tion, can occur almost immediately. paired absorption of DLV, yielding a decrease of In humans, CYP3A is the largest fraction of the 41% in the area under the plasma concentration- total CYP content.[230] CYP3A4 is responsible for time curve (AUC) [table III].[28] A similar effect the metabolism of a broad spectrum of drugs, in- on IDV when coadministered with antacids can be cluding the PIs and the NNRTIs (table I). Further- expected. more, CYP3A4 is located in the small bowel and Originally, DDI tablets were formulated with a liver and is, therefore, also involved in presystemic buffer (because of instability of DDI in the pres- (first-pass) metabolism.[229] ence of gastric acid) that contains calcium carbon- As mentioned earlier, P-glycoprotein acts as an ate and magnesium hydroxide and can influence energy-dependent efflux pump that exports sub- drug absorption.[20] Coadministration of fluoro- strates out of the cell. P-glycoprotein is expressed quinolones and these tablets results in complex- in the epithelial cells of the gastrointestinal tract,

 Adis International Limited. All rights reserved. Clin Pharmacokinet 2003; 42 (3) 228 © Adis International Limited. Allrights reserved. Table II. Index and abbreviations of the coadministered drugs involved in drug interactions with antiretrovirals Coadministered Abbreviation Coadministered Abbreviation Coadministered Abbreviation Coadministered Abbreviation Coadministered Abbreviation drug drug drug drug drug Acenocoumarol ACE CLR γ-Hydroxybutyrate GHB Morphine MOR Ranitidine RAN Acetylsalicylic ASA Clozapine CLZ Ganciclovir GAN Mucosal MUC Ribavirin RIB acid (aspirin) protectives Albendazole ALB Codeine COD Garlic GAR Nefazodone NEF Rifabutin RFB supplements Alendronate See Corticosteroidsa COR Gemfibrozil GEM Nicardipine See calcium Rifampicin RIF bisphosphonates channel (rifampin) antagonists Alfentanil ALF See Gentamicin See Nifedipine See calcium Risperidone RIS aminoglycosides channel antagonists Alimemazine ALI Cyclophosphamide CYC GLU Nimodipine See calcium Roxithromycin ROX channel antagonists See barbiturates Cyclosporin CsA Grapefruit juice GRJ Nisoldipine See calcium Salicylic acid SAC channel antagonists Allopurinol ALU Dapsone DAP Haloperidol HAL Nitrendipine See calcium See channel barbiturates antagonists ALP Daunorubicin DAU Heptobarbital See Nitrofurantoin NIT Sertraline See SSRIs barbiturates Amikacin See Demeclocycline See See Nizatidine NIZ SSRIs SSRI aminoglycosides tetracyclines barbiturates Aminoglycosides AMG Desipramine DES Hydralazine HYD Norethindrone See oral Sildenafil SIL contraceptives Amiodarone AMI Dexamethasone DEX Hydroxycarbamide HYX Norfloxacin See Simvastatin SIM fluoroquinolones Clin Pharmacokinet 2003;42(3) Amitriptyline See tricyclic Dextropropoxyphene DRX Ifosfamide IFS Nortriptyline See tricyclic Sirolimus SIR antidepressants antidepressants

Amlodipine See calcium DIA Imipramine See tricyclic Ofloxacin See Sparfloxacin See

channel antidepressants fluoroquinolones fluoroquinolones de Maatet al. antagonists See barbiturates Digoxin DIX Interferon-α INFα Olanzapine OLE St Johns wort SJW Drug InteractionswithAntiretrovirals © Adis International Limited. Allrights reserved. Amphotericin B AMB See ergot Interleukin-2 IL-2 Omeprazole OME Streptomycin See amino- derivatives glycosides Antacids ANT Diltiazem DIL Iodoquinol IDO Oral OC Sulfadiazine SUF contraceptives See barbiturates Disopyramide DSP Isoniazid INH OXE Sulfamethoxazole SUL Astemizole AST Disulfiram DIS Isotretinoin ISO Oxytetracycline See Tacrolimus TAC tetracyclines Atorvastatin ATR Dothiepin See tricyclic Isradipine See calcium Pamidronate See Tamoxifen TAM antidepressants channel bisphosphonates antagonists Atovaquone ATO Doxepin See tricyclic Itraconazole ITR Paclitaxel PAC Terfenadine TER antidepressants Aurothioglucose AUR Doxorubicin DOX Ketoconazole KET Paroxetine See SSRIs Tetracycline See tetra- cyclines Azithromycin AZI Doxycycline See Lacidipine See calcium Pefloxacin See Tetracyclines TET tetracyclines channel fluoroquinolones antagonists See barbiturates Encainide ENC Lansoprazole LAN Pentamidine PET Thalidomide THA Barbiturates BAR Etidronate See Levodopa DOP See Theophylline THE bisphosphonates barbiturates

Bepridil BEP Ergotamine See ergot Levofloxacin See Perazine PER Thioridazine THI derivatives fluoroquinolones

Bisphosphonates BIP Ergonovine See ergot Levomepromazine LEP Periciazine PEC Tiludronate See bisphos- derivatives phonates See barbiturates Ergot derivatives ERD Levothyroxine LEV Perphenazine PEZ Timolol TIM Bupropion BUP Erythromycin ERY Lidocaine LID PHB, see Tiotixene TIO barbiturates See barbiturates Ethambutol ETH Lomefloxacin See PHT Tramadol TRM fluoroquinolones Clin Pharmacokinet 2003;42(3)

Butobarbital See barbiturates Ethanol ETN Loperamide LOP Pimozide PIM Trazodone TRA Calcium channel CAC Ethinylestradiol See oral Loratadine LOR Pipotiazine PIP TRI antagonists contraceptives 229 Continued over page 230 © Adis International Limited. Allrights reserved. Table II. Contd Coadministered Abbreviation Coadministered Abbreviation Coadministered Abbreviation Coadministered Abbreviation Coadministered Abbreviation drug drug drug drug drug

Carbamazepine CAR Ethionamide ETI Lovastatin LOV Piroxicam PIR Tricyclic TRC antidepressants Chloramphenicol CHA Ethosuximide ETX Maprotiline See tricyclic Pravastatin PRA Trifluoperazine TRF antidepressants CHL Famotidine FAM MDMA MDMA PRZ Triflupromazine TRP Chlorpromazine CHP Felodipine See calcium Mebendazole MEB Prednisone PRE Trimethoprim TMP channel antagonists Chlortetracycline See Fentanyl FEN Medroxypro- MED Prednisolone PRD Trimipramine See tricyclic tetracyclines gesterone antidepressants Cimetidine CIM Flecainide FLE Mefloquine MEF Primaquine PRQ Tobramycin See amino- glycosides Ciprofloxacin CIP Fluconazole FLC Meperidine MEP PRI Trovafloxacin See fluoro- (pethidine) quinolones Cisapride CIS Flucytosine FLY Methadone MET Probenecid PRO Valproic acid VAL Cisplatin CIT Fluticasone See Methylergonovine See ergot Prochlorperazine PRC Verapamil VER corticosteroids derivatives Citalopram See SSRIs Fluoroquinolones FLQ Methylpheno- See Promethazine PRM Vincristine VIN barbital barbiturates Clarithromycin CLA FLX, see Metoprolol MEO Propafenone PRP Warfarin WAR SSRIs Clindamycin CLI FLU Metronidazole MEN Pyrazinamide PYR ZOL Clodronate See Fluvoxamine See SSRIs Mexiletine MEX Pyrimethamine PYM bisphosphonates

Clomipramine See tricyclic Foscarnet FOS MID Quinidine QUI antidepressants Clin Pharmacokinet 2003;42(3) CLO Fusidic acid FUA Minocycline See Quinine QUN tetracyclines de Maatet al.

a Inhaled or rectal. MDMA = methylenedioxymethamphetamine; SSRI = selective serotonin reuptake inhibitor. Drug InteractionswithAntiretrovirals © Adis International Limited. Allrights reserved. Table III. Overview of drug interactions of antiretrovirals drugs and coadministered drugs Coadministered agent Type of study Subjects Antiretroviral agent Interaction Effect of interaction Comments Advice References and dosage involved (n) and dosage mechanism Acenocoumarol (ACE) T AMP, DLV, EFV, Inhibition CYP3A? Conc. ACE ↑ (PI/DLV) Based on case Monitor INR 28 IDV, LPV/RTV, by PI; inhibition or ↓ (EFV/NVP) report with RTV NFV, NVP, SQV CYP2C9/2C19 by DLV/NFV?; induction CYP3A? by EFV/NVP T RTV Induction Conc. ACE ↓ Monitor INR 43,56 CYP2C9, 3A? by RTV Case report 1 HIV+, RTV Anticoagulant activity ↓, female prothrombin test ↑ Acetylsalicylic acid (ASA) In vitro AZT Inhibition of 0.5 mmol/L 97.8% Conc. AZT Monitor blood 57 (human liver glucuronidation by enzyme activity probably ↑; counts regularly microsomes) ASA remained; 10 mmol/L significance? 43.9% emzyme activity remained Albendazole (ALB) T RTV Inhibition/induction Conc. ALB ↑ or ↓ Influence on Monitor efficacy 58 CYP3A by RTV first pass, ALB, monitor hepatic leucocytes and elimination? LEs regularly Alfentanil (ALF) T AMP, DLV, IDV, Inhibition CYP3A Conc. ALF ↑ Based on study Monitor for [see also fentanyl] LPV/RTV, NFV, by PI/DLV with fentanyl increased RTV, SQV respiratory depression Alimemazine (ALI) T RTV Inhibition CYP2D6 Conc. ALI ↑; conc. Based on Monitor for ↑ by RTV, ALI RTV ↑ interaction with sedation. Dosage perphenazine reduction ALI, RTV may be needed. TDM RTV recommended.

Clin Pharmacokinet 2003;42(3) Allopurinol (ALU) S 2 HIV+ DDI single dose Inhibition tubular AUC, Cmax DDI ↑ Coadministration 20,21 300mg/day 200mg secretion by ALU? 312%, 232%, resp. not recommended

ALU 7 days 300mg/day S 14 vol Single dose 400mg AUC, Cmax DDI ↑ 113%, 69%, resp. Alprazolam (ALP) T AMP, DLV, EFV, Inhibition CYP3A Conc. ALP ↑ (PI/DLV) Risk for ↑ Coadministration 28,36 IDV, LPV/RTV, by PI/DLV, or ↓ (EFV/NVP) (PI/DLV) or ↓ not NFV, NVP, SQV induction CYP3A (EFV/NVP) recommended; by EFV/NVP sedation. A = oxazepam,

231 Continued over page 232 © Adis International Limited. Allrights reserved. Table III. Contd Coadministered agent Type of study Subjects Antiretroviral agent Interaction Effect of interaction Comments Advice References and dosage involved (n) and dosage mechanism ALP single dose 1mg Open-label 12 vol RTV 10 days Induction CYP3A4 AUC ALP ↓ 12%, During initial Coadministration 43,59-61 crossover 500mg bid by RTV Cmax ↓ 15.7% exposure not (escalation inhibition may recommended; scheme) predominate, A = oxazepam, while during lorazepam extended exposure induction may offset inhibition ALP single dose 1mg Double-blind, 10 vol RTV 200mg bid Inhibition hepatic CL ALP ↓ 41%, randomised, 2- (4 doses) CYP3A4 by RTV ↑ sedation way crossover Aminoglycosides (AMG) T DDC Inhibition of renal Increased risk for Frequent 24 elimination by peripheral neuropathy, clinical/laboratory AMG other AE monitoring. Adjust dosage DDC based on renal function Amiodarone (AMI) T AMP, DLV, EFV, Inhibition CYP3A Conc. AMI ↑ (PI/DLV) May result in CI (NFV, RTV), 28,36,39, LPV/RTV, NFV, by PI/DLV, or ↓ (EFV/NVP) potential dose increase 41,43 NVP, RTV, SQV induction CYP3A serious or life- (+NVP/EFV), by EFV/NVP threatening reduction AEs. (+PI/DLV) AMI may be needed, TDM AMI recommended AMI 200mg/day ss Case report 1 HIV+ IDV 800mg tid Inhibition hepatic Conc. AMI 0.9 → 1.3 Not above TDM AMI 62 CYP3A by IDV mg/L (↑ 44%) therapeutic recommended window in this case, but higher baseline conc. AMI →

Clin Pharmacokinet 2003;42(3) toxic values Amphotericin B (AMB) T AZT, DDC Similar toxicity Increased risk Avoid where 24,25 profile, inhibition haematological toxicity possible. Monitor renal elimination (AZT), peripheral blood counts by AMB (DDC) neuropathy (DDC) regularly (AZT)

Antacids containing S (30ml 12 HIV+ DDC single Gastric pH ↑ by BA/absorption DDC Not DDC >2h before 24 de Maatet al. magnesium + aluminium Maalox®) dose 1.5mg ANT ↓ 25% recommended ANT or carbonates (ANT) to ingest simultaneously Drug InteractionswithAntiretrovirals © Adis International Limited. Allrights reserved. ANT T DDI Similar ↑ risk AEs related to Monitor toxicity; 20 ingredients in ingredients DDI A = DDI EC formulation ANT Single-dose 12 vol DLV single Gastric pH ↑ AUC DLV ↓ 41 ± 19% DLV >1h before 28 dose 300mg by ANT or after ANT ANT T AMP, IDV Gastric pH ↑ by Absorption AMP/IDV ↓ Normal (acidic) AMP/IDV >1h 36,37 ANT pH necessary before or after for optimum ANT absorption IDV Astemizole (AST) T, in vitro AMP, DLV, EFV, Inhibition CYP3A Conc. AST ↑ Risk for cardiac CI; A = cetirizine, 28,30,36,37, (AMP) IDV, LPV/RTV, by PI/DLV arrhythmias acrivastine 39,41,43,45, NFV, RTV, SQV (↑ QT interval) 48,63 Atorvastatin (ATR) T AMP, IDV Inhibition CYP3A Conc. ATR ↑ Risk of Combination not 36,37 by PI myopathy recommended; including A = pravastatin, rhabdomyolysis fluvastatin ATR 20mg qd Case report 1 HIV+, DLV 400mg tid Inhibition CYP3A4 Generalised malaise Combination not 64 male by DLV with muscle pain in legs recommended; and lower back, A = pravastatin, nausea, vomiting, dark fluvastatin urine: acute renal failure

ATR 4 days 20mg qd S 12 vol LPV/RTV 14 days Inhibition CYP3A AUC, Cmax ATR ↑ 5–6- Risk of Combination not 65 400/100mg bid by LPV/RTV fold; no effect on LPV myopathy recommended; including A = pravastatin, rhabdomyolysis fluvastatin ATR 14 days 10mg qd Open-label, 15 vol NFV 14 days Inhibition CYP3A4 AUC ATR ↑ 74%; Risk of Combination not 41,66,67 sequential, 1250mg bid by NFV Cmax ATR ↑ 122% myopathy recommended; multiple-dose including A = pravastatin rhabdomyolysis ATR 5 days 40mg qd 3-way 8 vol NFV 5 days AUC ATR ↑ 31.7%; crossover 750mg tid Cmax ATR↑ 209% ATR 4 days 40mg qd Randomised, 14 vol RTV/SQV-SGC Inhibition CYP3A AUC ATR ↑ 347%; Risk of Combination not 43,45,48,68 open-label, 4 days 400/400mg by RTV/SQV AUC total active ATR myopathy recommended; multiple dose bid ↑ 79% including A = pravastatin,

Clin Pharmacokinet 2003;42(3) rhabdomyolysis fluvastatin Atovaquone (ATO) Crossover 14 HIV+ AZT 12 days Inhibition AUC AZT ↑ 33%; Clinical Monitor blood 25,69 12 days 750mg bid male 200mg tid glucuronidation CL AZT ↓ 34%; significance counts regularly by ATO ratio GAZT : AZT ↓ unknown 31%; PK ATO ↔ ATO T LPV/RTV, RTV Induction Conc. ATO ↓ Clinical Dose increase 39,43 glucuronidation significance ATO may be by LPV/RTV unknown needed 233 Continued over page 234 © Adis International Limited. Allrights reserved. Table III. Contd Coadministered agent Type of study Subjects Antiretroviral agent Interaction Effect of interaction Comments Advice References and dosage involved (n) and dosage mechanism Aurothioglucose (AUR) T DDC, DDI, D4T Similar toxicity Peripheral neuropathy Avoid where 20,21,24 profile possible, monitor closely for peripheral neuropathy

Azithromycin (AZI) Open-label, 2- 12 vol NFV 11 days Inhibition P-gp AUC, Cmax AZI ↑ No increase TDM NFV 70 single dose 1200mg way crossover 750mg tid by NFV 107%, 107%, resp.; in AEs recommended AUC, CLoral M8 ↓ 24%, ↑ 30%, resp.; AUC, t1⁄2β NFV ↓ 28%, 24% Barbiturates (BAR) T AMP, DLV, EFV, Induction CYP3A Conc. PI/NNRTI ↓; Based on TDM [see also phenobarbital] IDV, LPV/RTV, by BAR/EFV/ conc. BAR ↑ (PI/DLV) predicted PI/NNRTI/BAR NFV, NVP, RTV, NVP, inhibition or ↓ (EFV/NVP) interaction recommended; SQV CYP3A by PI/DLV with PHB A = valproic acid (anticonvulsant) Bepridil (BEP) T AMP, DLV, IDV, Inhibition CYP3A Conc. BEP ↑ Risk for cardiac Avoid where 4,36,39,43 NFV, LPV/RTV, by PI/DLV arrhythmias possible or CI RTV, SQV (AMP, RTV used as sole PI) Bisphosphonates (BIP) T DDI Chelation with ↓ absorption BIP BIP >2h before cations in DDI DDI; A = DDI EC tablets

Bupropion (BUP) 10 µmol/L In vitro NFV, RTV Inhibition CYP2B6 NFV: IC50 2.5 ± 0.4 IC50 < clinical Dose increase 30,43,71 (human liver 0–50 µmol/L by NFV/RTV µmol/L plasma (EFV/NVP), microsomes) concentration reduction (>50%) → in vivo [PI] BUP may be interaction needed. possible: ↑ risk for convulsions.

BUP T EFV, NVP Induction CYP2B6 RTV: IC50 2.2 ± by EFV/NVP 0.1µmol/L; conc. BUP ↓ Clin Pharmacokinet 2003;42(3) Calcium channel T AMP, DLV, IDV, Inhibition CYP3A Conc. CAC ↑↑ risk for Dosage reduction 28,36,37,39, antagonists NFV, LPV/RTV, by PI/DLV hypotension CAC may be 41,43,45 (dihydropyridines) [CAC] RTV, SQV needed de Maatet al. Drug InteractionswithAntiretrovirals © Adis International Limited. Allrights reserved. (CAR) T AMP, EFV, Induction CYP3A Conc. PI/NNRTI ↓, Potentially TDM PI/NNRTI, 12,36,39,41, LPV/RTV, NFV, by CAR/NVP/ conc. CAR ↑ (PI), conc. significant CAR 45,48,72 NVP, SQV EFV, inhibition CAR ↓ (EFV/NVP) recommended; CYP3A by PI A = amitriptyline/ gabapentin (PHN); valproic acid/lamotrigine (anticonvulsant) CAR Population PK 8 HIV+ DLV Induction CYP3A Substantial reduction 28 data by CAR, inhibition Cmin DLV; conc. CAR ↑ CYP3A by DLV (T) CAR 200mg qd Case report 1 HIV+ IDV 800mg tid (ss) Induction CYP3A4 Plasma conc. IDV ↓; 37,73 [incl. AZT/3TC] by CAR; inhibition plasma conc. CAR CYP3A4 by IDV high in contrast to low dose used CAR (ss) Case report 2 HIV+ RTV 400mg bid Inhibition CYP3A4 Conc. CAR ↑ 3-4-fold Possibly conc. 12,30,43, (incl. SQV 400 bid (possibly PI/NNRTI ↓ 74,75 or SQV 600mg bid CYP2C8) by and EFV 600mg ARV drugs qd) Chloramphenicol (CHA) In vitro AZT Inhibition 0.5 mmol/L 63.3% Conc. AZT Monitor blood 57 (human liver glucuronidation enzyme activity probably ↑. counts regularly microsomes) by CHA remained; 10 mmol/L Significance? 11.3% emzyme activity remained CHA T DDC, DDI, D4T Similar toxicity Peripheral neuropathy Avoid where 20,21,24 profile possible, monitor for peripheral neuropathy Chlordiazepoxide (CHL) T RTV Inhibition CYP3A Conc. CHL ↑ Metabolism Dosage reduction by RTV CHL via CHL may be CYP3A. Risk needed; for ↑ sedation. A = oxazepam, lorazepam Chlorpromazine (CHP) T RTV Inhibition CYP2D6 Conc. CHP ↑, Based on Dose reduction Clin Pharmacokinet 2003;42(3) by RTV, CHP conc. RTV ↑ interaction with CHP, RTV may perphenazine be needed. TDM RTV recommended Cimetidine (CIM) single Single dose 12 HIV+ DDC single dose Inhibition renal AUC DDC ↑ 36%; Monitor for 24 dose 800mg 1.5mg tubular secretion CLR DDC ↓ 24% peripheral by CIM neuropathy; decrease dose DDC if warranted 235 Continued over page 236 © Adis International Limited. Allrights reserved. Table III. Contd Coadministered agent Type of study Subjects Antiretroviral agent Interaction Effect of interaction Comments Advice References and dosage involved (n) and dosage mechanism CIM T DLV ↑ gastric pH ↓ absorption DLV Clinical Long-term use 28 by CIM significance CIM with DLV not unknown recommended. TDM DLV recommended

CIM S 11 HIV+ NVP (ss) Inhibition CYP3A Cmin NVP ↑ 21% Significance? TDM NVP 33 by CIM recommended Ciprofloxacin (CIP) 3 days Open-label, 16 HIV+ DDI 3 days Formation of AUC DDI ↓ 21%; DDI EC single CIP 2h prior to 20,76-78 750mg bid, 2h prior to DDI multiple-dose 200mg bid chelation complex Cmax DDI ↓ 33%; dose 400mg + DDI or 6h after CIP and Mg/Al in AUC CIP ↓ 26% CIP single DDI; A = DDI EC DDI tablets dose 750mg → no effect CIP single dose 750mg, Randomised, 12 vol DDI-placebo AUC CIP ↓ 98%; concomitant administration 2-treatment tablets bid Cmax CIP ↓ 93%; (see also fluoroquinolones) crossover tmax CIP ↓ 52% Cisapride (CIS) T AMP, DLV, EFV, Inhibition CYP3A4 Conc. CIS ↑ Risk for cardiac CI; A = 28,30,36,37, IDV, LPV/RTV, by PI/NNRTI arrhythmias metoclopramide 39,41,43, NFV, RTV, SQV 45,48 Cisplatin (CIT) T DDC, DDI, D4T Similar toxicity Peripheral neuropathy Avoid where 20,21,24 profile possible, monitor for peripheral neuropathy Clarithromycin (CLA) Open-label, 12 vol, male AMP 4 days Inhibition CYP3A4 AUC AMP ↑ 18%; Dose TDM AMP 36,79 4 days 500mg bid randomised, 1200mg bid (P-gp?) by CLA Cmax, Cmin AMP ↑ 15% adjustment recommended multiple-dose, and 39%, resp.; CLA not 3-period CL AMP ↓ 15%; necessary crossover Cmax CLA ↓ 10%

CLA 7 days 500–3000mg Crossover 15 HIV+, AZT 3 days ↓ absorption AUC, Cmax, tmax AZT ↓ Possibly not Separate 80 bid male 100mg 6×d by CLA 25%, 41%, ↑ 84% clinically administration relevant >2h is recommended Clin Pharmacokinet 2003;42(3) CLA 7 days 500mg bid (see Sequential, 10 HIV+ D4T 7 days ↓ absorption Cmax D4T ↓ 35% when Significance? 81 also fluconazole + D4T and eight-part, 40mg bid by CLA? combined with CLA + rifabutin + D4T) multiple-dose, RFB + FLU non-blinded, randomised de Maatet al. Drug InteractionswithAntiretrovirals © Adis International Limited. Allrights reserved. CLA 500mg bid S 6 HIV+ DLV 300mg tid Inhibition CYP3A AUC DLV ↑ 44%; CLA PK Maximum 28 by DLV, CLA AUC CLA ↑ 100%; compared with dosage CLA AUC 14OH-CLA ↓ 75% HCs 1 g/day; A = azithromycin; reduce dosage CLA by 50–75% in patients with CLCR <60ml/min; TDM DLV recommended CLA 7 days 500mg bid Multiple-dose 12 vol EFV 7 days Induction CYP3A4 AUC CLA ↓ 26%; Clinical Maximum 30,82 400mg qd by EFV, inhibition Cmax CLA ↓ 39%; significance dosage CLA CYP3A4 by CLA AUC, Cmax 14OH-CLA unknown for 1 g/day; A = ↑ 34% and 49%, resp.; CLA, effect on azithromycin; Cmax EFV ↑ 11% EFV not monitor for rash relevant; 46% developed rash CLA 7 days 500mg bid S ? IDV 7 days Inhibition CYP3A4 AUC IDV ↑ 29%; Maximum 37,83 800mg tid by IDV, CLA AUC CLA ↑ 53% dosage CLA 1g/day; A = azithromcyin

CLA 7 days 500mg bid Multiple-dose, 14 vol, male 7 days 800mg tid Inhibition hepatic Cmin IDV ↑ 52%; AUC, CLA wide Reduce dosage randomised, CYP3A4 by CLA, Cmax CLA ↑ 47%, 19%; safety margin, CLA by 50–75% 3-period, inhibition CYP3A4 AUC, Cmax 14OH-CLA AE IDV in patients with crossover, by IDV ↓ 49%, 48% associated with CLCR <60ml/min; placebo- Cmax/AUC TDM IDV controlled rather than Cmin recommended CLA T LPV/RTV, NFV Inhibition CYP3A Conc. CLA and/or PI ↑ Maximum 39,41 by PI, CLA dosage CLA 1g/day; A = azithromycin; reduce dosage CLA by 50–75% in patients with CLCR <60ml/min; TDM PI

Clin Pharmacokinet 2003;42(3) recommended

CLA ss 500mg bid Multiple dose 15 HIV+ NVP 14 days Induction CYP3A AUC CLA ↓ 30%, Cmax, Total exposure TDM NVP 84-86 200mg qd, by NVP, inhibition Cmin CLA ↓ 46% and to CLA (incl. recommended thereafter CYP3A by CLA 21%, resp.; AUC NVP metabolite) not 200mg bid ↑ 26% changed 237 Continued over page 238 © Adis International Limited. Allrights reserved. Table III. Contd Coadministered agent Type of study Subjects Antiretroviral agent Interaction Effect of interaction Comments Advice References and dosage involved (n) and dosage mechanism CLA 10 days 500mg bid Case report 1 HIV+, 2 months Accumulation of Hyperactivity: pressure male 200mg bid active 14-OH of speech, poor metabolite of CLA concentration, by NVP extreme anxiety, suicidal/homicidal ideation

CLA 4 days 500mg bid Open-label, 22 vol RTV 4 days Inhibition hepatic AUC RTV ↑ 13%; Cmax CLA → Maximum 43,87 randomised, 200mg tid CYP3A4 by RTV, RTV ↑ 15%; Cmin RTV 14OH-CLA dosage CLA 3-period, CLA ↑ 15%; AUC CLA completely 1g/day; A = crossover (14OH-CLA) ↑ 77% inhibited by azithromycin; (↓ 100%); Cmax CLA RTV reduce dosage of (14OH-CLA) ↑ 31% CLA by 50–75% in patients with (↓ 99%); Cmin CLA ↑182% CLCR <60ml/min; TDM RTV recommended CLA 7 days 500mg bid Multiple dose 12 vol SQV-SGC 7 days Inhibition CYP3A4 AUC CLA (14OH-CLA) Maximum 88,89 1200mg tid by CLA and SQV ↑ 45% (↓ 24%); dosage CLA Cmax CLA (14OH-CLA) 1g/day; A = ↑ 39% (↓ 34%); azithromycin; AUC SQV ↑ 177%; reduce dosage of Cmax SQV ↑187% CLA by 50–75% in patients with CLCR <60ml/min; TDM SQV recommended Clindamycin (CLI) T AMP, DLV, IDV, Inhibition CYP3A Conc. CLI ↑ Combination not 45 LPV/RTV, NFV, by PI/DLV recommended; RTV, SQV A = azithromycin, (flu)-cloxacillin Clonazepam (CLO) T AMP, DLV, IDV, Inhibition CYP3A Conc. CLO ↑ Monitor for 43 LPV/RTV, NFV, by PI/DLV increased

Clin Pharmacokinet 2003;42(3) RTV, SQV sedation, dose reduction CLO may be needed Clorazepate (CLR) T AMP, RTV Inhibition CYP Conc. CLR ↑ Sedation, CI; A = 7,12,36,43 by RTV respiratory lorazepam, depression oxazepam de Maatet al. Clozapine (CLZ) T RTV Induction CYP1A2 Conc. CLZ ↓ CI 4,7 by RTV Drug InteractionswithAntiretrovirals © Adis International Limited. Allrights reserved. Codeine (COD) T RTV Inhibition CYP COD → morphine ↓ Analgesic 72 by RTV efficacy ↓ Corticosteroids (COR) T DLV, IDV, Inhibition Systemic conc. COR ↑ Monitor for [see also fluticasone] LPV/RTV, (presystemic) symptoms of NFV, SQV CYP by PI/DLV hypercorticism Cyclosporin (CsA) T AMP, DLV, IDV, Inhibition CYP3A Conc. CsA, PI/NNRTI ↑ TDM CsA, 36,39,41,43 LPV/RTV, NFV, by PI/DLV, CsA PI/NNRTI RTV recommended CsA ss 175mg bid Case report 1 HIV+, EFV 600mg qd Induction CYP3A4 Conc. CsA ↓ 75% 1 Frequent TDM 90 male by EFV, inhibition month after start EFV CsA, EFV CYP3A by CsA (?) recommended CsA T NVP Inhibition CYP3A Conc. CsA ↓, Based on TDM CsA, by CsA, induction conc. NVP ↑ interaction PI/NNRTI CYP3A by NVP with EFV recommended CsA ss 150mg bid Case report 1 HIV+ SQV 1200mg tid Similar Conc. CsA ↑ 3-fold, TDM CsA, SQV 91 (added to CsA) metabolism via fatigue, headache, GI recommended CYP3A, P-gp discomfort, AUC SQV ↑ Cyclophosphamide (CYC) T AMP, DLV, IDV, Inhibition CYP3A Conc. CYC ↑; TDM PI/NNRTI LPV/RTV, NFV, by PI/DLV, metabolism to active recommended; RTV, SQV induction CYP by metabolite ↓; monitor blood CYC conc. PI/NNRTI ↓ counts regularly Dapsone (DAP) T AZT Similar toxicity Haematological toxicity Monitor blood 25 profile counts regularly DAP T DDC, D4T Similar toxicity Peripheral neuropathy Avoid where 23,24 profile possible, monitor for peripheral neuropathy

DAP single dose 100mg S 6 HIV+ DDI EC 14 days No change AUC / Cmax Multiple dose DAP should be 20,21,92,93 200mg bid studies show administered > no clinically 1h before or 2h significant PK after DDI tablets. interaction, but A = DDI EC conflicting reports Clin Pharmacokinet 2003;42(3) DAP Multiple dose, ? DDI ↓ absorption DDI Avoid where case reports by DDI possible, monitor for peripheral neuropathy DAP T DDI Similar toxicity Peripheral neuropathy profile DAP T DLV, SQV Inhibition CYP3A Conc. DAP ↑ Monitor blood 28,45 by DLV/SQV counts regularly 239 Continued over page 240 © Adis International Limited. Allrights reserved. Table III. Contd Coadministered agent Type of study Subjects Antiretroviral agent Interaction Effect of interaction Comments Advice References and dosage involved (n) and dosage mechanism Daunorubicin (DAU) T AMP, DLV, IDV, Inhibition CYP3A Conc. DAU ↑ Consider ↑ risk Monitor blood LPV/RTV, NFV, by PI/DLV for cardiotoxicity counts regularly, RTV, SQV dosage reduction DAU may be needed.

Desipramine (DES) In vitro RTV 5–25, IDV 10– Mixed competitive Ki: RTV (4.84) > IDV Dosage reduction 43,94,95 0–300 µmol/L (human liver 25, SQV 25–50, and (15.6) > SQV (24.0) > DES may be microsomes) NFV 25–50 µmol/L noncompetitive NFV (51.9) [µmol/L] needed, inhibition CYP2D6 TDM DES by PI recommended DES single dose 100mg S 14 vol RTV 12 days AUC DES (2OH-DES) (see also tricyclic escalating to ↑ 145% (↓ 15%); antidepressants) 500mg bid Cmax DES (2OH-DES) ↑ 22% (↓ 67%) Dexamethasone (DEX) T AMP, DLV, EFV, Induction CYP3A4 Conc. PI/NNRTI ↓, TDM PI/NNRTI 28,30,36,37, IDV, LPV/RTV, by DEX, conc. DEX ↑ (PI/DLV) recommended, 39,43,45,48 NFV, NVP, EFV/NVP, or ↓ (EFV/NVP) dosage increase RTV, SQV inhibition CYP3A4 (EFV/NVP), by PI/DLV reduction (PI/ DLV) DEX may be needed Dextropropoxyphene T RTV Inhibition Conc. DRX ↑↑ risk for CI 43 (DRX) CYP3A/2D6 sedation, CNS by RTV toxicity Diazepam (DIA) T AMP, DLV, IDV, Inhibition CYP3A Conc. DIA ↑ Risk for ↑ CI (RTV); 36,39,43,72 NFV, LPV/RTV, by PI/DLV sedation. A = lorazepam, RTV, SQV oxazepam Digoxin (DIX) Case report 1 HIV+, IDV/RTV Inhibition P-gp in Nausea, vomiting, TDM DIX 96 female 800/200mg bid the small intestine mildly dehydrated. recommended or proximal renal Conc. DIX (5h post tubules by RTV ingestion) 7.2 nmol/L (± 2.5 × normal upper Clin Pharmacokinet 2003;42(3) level) Diltiazem (DIL) T AMP, DLV, IDV, Inhibition CYP3A Conc. DIL ↑ Dosage reduction 36,43 LPV/RTV, NFV, by PI/DLV DIL may be RTV, SQV needed

Disopyramide (DSP) T RTV Inhibition CYP3A Conc. DSP ↑ Cardiac events Avoid where 43 de Maatet al. by RTV have been possible, dosage reported reduction DSP with this >50% may be combination needed Drug InteractionswithAntiretrovirals © Adis International Limited. Allrights reserved. Disulfiram (DIS) T DDC, DDI, D4T Similar toxicity Peripheral neuropathy Avoid where 20,21,24 profile possible, monitor for peripheral neuropathy DIS T LPV/RTV liquid, Irreversible Disulfiram-like LPV/RTV and A = LPV/RTV or 39,43 RTV liquid inhibition ADH reactions by ↑ RTV liquids RTV capsules by DIS conc. acetaldehyde contain alcohol Doxorubicin (DOX) T AMP, DLV, IDV, Inhibition CYP3A Conc. DOX ↑ Consider ↑ risk Monitor blood LPV/RTV, NFV, by PI/DLV for cardiotoxicity counts regularly, RTV, SQV dosage reduction DOX may be needed DOX In vitro DDC Inhibition of >50% inhibition of Clinical 24 phosphorylation phosphorylation relevance by DOX unknown Encainide (ENC) T LPV/RTV, RTV Inhibition CYP2D6 Conc. ENC ↑ Based on CI CI by LPV/RTV, RTV for FLE Ergot derivatives (ERD) T AMP, DLV, EFV, Inhibition CYP3A4 Conc. ERD ↑ Ergotism = CI; A = 28,30,36,39, LPV/RTV, SQV by PI/DLV vasospasm paracetamol 45,48 (acetaminophen)/ sumatriptan ERD T IDV Inhibition hepatic Conc. ERD ↑ Ergotism = CI; A = 37,97 CYP3A4 by IDV vasospasm paracetamol/suma triptan Ergotamine 1mg bid Case report 1 HIV+ IDV 800mg tid (incl. Conc. ERD not 3TC 150mg/D4T determined, ergotism 40mg bid) ERD T NFV Inhibition CYP3A Conc. ERD ↑ Ergotism = CI; A = 41,98 by NFV vasospasm paracetamol/suma triptan Ergotamine single Case report 1 HIV+, Pain, oedema, dose 2 mg female cyanosis feet and hands. Symptoms resolved after 6–15

Clin Pharmacokinet 2003;42(3) days ERD T RTV Inhibition CYP3A4 Conc. ERD ↑ Ergotism = CI; A = 43,99,100 by RTV vasospasm paracetamol/suma triptan Ergotamine single dose Case report 2 HIV+ RTV 600mg bid Ergotism Toxicity of ERD 1mg (n = 1) or 5 days linked to peak 3mg (n = 1) serum conc. 241 Continued over page 242 © Adis International Limited. Allrights reserved. Table III. Contd Coadministered agent Type of study Subjects Antiretroviral agent Interaction Effect of interaction Comments Advice References and dosage involved (n) and dosage mechanism Erythromycin (ERY) T AMP, DLV, IDV, Inhibition CYP3A Conc. ERY ↑ or Based on TDM PI/NNRTI NFV, LPV/RTV, by ERY or PI/DLV PI/NNRTI ↑ interaction of recommended, RTV ERY + SQV dosage reduction ERY may be needed. Monitor for GI toxicity

ERY Monitoring 24 HIV+ NVP Inhibition CYP3A Cmin ss NVP ↑ 12% Probably not TDM NVP 33 plasma conc. by macrolides significant recommended (ERY)

ERY 7 days 250mg qid Open-label, 11 HIV+ SQV-SGC 7 days Inhibition CYP3A4 AUC, Cmax SQV ↑ No dosage 101 substudy 1200mg tid (ss) by ERY 99%, 106%, resp. adjustment necessary Ethambutol (ETH) T DDI Similar toxicity Peripheral neuropathy, Avoid where 4,92 profile ocular effects possible, monitor for peripheral neuropathy, neuritis optica Ethanol (ETN) 0.7mg/kg Open-label, 25 HIV+ ABC single dose Competition for AUC ABC ↑ 41%, Not considered 18,102,103 ↑ ↑ randomised, 3- male 600mg metabolism by t1⁄2β 26%, Cmax 15% clinically way-crossover ADH significant Ethionamide (ETI) T DDC, DDI, D4T Similar toxicity Peripheral neuropathy Avoid where 20,21,24 profile possible, monitor for peripheral neuropathy Ethosuximide (ETX) T RTV Inhibition CYP3A Conc. ETX ↑ Risk for ↑ TDM ETX 43 by RTV sedation recommended. Dosage reduction ETX (>50%) may be needed Famotidine (FAM) T DLV, IDV ↑ gastric pH ↓ absorption DLV, IDV Clinical Long-term use 28 by FAM significance FAM with DLV,

Clin Pharmacokinet 2003;42(3) unknown IDV not recommended Fentanyl (FEN) single dose Double-blind, 11 vol RTV 3 days Inhibition CYP3A4 AUC FEN ↑ 170%, Fatal Small bolus FEN: 104 5 µg/kg IV 2min placebo- 300mg tid by RTV CL FEN ↓ 67% respiratory no dose controlled, depression adjustment.

crossover, Continuous de Maatet al. 2 phases administration FEN: reduce dosage FEN Drug Interactions with Antiretrovirals 243 106 25,105 43,108 43,110,111 28 109 107 30 25 20,21 Continued over page TDM IDV recommended Monitor blood counts regularly CI 39,43 TDM RTV recommended Dose reduction FLX >50–60%, then adjustment as necessary (RTV) TDM DLV recommended TDM SQV recommended TDM NFV recommended TDM EFV recommended counts regularly FLQ 2h prior to DDI or 6h after EC = DDI A DDI; Probably not clinically significant Risk for cardiac arrhythmias Significance? 81 Probably not clinically significant One case also used GRJ Probably not clinically significant ↑ 50% ±

50%, 12%, ↑ 15% 16%, 74%, 84%, 35% when ↓ ↑ 24%, 13%, absorption , CL SQV 10% ↑ 128% ↑ ↑ ↑ ↑ ↓ 26–27% ↓ ↓ ↓ ↓ ↑ ↓ max DLV AZT AZT D4T IDV RTV AZT AZT IDV

β 2 ⁄ max max max min max trough 1 50%, 56%, respectively AUC AZT AZT AUC C Conc. FLE t combined with CLA + RFB + FLC EFV AUC C PK FLC? C AUC IDV IDV AUC Development serotonin syndrome after introduction PI/NNRTI Haematological toxicity Monitor blood CL NFV C AUC, C AUC, AUC RTV RTV AUC C Probably both drugs C by FLC, substrate competition for UDPGT binding sites by LPV/RTV, RTV Inhibition CYP3A by FLC, induction CYP3A by EFV Induction CYP?, inhibition absorption by FLC Inhibition CYP by PI/EFV profile Inhibition CYP2C19 by FLC Inhibition absorption by FLC? Inhibition CYP3A4 and/or P-gp in gut wall by FLC Inhibition CYP3A4 in gut wall by FLC chelation complex FLQ and Mg/Al in DDI tablets by FLX days 4 ⁄ 3 400mg qd 1000mg tid RTV, SQV NFV 500 or 750mg tid bid 1200mg tid days 200mg 4dd 12 HIV+ AZT 200mg bid ss Inhibition CYP3A4 23 HIV+ (n = 174) 10 HIV+ D4T 7 days 40mg 5 HIV+ SQV 6 days 8 vol RTV (liquid) 4 11 HIV+ IDV 7 36 HIV+ DLV Inhibition CYP2D6 Randomised, 2-period, 2-treatment crossover pharmacokinetic data Sequential, eight-part, multiple-dose, non-blinded, randomised Open-label, crossover randomised, 2-period crossover period, placebo- controlled, crossover T DDI Formation of PK data (FLQ) (FLC) 7 days (FLY) T AZT toxicity Similar (FLX) Population (FLE) T LPV/RTV, RTV Inhibition CYP2D6 Fluconazole 400mg qd FLC Population FLC 7 days 200mg qd (see also clarithromycin + D4T and rifabutin + D4T) Flecainide FLC day 1 400mg, then 5 days 200mg qd FLC 7 days 200mg qd S 10 vol 7 days EFV FLX 20-40mg/day Case study 5 HIV+ EFV, IDV, Flucytosine FLC 4 days 200mg Open-label, FLC 8 days 400mg qd Multiple-dose 3- Fluoroquinolones [see also ciprofloxacin] Fluoxetine

© Adis International Limited. All rights reserved. Clin Pharmacokinet 2003; 42 (3) 244 © Adis International Limited. Allrights reserved. Table III. Contd Coadministered agent Type of study Subjects Antiretroviral agent Interaction Effect of interaction Comments Advice References and dosage involved (n) and dosage mechanism FLX 8 days 30mg bid (see Phase I, 16 vol RTV (liquid) single Inhibition CYP2D6 AUC RTV ↑ 19% ss RTV: ↓ also selective serotonin open-label dose 600mg (postabsorption) impact reuptake inhibitors) by FLX CYP2D6 with multiple doses, induction 3A by RTV Fluticasone (FLT) 500mg Case report 1 HIV+ AMP/RTV Inhibition CYP Hypercorticism (moon 112 bid inhaled (see also 600/100mg bid by RTV facies, acute weight corticosteroids) gain, diffuse acne, candidal oesophagitis). Undetectable cortisol, ACTH plasma conc. Flurazepam (FLU) T AMP, RTV Inhibition CYP3A Conc. FLU ↑ Risk for ↑ CI; A = 36,43 by AMP, RTV sedation, oxazepam, respiratory lorazepam depression Foscarnet (FOS) T DDC Inhibition renal Increased risk for Monitor for 24 elimination by FOS peripheral neuropathy, peripheral other AE neuropathy. Adjust dosage DDC based on renal function Fusidic acid (FUA) Case report 1 HIV+ RTV/SQV Inhibition CYP3A4 RTV↑ 19.3 → 43.4 Avoid where 113 500mg tid 400/400mg bid by FUA and mg/L; SQV↑ 11.2 → possible, TDM RTV/SQV 16.3 mg/L; FUA high RTV/SQV conc. and decreased recommended elimination. Acute onset of nausea, fatigue, arthralgias, vertigo, jaundice γ-Hydroxybutyrate (GHB) Case report 1 HIV+ RTV/SQV Inhibition GHB intoxication: loss Discourage 114 [+ MDMA] ±10 mg/kg 400/400mg bid (presystemic) of consciousness, coadministration Clin Pharmacokinet 2003;42(3) metabolism by seizurelike activity, of illicit RTV/SQV respiratory depression, substances rapid/complete recovery Ganciclovir (GAN) S 8 HIV+ AZT Induction CL AZT ↑ Effect < usual Monitor blood 4,25,115, enzymes by GAN; inter- and counts regularly, 116 related to CMV intraindividual dosage reduction de Maatet al. disease? variability AZT may be needed Drug InteractionswithAntiretrovirals © Adis International Limited. Allrights reserved. GAN 7 days 1000mg Multicentre, 12 HIV+ AZT 7 days 100mg ↑ absorption by AUC AZT ↓ ±30%; tid PO open-label, 5 times/day GAN AUC0-4 AZT ↑ 20%; randomised, Cmax AZT ↑ 62% crossover GAN T AZT Similar toxicity Haematological toxicity profile GAN 4 days 1000mg tid Open-label, 10 HIV+ DDC 4 days ↑ absorption AUC GAN ↑ 22.2% Monitor blood 117 multidose, 3- and CMV+ 0.75mg tid by DDC counts regularly way crossover GAN 13 days Multicentre, 12 HIV+ DDI 13 days ↓ intestinal (sim) AUC DDI ↑ Note: Administer GAN 20,21,116, 1000mg tid PO open-label, 200mg bid absorption by 108%; (seq) AUC DDI neuropathy, and DDI 118 randomised, DDI; alteration ↑ 115%; (sim) GAN ↔; pancreatitis simultaneously, crossover absorption, (seq) AUC GAN ↓ 21% DDI conc. monitor for metabolism DDI dependent peripheral by GAN (?) neuropathy, pancreatitis

GAN 3 days 2000mg tid PO Open-label, 16 HIV+ DDI 3 days ↑ extent of GAN→DDI: AUC, Cmax n = 12 DDI PK; randomised, 200mg bid absorption by GAN DDI ↑ 124%, 87%, n = 9 GAN PK 3-period resp.; DDI→GAN: crossover AUC, Cmax DDI ↑ 87%, 59%, resp. Garlic supplements 2-treatment, 3- 9 vol SQV 3 days Induction AUC SQV ↓ 51%; After 10-day Use GAR with 119 (GAR): allicin/allin period, single- (4 male, 1200mg tid intestinal CYP Cmax SQV ↓ 54%; washout AUC, caution when 4.64/11.2mg caplet sequence, 5 female) (P-gp?) by GAR Cmin SQV ↓ 49% Cmin, Cmax SQV is used as 20 days bid longitudinal returned to 60– sole PI. TDM 70% of baseline SQV recommended GAR T AMP, DLV, EFV, Induction CYP Conc. PI/NNRTI ↓ Based on TDM PI/NNRTI IDV, LPV/RTV, (P-gp) by GAR interaction recommended NFV, NVP with SQV

Gemfibrozil (GEM) Placebo- 14 HIV+ RTV/SQV both ? Cmin RTV ↑ 45%; TDM RTV/SQV 120 600mg bid controlled 400 or 600mg bid; effect on SQV? recommended (interim RTV 600mg bid analysis) Glutethimide (GLU) T DDC, DDI, D4T Similar toxicity Peripheral neuropathy Avoid where 20,21,24 Clin Pharmacokinet 2003;42(3) profile possible, monitor for peripheral neuropathy Grapefruit juice (GRJ) Single-dose Vol IDV single dose Inhibition AUC IDV ↓ 26% TDM IDV 29,37,121 single dose 240ml 400mg intestinal recommended CYP3A4, induction P-gp by GRJ 245 Continued over page 246 © Adis International Limited. Allrights reserved. Table III. Contd Coadministered agent Type of study Subjects Antiretroviral agent Interaction Effect of interaction Comments Advice References and dosage involved (n) and dosage mechanism

GRJ double-strength 180ml Randomised, 14 HIV+ IDV ss 800mg tid + ↑ gastric pH AUC IDV ↔; tmax ↑ Effect GRJ on crossover, by GRJ 39%; gastric pH ↑ 130% BA IDV is open-label variable GRJ single dose Single-dose 12 vol SQV single dose Inhibition CYP3A (1) AUC SQV ↑ 39%; ‘Boosting’ BA TDM SQV 122,123 150(1)/300(2)ml 600mg by GRJ (1) Cmax SQV ↑ 63%; recommended (2) AUC SQV ↑ 121%; (2) Cmax SQV ↑ 120% GRJ 2 x 200ml single- Open crossover 8 vol SQV single dose Inhibition (1) AUC SQV ↑ 50%; strength 600mg PO (1); intestinal CYP3A4 (1) F SQV ↑ 100%; single dose by GRJ (2) PK SQV ↔ 12mg IV (2) Haloperidol (HAL) T RTV Inhibition CYP2D6 Conc. HAL ↑ Risk for Dosage reduction 12 by RTV extrapyramidal HAL may be symptoms needed Hydralazine (HYD) T DDC, DDI, D4T Similar toxicity Peripheral neuropathy Avoid where 20,21,24 profile possible, monitor for peripheral neuropathy Hydroxycarbamide (HYX) T AZT Similar toxicity Haematological toxicity Avoid where 4,25 profile possible, monitor blood counts regularly Ifosfamide (IFS) T AMP, DLV, IDV, Inhibition CYP3A Conc. IFS ↑; Monitor blood LPV/RTV, NFV, by PI/DLV metabolism to active counts regularly RTV, SQV metabolite ↓ Interferon-α (INFα) T AZT Similar toxicity Haematological toxicity Dose reduction or 4,25 profile interruption of one or both agents. Monitor blood counts regularly Clin Pharmacokinet 2003;42(3) Interleukin-2 (IL-2) 5 days Prospective, 9 HIV+ IDV 800mg tid, for Inhibition CYP AUC IDV ↑ 88% Cytokines TDM IDV 124 3-12 MIU/day, continuous open-label, at least 4 weeks by IL-2 suppress recommended infusion nonrandomised mRNA of CYP isoenzymes by ↓

transcriptional de Maatet al. rate of corresponding gene Drug InteractionswithAntiretrovirals © Adis International Limited. Allrights reserved. Iodoquinol (IDO) T DDC, DDI, D4T Similar toxicity Peripheral neuropathy Avoid where 20,21,24 profile possible, monitor for peripheral neuropathy Isoniazid (INH) T DDC, DDI, D4T Similar toxicity Peripheral neuropathy Avoid where 20,21,24 profile possible, monitor for peripheral neuropathy Isotretinoin (ISO) 50mg qd Case report 1 HIV+, RTV/IDV Inhibition CYP3A Dry skin, cheilitis with Syndrome Avoid where 125 male 400/400mg bid by RTV/IDV, painful fissures lips, disappeared possible (incl AZT/3TC) intracellular growth, dull curly hair, after 50mg blockage of ‘sticky skin’ minocycline CRABP-1 by RTV/IDV Itraconazole (ITR) T AMP, DLV, EFV, Inhibition CYP3A Conc. ↑ ITR and/or Based on Avoid dosages 36,39,43,45, LPV/RTV, NFV, by PI/DLV and/or PI/DLV; conc. ITR ↓ interaction ITR >200mg/day 48 NVP, RTV, SQV ITR, induction (EFV/NVP) study with KET (PI/DLV). TDM CYP3A by PI/NNRTI EFV/NVP recommended. A = fluconazole ITR S DDI ↑ gastric pH ↓ absorption ITR Based on Administer ITR 20,21,126 by DDI interaction with >2h prior to DDI, KET or >2h after DDI. A = DDI EC or itraconazole liquid ITR 200mg bid Multiple-dose IDV 600mg tid Inhibition CYP3A4 AUC IDV ↑ AUC ≈ AUC TDM IDV 37 by ITR IDV 800mg tid recommended, administered dosage reduction alone for 1 IDV may be week needed. A = fluconazole

Ketoconazole (KET) Open-label, 12 vol, male AMP single dose Inhibition CYP3A AUC, Cmax AMP ↑ ↑ BA AMP by Dose reduction 36,127,128 single dose 400mg randomised, 1200mg by KET, AMP 31%, ↓ 16%, resp. KET, may alter KET may be balanced, AUC, Cmax KET ↑ 44%, both BA and needed when single-dose, ↑ 19%, resp. CL of KET KET >400mg/day. 3-period A = fluconazole Clin Pharmacokinet 2003;42(3) crossover KET Concurrently/ AMP Inhibition CYP3A AUC AMP ↑ 32%, historically by KET Cmax AMP ↓ 16% controlled trials

KET 4 days 200mg qd, Open-label, 12 HIV+, DDI (buffered ↑ gastric pH AUC DDI ↓ 8%, Cmax Effect is within Administer KET 20,21,78, 2h before DDI randomised, 3- male powder for oral by DDI DDI ↓ 12%, no effect variability >2h prior to DDI. 129 way crossover solution) on KET A = DDI EC 247 Continued over page 248 © Adis International Limited. Allrights reserved. Table III. Contd Coadministered agent Type of study Subjects Antiretroviral agent Interaction Effect of interaction Comments Advice References and dosage involved (n) and dosage mechanism

KET Population PK 26 HIV+ DLV Inhibition CYP3A Ctrough DLV ↑ ± 50% TDM DLV 28 data by KET recommended KET single dose 400mg Single dose IDV single dose Inhibition CYP3A AUC IDV ↑ 68% Reduce dose IDV 37 400mg by KET to 600mg tid, TDM IDV recommended KET 400mg qd Multiple dose IDV 600mg tid AUC IDV ↓ 18% (compared with 800mg tid) KET single dose 200mg S 12 LPV/RTV 16 days Inhibition CYP3A AUC KET ↑ 3-fold, Avoid dosages 39 400/100mg bid by LPV/RTV no effect on LPV KET > 200 mg/day. A = fluconazole KET 7 days 400mg qd Randomised, 12 vol NFV 6 days Inhibition CYP3A AUC NFV ↑ 35%, Not clinically No dosage 41,130,131 crossover 500mg tid by KET Cmax NFV ↑ 25% significant. In adjustment vitro data: KET (TDM NFV may cause recommended) modest elevation in NFV conc.

KET 32 days 400mg qd Open-label 22 HIV+ NVP 28 days Induction CYP3A AUC KET ↓ 63%, Cmax CI; A = 33,132 single arm 200mg bid (1st 2 by NVP, inhibition KET ↓ 40%, Cmax, Cmin fluconazole weeks 200mg qd) CYP3A by KET NVP ↑ ± 15–20% (HC)

KET 7 days 200mg qd S 12 HIV+ RTV 10 days Inhibition CYP3A AUC, Cmax RTV ↑ 18, Avoid dosages 43 500mg bid by RTV and KET 10%, resp., AUC, Cmax KET > KET ↑ 3.4-fold, 55%, 200mg/day. resp. A = fluconazole

KET 10 days 200 or Two-period, 3- 12 HIV+, RTV/SQV Inhibition hepatic AUC, t1⁄2 β, Cmin, CL/F No dosage 133 400mg qd group, dose- male 400/400mg bid CYP3A by KET, SQV ↑ 37%, 38%, adjustment, TDM escalation, (RTV/SQV?), 94%,↓ 27%, resp. RTV/SQV

longitudinal PK inhibition CSF-to- AUC, t1⁄2β, Cmin, CL/F recommended Clin Pharmacokinet 2003;42(3) plasma active RTV ↑ 29%, 31%, transport by KET 62%, ↓ 22%, resp. CSF RTV conc. ↑ 2.8-fold. CSF SQV conc. ↑ 3.6-fold de Maatet al. KET 6 days 200mg qd Multiple dose 12 vol SQV-HGC 6 days Inhibition hepatic AUC SQV ↑ 130%, No dosage 45,88,101 study 600mg tid CYP3A by KET Cmax SQV ↑ 147% adjustment, TDM SQV recommended Drug InteractionswithAntiretrovirals © Adis International Limited. Allrights reserved. KET 7 days 400mg qd Retrospective ? SQV-SGC single AUC SQV ↑ 190%, review dose 1200mg Cmax SQV ↑ 171% KET 7 days 200mg qd Open-label, 11 HIV+ SQV-SGC AUC SQC ↑ 69%, substudy 1200mg tid (ss) Cmax SQV ↑ 36% Lansoprazole (LAN) T DLV, IDV ↑ gastric pH ↓ absorption DLV, IDV Normal acidic TDM DLV/IDV 28,37,134 by LAN pH necessary recommended for optimum absorption LAN 15mg qd (a)/15mg bid Case reports 4 HIV+ (a) DLV 600mg (a) low trough conc. (b) [n = 2] (see also bid, (b) DLV DLV, (b) no effect on omeprazole) 800mg bid, IDV DLV, low trough conc. 1200mg bid IDV Levodopa (DOP) 700–750 Case report 1 HIV+ IDV 800mg tid Inhibition After 4 weeks: severe Potentially be Dosage reduction 135 mg/day + DOPA oxidative dyskinesias occurring used to DOP may be decarboxylase inhibitor reactions by IDV, at peak dose periods, potentiate necessary or delayed on-periods lasted the DOP? dopaminergic whole day without receptor fluctuations hypersensitivity by IDV Levomepromazine (LEP) T RTV Inhibition CYP2D6 Conc. LEP ↑, conc. Based on Dosage reduction by RTV, LEP RTV ↑ interaction with LEP, RTV may perphenazine be needed. TDM RTV recommended Levothyroxine (LEV) Case report 1 HIV+, IDV 800mg tid Competition Hypercholesterolaemia High 136 0.125mg qd female followed by NFV glucuronidation by within 1–2 weeks, during PEP may 1250mg bid AZT/IDV (?) headache, nausea, be reversible, (PEP regimen which resolved with may not require +AZT/3TC) switch to NFV, and intervention fatigue LEV 0.125mg qd Case report 1 HIV+, RTV/SQV Induction TSH levels↑ Adjust dosage 137 male 400/600mg bid glucuronosyl- LEV based on transferase by thyroid function RTV testing Clin Pharmacokinet 2003;42(3) Lidocaine (LID) T AMP, DLV, IDV, Inhibition CYP3A Conc. LID ↑ Risk for cardiac Use with caution, 28,36,39,43 LPV/RTV, NFV, by PI/DLV arrhythmias TDM LID RTV, SQV recommended

Loperamide (LOP) Randomized, 12 vol RTV single Inhibition CYP3A AUC, Cmax, CLoral LOP Lack of central No dosage 138 single dose 16mg double-blind, 2- dose 600mg by RTV ↑ 223%, 17%, effects when adjustment way crossover ↓ 70%, resp. combined with necessary RTV → no P- gp involvement 249 Continued over page 250 © Adis International Limited. Allrights reserved. Table III. Contd Coadministered agent Type of study Subjects Antiretroviral agent Interaction Effect of interaction Comments Advice References and dosage involved (n) and dosage mechanism Loratadine (LOR) T RTV Inhibition CYP3A Conc. LOR ↑ Risk for A = cetirizine, 58 (2D6) by RTV tachycardia, acrivastine headache Lovastatin (LOV) T AMP, DLV, IDV, Inhibition CYP3A4 Conc. LOV ↑ Risk of Combination not 36,37,39,41, LPV/RTV, NFV, by PI/DLV myopathy recommended. 43,45,48 RTV, SQV including A = pravastatin, rhabdomyolysis fluvastatin (not with NFV) Mebendazole (MEB) T RTV Inhibition CYP? Conc. MEB ↑ Risk for ↑ by RTV diarrhoea, suggest supportive care Medroxyprogesterone T RTV Inhibition CYP3A Conc. MED↑ (MED) by RTV

Mefloquine (MEF) 3 days Open-label, 12 vol (I), RTV 7 days Reduction bile I: CL, AUC, Cmax RTV Despite strong TDM RTV 139 250mg qd, then 250 nonfasting, 11 vol (II) 200mg bid (I), production by ↑ 45%, ↓ 31%, 36%. inhibition recommended mg/week (I). 3-treatment, single dose MEF → ↓ II: no effect CYP3A4 from 3 days 250mg qd, then 3-period, 200mg (II) solubility/absorption single 200mg 250mg/4 weeks (II) longitudinal RTV in small dose RTV, no intestine effect on MEF PK Meperidine (MEP) Open-label 8 vol RTV 10 days Induction CYP1A2 AUC MEP ↓ 62%, N-MEP = Dosage increase 43,140 [= pethidine], single oral 500mg bid by RTV, Cmax MEP ↓ 59%. normeperidine and long-term dose 50mg concomitant n = 6: AUC N-MEP use of MEP not induction/inhibition ↑ 47%, Cmax N-MEP recommended competing ↑ 87% due to ↑ conc. N- metabolic MEP which has pathways, both analgesic inhibition P-gp and CNS activity in gut wall (seizures)

Methadone (MET) S 16 vol AMP 10 days Both metabolised AUC24 (R)-MET, Interim analysis Adjustment 141,142 ↓

Clin Pharmacokinet 2003;42(3) maintenance 12.5– 1200mg bid via CYP3A4 (S)-MET 12%, 37%, (12 subjects): dosage MET may 112.5mg/day resp. Cmax (R)-MET, opioid PD be necessary (S)-MET ↓ 24%, 45%, measures did resp. AMP PK no not change change ↓

MET Prospective, 5 HIV+ AMP (+ ABC Induction CYP3A4 Conc. MET 35% n = 2 nausea de Maatet al. cross-over 600mg/day) 14 by AMP (effect of days 1200mg bid ABC cannot be excluded) Drug InteractionswithAntiretrovirals © Adis International Limited. Allrights reserved. MET Prospective 5 HIV+ AZT morning dose Inhibition CL AZT ↓ 45% Monitor blood 25,115,143 100–500mg glucuronidation by counts regularly, MET (in vitro) consider dosage reduction to 400/500mg AZT daily when symptoms suggestive of AZT toxicity are observed MET maintenance S 9 HIV+ AZT 200mg n = 4 AUC AZT ↑ 30–90mg daily every 4h 2-fold; n = 5 AUC AZT = AUC control MET maintenance Within-subject 8 HIV+ AZT 200mg tid Inhibition Type 2 Acute effect: PO AUC Higher MET UDPGT by MET AZT ↑ 41%; IV AUC conc. in long- AZT ↑ 19%. Long-term term phase (IV); effect: PO AUC AZT ↑ first pass ↑ 29%; IV AUC AZT metabolism ↑ 41% (PO)

MET maintenance Open-label, 17, 10 D4T 40mg bid ↓ GI motility by AUC d4T ↓ 25%, Cmax Effect on MET 144 intersubject (9, 5 HIV+) MET → ↓ d4T ↓ 44%, tmax d4T ↑ not clinically (parallel design) absorption d4T 2-fold, Ctrough MET ↓ significant

MET chronic maintenance Parallel design 16, 10 DDI EC single ↓ GI motility by AUC DDI ↓ 41%, Cmax Appropriate 20,21,144 dose 200mg MET → ↓ DDI ↓ 59% dosages DDI absorption DDI have not been established MET maintenance Open-label, 17, 10 DDI 200mg bid AUC DDI ↓ 60%, Effect on MET intersubject (9, 5 HIV+) Cmax DDI ↓ 66%, not clinically (parallel design) Ctrough MET ↓ significant MET 100mg maintenance Case report 1 HIV+ EFV600mg qd Induction CYP3A4 Typical withdrawal Regimen + Dosage 145-147 by EFV symptoms: tiredness, D4T 40mg bid, increments MET headache, cold sweats 3TC 150mg bid of 10mg with and shivering. Conc. daily supervision (R)-MET ↓ ±46%, of dosage and (S)-MET ↓ ±72% clinical evaluation Clin Pharmacokinet 2003;42(3) MET 30mg maintenance Case report 1 HIV+, EFV 600mg qd Withdrawal symptoms Regimen + male after 2 days D4T, DDI

MET 35–100mg Crossover 11 HIV+ EFV 14 or 21 days Cmax, AUC24 MET↓ Dose increase maintenance 600mg qd 48%, 57%, MET dose not as large as ↑ 22% would be expected by individual’s PK. Higher initial

dose = higher 251 increase Continued over page 252 © Adis International Limited. Allrights reserved. Table III. Contd Coadministered agent Type of study Subjects Antiretroviral agent Interaction Effect of interaction Comments Advice References and dosage involved (n) and dosage mechanism MET 7 days 20–60mg daily S ? IDV 7 days Inhibition CYP3A No change AUC MET, TDM IDV 37 800mg tid by IDV little or no change AUC recommended IDV MET single dose 5mg S 11 vol LPV/RTV 10 days Induction CYP AUC MET ↓ 53%, Dosage increase 39 400/100mg bid by LPV/RTV Cmax MET ↓ 45% MET may be needed MET Part of case 2 HIV+ NFV Induction Conc. ss MET ↓ ± 55% Dosage increase 148-150 series isoenzymes of MET may be CYP other than needed, TDM 3A4 by NFV NFV/M8 may be recommended MET maintenance Prospective 14 HIV+ NFV 1250mg bid Plasma concentration No withdrawal 10–140mg/daily (+)-MET, (–)-MET ↓ symptoms, no 47%, 39%, respectively dosage adjustment MET maintenance Retrospective 36 HIV+ NFV 750mg tid 34/36 unchanged dose, 20–110mg/daily case series and 1250mg bid 1/36 dose increase, 1/36 dose reduction

MET 40–120mg/day Non-crossover 16 vol NFV 5 days Inhibition AUC, Cmax M8 ↓ 47%, MET PK not 1250mg bid metabolism NFV 53%, respectively determined to M8 by MET MET chronic maintenance Retrospective 7 HIV+ NVP Induction CYP3A4 Withdrawal symptoms Use MET Dosage 33,146, chart review by NVP 4–8 days after start trough conc. at increments MET 151-153 NVP. Trough conc. baseline and of 10mg with MET ↓ titrate daily supervision of dosage and clinical evaluation MET 80mg Case report 1 HIV+, NVP Withdrawal symptoms, Twice daily female dose to 130mg MET may be needed MET Case series 5 HIV+ NVP 4/5 mild–severe Clin Pharmacokinet 2003;42(3) withdrawal symptoms MET 40mg maintenance Case report 1 HIV+, NVP (+D4T Withdrawal symptoms Rechallenge: male and DDI) after 2 days recurrence symptoms de Maatet al. Drug InteractionswithAntiretrovirals © Adis International Limited. Allrights reserved. MET Part of case 1 HIV+ RTV Induction CYP3A Conc. ss MET ↓ ± 56% Dosage 43,148, series as well as GT, increments MET 154-156 1A2, possibly of 10mg with 2C9 by RTV daily supervision of dosage and clinical evaluation MET single dose 5mg Crossover 11 vol RTV 15 days AUC MET ↓ 36%, C = single dose 20mg study, dose- 500mg bid Cmax MET ↓ 38% normalised MET 90mg/day Case report 1 HIV+, RTV/SQV Induction Shakiness, blurred male 400/400mg bid CYP3A4, may be vision, anxiety, that 2C9 induction hypotension etc offsets 3A4/2D6

MET maintenance Crossover 12 HIV+ 15 days RTV/SQV Induction AUCtotal (R)-MET ↓ PD evaluations 400/400mg bid CYP2C19, 32%, AUCfree (R)-MET showed no (RTV liquid) CYP2B6 by RTV ↓ 20%, 37% of ↓ in difference total (R)-MET conc. = protein displacement MET T SQV (sole PI) [see Induction/inhibition Conc. MET ↑ or ↓ Based on Dosage also combination (?) CYP3A by similar adjustment may with RTV] SQV metabolism be needed via CYP3A Methylenedioxy Case report 1 HIV+, RTV 600mg bid Hepatic inhibition Conc. MDMA 4.56 Patient Discourage 114,157,158 metamphetamine (MDMA) male CYP2D6 by RTV, mg/L (normally 0.5 deficiency in coadministration ±180mg deficiency in mg/L); hypertonic, CYP2D6, illicit substances CYP2D6, sweating profusely, impaired impaired hepatic tachypnoeic, hepatic function tachycardia, cyanosed function? Patient died MDMA (+ GHB) Case report 1 HIV+, RTV/SQV Inhibition Sustained effect male 400/400mg bid metabolism MDMA: repetitive, by RTV clonic contractions of legs, and left side body MDMA + amyl nitrate Case report 1 HIV+, RTV/SQV Inhibition CYP by Autopsy: moderate male 400/400mg bid NO (metabolite atheroma, up to 40%

Clin Pharmacokinet 2003;42(3) amyl nitrate), occlusion; MDMA inhibition CYP2D6 plasma conc. 0.5 mg/L, by RTV traces DIA/nor-DIA in blood Metoprolol (MEO) T RTV Inhibition CYP2D6 Conc. MEO ↑ Dosage reduction 43 by RTV (>50%) MEO may be needed 253 Continued over page 254 © Adis International Limited. Allrights reserved. Table III. Contd Coadministered agent Type of study Subjects Antiretroviral agent Interaction Effect of interaction Comments Advice References and dosage involved (n) and dosage mechanism Metronidazole (MEN) T AMP, DLV, IDV, Inhibition CYP3A Conc. MEN ↑↑ risk for Dose reduction NFV, SQV by PI/DLV convulsions MEN may be necessary MEN T DDC, DDI, D4T Similar toxicity Peripheral neuropathy Avoid where 20,21,24 profile possible, monitor for peripheral neuropathy MEN T LPV/RTV(-liquid), Irreversible Disulfiram-like LPV/RTV and CI (liquid). A = 39 RTV(-liquid) inhibition ADH by reactions by ↑ conc. RTV liquids LPV/RTV, RTV MEN, inhibition acetaldehyde, contain alcohol, capsules. CYP3A by RTV conc. MEN ↑ ↑ risk for Dosage reduction convulsions MEN may be necessary Mexiletine (MEX) T RTV Inhibition CYP2D6 Cardiac events have Use with caution. 43 by RTV been reported with this Dosage reduction combination (>50%) MEX may be needed Midazolam (MID) T AMP, DLV, EFV, Inhibition CYP3A Conc. MID ↑ Risk for CI 28,30,36,37, IDV, LPV/RTV, by PI/DLV/EFV prolonged or ↑ 39,41,43,159 NFV, RTV sedation, respiratory depression MID 2–15mg IV bolus form Outpatient 73 HIV+ PI No change in ↑ Sedation? A = oxazepam, bronchoscopies oxygenation or lorazepam procedure time MID 5mg IV Case report 1 HIV+, SQV-HGC Inhibition CYP3A4 Flumazenil 300µg IV Control: Combination not 45,48,160, male 600mg tid by SQV necessary, >5h free of awaking recommended 161 sedative effects spontaneously, >2h free of sedative effects

MID 7.5mg Double-blind, 12 vol SQV-SGC 5 days Inhibition CYP3A4 PO: AUC, Cmax MID ↑ Initial dosage

Clin Pharmacokinet 2003;42(3) PO 0.05mg/kg IV randomised, 1200mg tid in gut wall, liver 2.3-, 5-fold, resp.; Cmax reduction of 50%; 2-phase by SQV αOH-MID ↓ 38%. careful titration crossover IV: AUC, CL MID ↑ 2.4- fold, ↓56%, resp.; Cmax αOH-MID ↓ 43%

Morphine (MOR) T RTV Induction CYP3A, Conc. MOR ↓ Dose increase 43,72 de Maatet al. incl. GT, CYP1A2, MOR may be and possibly needed to get CYP2C9 by RTV desired effect Drug InteractionswithAntiretrovirals © Adis International Limited. Allrights reserved. Mucosal protectives T DDC, DLV, IDV ↑ gastric pH ↓ absorption DDC, DDC, DLV, IDV containing bismuth (MUC) by MUC DLV, IDV >1h before or after MUC Nefazodone (NEF) T AMP, DLV, IDV, Inhibition CYP3A Conc. NEF ↑ Dosage reduction 12,43 LPV/RTV, NFV, by PI/DLV NEF may be SQV needed. NEF 7 days 75mg bid, Case report 1 HIV+ RTV ss Inhibition CYP3A4 Headache, confusion, Start with ≤50– 162 2 days 150mg bid by RTV dizziness, nausea, 100mg qd and intense anxiety, increase slowly if agitation necessary Nitrofurantoin (NIT) T DDC, DDI, D4T Similar toxicity Peripheral neuropathy Avoid where 20,21,24 profile possible, monitor for peripheral neuropathy Nizatidine (NIZ) T DLV, IDV ↑ gastric pH ↓ absorption DLV, IDV Clinical Long-term use 28 by NIZ significance NIZ with DLV, unknown IDV not recommended. TDM DLV/IDV recommended ↓ Olanzapine (OLE) Crossover 14 vol RTV 12 days Induction CYP1A2 AUC, t1⁄2β , CL/F OLE All had wild Dosage increase 163 single dose 10mg escalated to and GT by RTV 53%, 50%, ↑ 115%, type CYP1A2 OLE may be 500mg bid resp. genotype needed to get desired effect Omeprazole (OME) T DLV ↑ gastric pH ↓ absorption DLV Clinical Long-term use 28,134 by OME significance OME with DLV unknown not recommended OME 20mg bid (n = 1) Case reports 4 HIV+ DLV ss ↓ trough conc. DLV 1/4 used [rabeprazole 20mg qd (n = rabeprazole 1)] (see also lansoprazole) 20mg qd → ↓ trough conc. DLV OME 20–40mg daily Retrospective 9 HIV+ IDV 800mg tid Induction 3A by n = 4 <95% confidence Variable effect: A = ranitidine 164,165 case series OME; pH ↑ by interval of ref., n = 4 interindividual (only pH ↑), IDV → ↓ within 95% confidence variability IDV Clin Pharmacokinet 2003;42(3) OME 1000mg tid solubility IDV interval, n = 1 > 95% PK? confidence interval of ref. OME 14 days 40mg qd Multiple dose 8 vol, male IDV single Hepatic induction, d5: AUC IDV ↓ 2.4%. TDM IDV OME dose 800mg ↓ absorption by d14: AUC IDV ↓ 9.5% recommended OME (n = 4: >25% ↓) 255 Continued over page 256 © Adis International Limited. Allrights reserved. Table III. Contd Coadministered agent Type of study Subjects Antiretroviral agent Interaction Effect of interaction Comments Advice References and dosage involved (n) and dosage mechanism Oral contraceptives (OC), In vitro AZT Inhibition 0.5 mmol/L 46.8% Conc. AZT Monitor blood 57 ethinylestradiol (EE) (human liver glucuronidation enzyme activity probably ↑. counts regularly component microsomes) by EE remained; 10 mmol/L Significance? 21.0% enzyme activity remained OC-EE T - AMP ? Effect on EE not Use additional 36 known, probably conc. methods of birth EE ↓ control

OC-EE single dose S 13 vol EFV 10 days Not fully AUC EFV ↑ 2%, Cmax Clinical Use additional 30,166 400mg qd characterised: EFV ↑ 5%, AUC EE ↑ significance methods of birth CYP-mediated, 37%, Cmax EE ↑ 8% unknown control glucuronidation

OC-EE 7 days 35µg S 12 vol LPV/RTV Induction CYP AUC EE ↓ 42%, Cmax Use additional 39,167 ® (Ortho Novum ) 400/100mg bid by LPV/RTV EE ↓ 41%, Cmin EE ↓ methods of birth 58% control

OC-EE 15 days 35µg S 12 NFV 7 days Induction of AUC EE ↓ 47%, Cmax Use additional 14,41 750mg tid estrogen EE ↓ 28% methods of birth glucuronidation control by NFV

OC-EE single dose 50µg Open-label, 23 vol RTV 16 days Induction AUC EE ↓ 41%, Cmax Use additional 43,168 multiple-dose escalating dose glucuronidation, EE ↓ 32% methods of birth to 500mg bid and CYP- control mediated pathway

OC, norethindrone (NET) S 12 vol LPV/RTV 14 days Induction AUC, Cmax, Cmin NET ↓ Use additional 39,167 component, 21 days 1mg 400/100mg bid metabolism by 17%, 16%, 32% methods of birth qd (Ortho Novum®) LPV/RTV control

OC-NET 15 days 0.4mg qd S 12 vol NFV 7 days Induction AUC NET ↓ 18%, Cmax Clinical Use additional 41 750mg tid metabolism NET ↔ significance methods of birth by NFV unknown control OC-NET/EE 7 days 1mg S ? IDV 7 days Inhibition CYP3A4 AUC EE ↑ 24%, AUC Clinical Use additional 37 NET/35µg EE qd 800mg tid by IDV NET ↑ 26% significance methods of birth Clin Pharmacokinet 2003;42(3) (Ortho Novum®) unknown control OC-NET/EE single dose Open-label, 14 HIV+ NVP 14 days Induction CYP3A4 AUC NET/EE ↓ PK analysis on Use additional 169 ® ↓ (Ortho Novum ) crossover 200mg, qd, by NVP 18/29%, t1⁄2β EE 26%, 10 subjects methods of birth thereafter no effect on NVP PK control 200mg bid de Maatet al. Drug InteractionswithAntiretrovirals © Adis International Limited. Allrights reserved. Oxazepam (OXE) In vitro AZT Inhibition 0.5 mmol/L 89.5% Probably conc. 57,170 (human liver glucuronidation enzyme activity AZT ↑. microsomes) by OXE remained, 10 mmol/L Significance? 67.9% enzyme activity remained OXE 2 days 15mg tid 3-phase, 6 HIV+ AZT 2 days Frequency crossover 100mg every 4h headache ↑ 2 Paclitaxel (PAC) 100mg/m Case report 1 HIV+, Different ARV Similar AUC, Cmax PAC ↓ Modify dose PAC 171,172 3h infusion male drugs (RTV/SQV metabolism: when necessary. or IDV, NVP) CYP, P-gp Monitor leucocytes regularly PAC 100mg/m2 3h infusion Case report 2 HIV+, DLV + SQV Inhibition CYP3A Mucositis, febrile 1 PAC dose male/ by DLV, SQV neutropenia, total biweekly female alopecia (n = 1), 60mg/m2 3h respiratory distress infusion = (n = 1) tolerable AE Pentamidine (PET) T DDI, 3TC, D4T Similar toxicity Pancreatitis Avoid where 4 profile possible, monitor for pancreatitis Perazine (PER) T RTV Inhibition CYP2D6 Conc. PER ↑. Based on Dosage reduction by RTV, PER Conc. RTV ↑ interaction with PER, RTV may perphenazine be needed. TDM RTV recommended Periciazine (PEC) T RTV Inhibition CYP2D6 Conc. PEC ↑. Based on Dosage reduction by RTV, PEC Conc. RTV ↑ interaction with PEC, RTV may perphenazine be needed. TDM RTV recommended Perphenazine (PEZ) T RTV Inhibition CYP2D6 Conc. PEZ ↑. Dosage reduction 12,43 by RTV, PEZ Conc. RTV ↑ PEZ, RTV may be needed

Phenobarbital (PHB) Population 8 HIV+ DLV Induction CYP3A Ctrough DLV ↓. TDM DLV/PHB 28 [see also barbiturates] PK data by PHB, inhibition Conc. PHB ↑ recommended. Clin Pharmacokinet 2003;42(3) CYP3A by DLV (T) A = valproic acid Phenytoin (PHT) T AMP, EFV, IDV, Induction CYP3A Conc. PI/NNRTI ↓. TDM PI/NNRTI/ 30,36,37,39, LPV/RTV, NVP, by PHT/EFV/ Conc. PHT ↑ (PI) or PHT 43,45,48 RTV, SQV NVP, inhibition ↓ (EFV/NVP) recommended. CYP3A by PI A = valproic acid PHT single dose 300mg S 12 HIV+ AZT 200mg 4dd, ? CL AZT ↓ 30%. Monitor blood 25 ss conditions PK PHT ↔ counts regularly 257 Continued over page 258 © Adis International Limited. Allrights reserved. Table III. Contd Coadministered agent Type of study Subjects Antiretroviral agent Interaction Effect of interaction Comments Advice References and dosage involved (n) and dosage mechanism PHT T DDC, DDI, D4T Similar toxicity Peripheral neuropathy Avoid where 20,21,24 profile possible, monitor for peripheral neuropathy

PHT Population 8 HIV+ DLV Induction CYP3A Ctrough DLV ↓. Conc. TDM PHT/DLV 28 PK data by PHT, inhibition PHT ↑ recommended. CYP3A by DLV (T) A = valproic acid

PHT 7 days 300mg qd Parallel design 15, 12 vol NFV 7 days Induction CYP3A AUC24, Cmax, Cmin PHT Possibly conc. TDM PHT/NFV 41,173,174 1250mg bid by NFV ↓ 30%, 21%, 39%, NFV ↓ recommended. resp.; NFV/M8 not A = valproic acid determined PHT ss 300mg/day Case report 1 HIV+, NFV 750mg tid Induction CYP by Numbness left upper Interaction via male NFV ? (or inter- limb followed by CYP2C9, action with generalised tonic-clonic 2C19? AZT/ D4T) seizure; serum conc. PHT ↓ Pimozide (PIM) T AMP, DLV, IDV, Inhibition CYP3A Conc. PIM ↑ Risk for cardiac Combination not 36,37,39,43 LPV/RTV, NFV, by PI/DLV toxicity recommended. RTV, SQV CI (AMP, IDV, LPV/RTV) Pipotiazine (PIP) T RTV Inhibition CYP2D6 Conc. PIP ↑. Based on Dosage reduction by RTV, PIP Conc. RTV ↑ interaction with PIP, RTV may be perphenazine needed. TDM RTV recommended. Piroxicam (PIR) T RTV Inhibition Conc. PIR ↑ Risk for ↑ GI CI. A = 7,44 metabolism by and CNS diclofenac, RTV toxicity ibuprofen

Pravastatin (PRA) 4 days S 12 vol LPV/RTV 14 days Inhibition CYP3A AUC, Cmax PRA ↑ 33%, PRA is to No dosage 65 20mg qd 400/100mg bid by LPV/RTV 26%, resp. AUC, Cmax, minor extent adjustment Cmin LPV ↓ 5%, 2%, metabolised by required

Clin Pharmacokinet 2003;42(3) 12%, resp. CYP3A PRA 4 days 40mg qd Randomised, 14 vol RTV/SGQ-SGC 4 Induction AUC PRA ↓ 50% Higher doses 68 open label, days 400/400mg glucuronidation PRA may be multiple dose bid by RTV needed Prazepam (PRZ) T RTV Inhibition CYP3A Conc. PRZ ↑ Based on A = oxazepam, by RTV similar lorazepam de Maatet al. metabolism via CYP3A Drug InteractionswithAntiretrovirals © Adis International Limited. Allrights reserved. Prednisone (PRE) T RTV Inhibition CYP3A Conc. PRE ↑ Monitor toxicity 43 by RTV PRE, dosage reduction (>50%) may be necessary Prednisolone (PRD) T RTV Inhibition CYP3A Conc. PRD ↑ Based on Monitor toxicity 43 by RTV interaction PRD, dosage with PRE reduction may be necessary Primaquine (PRQ) T AZT Similar toxicity Peripheral neuropathy Avoid where 4,25 profile possible, monitor blood counts regularly Primidone (PRI) T AMP, EFV, DLV, Induction CYP3A Conc. PI/NNRTI ↓ Chemically TDM PI/NNRTI 28,30,36,37, IDV, LPV/RTV, by PRI related to recommended. 39,41,43,45, NFV, RTV, SQV barbiturates A = valproic acid 48

Probenecid (PRO) 2-part, 8 HIV+ AZT 3 days 200mg Inhibition hepatic AUC AZT ↑ 80%. CLR Avoid 25,175-178 3 days 500mg tid open-label every 4h glucuronidation, GAZT ↓ 58% combination renal organic where possible, anion secretory reduce dosage mechanism by AZT. Monitor PRO blood counts regularly. PRO 28 days 500mg tid S 8 vol, male AZT 200mg tid n = 4: completed study, 3/4 severe rash n = 4: discontinuation and PRO because of rash constitutional symptoms PRO 3 days 500mg every S 2 vol, male AZT single dose AUC AZT ↑ 115%, CL 6h, >3h prior to AZT 200mg AZT ↓ 51%, AUC GAZT ↑ >3.5-fold PRO 500mg every 6h, Balanced, 7 HIV+ AZT 2mg/kg tid AUC AZT, CL ↑ 106%, separated >2h from AZT crossover (oral solution) ↓ 45%, resp. dose GAZT/AZT urine ↓58% PRO 500mg >2h prior and Randomised 2- 12 HIV+ DDC single dose Inhibition tubular AUC DDC ↑54%, CL Specific Monitor for 24,179 >4h after DDC way crossover 1.5mg secretion by PRO DDC ↓ 37%, CLR DDC nucleoside peripheral ↓ transport neuropathy, Clin Pharmacokinet 2003;42(3) 42% system? dosage reduction DDC may be needed Prochlorperazine (PRC) T RTV Inhibition CYP2D6 Conc. PRC ↑. Based on Dosage reduction by RTV, PRC Conc. RTV ↑ interaction with PRC, RTV may perphenazine be needed. TDM RTV recommended 259 Continued over page 260 © Adis International Limited. Allrights reserved. Table III. Contd Coadministered agent Type of study Subjects Antiretroviral agent Interaction Effect of interaction Comments Advice References and dosage involved (n) and dosage mechanism Promethazine (PRM) T RTV Inhibition CYP2D6 Conc. PRM ↑. Conc. Based on Dosage reduction by RTV, PRM RTV ↑ interaction with PRM, RTV may perphenazine be needed. TDM RTV recommended Propafenone (PRP) T LPV/RTV, RTV Inhibition CYP2D6 Conc. PRP ↑ Risk for cardiac CI 39,43 by PI arrhythmias Pyrazinamide (PYR) Prospective, 4 HIV+/ AZT ? n = 4: very low PYR 2h serum Avoid combination 180 observational TBC+, 7 conc. concentrations HIV+/ were drawn TBC+ (controls) Pyrimethamine (PYM) T AZT Similar toxicity Haematological toxicity Avoid where 4,25 profile possible, monitor blood counts regularly PYM T RTV Inhibition/induction Variable or Monitor blood 14 CYP3A by RTV unknown effect counts and efficacy PYM regularly Quinidine (QUI) T AMP, DLV, Inhibition CYP3A Conc. QUI ↑ Risk for cardiac CI (RTV, NFV). 28,36,39,41, LPV/RTV, NFV, by PI/DLV toxicity A = indinavir, 43,45 RTV, SQV TDM QUI recommended Quinine (QUN) T RTV Inhibition CYP3A Conc. QUN ↑ Risk for cardiac Monitor toxicity 43 by RTV toxicity QUN, dose reduction QUN may be needed

Ranitidine (RAN) single Open, 12 HIV+ DDI single dose ↑ BA by ↑ gastric AUC, Cmax DDI ↑ 14%, No dosage RAN 2h prior to 20,181 dose 150mg, 2h prior to DDI randomised, 3- 375mg pH by RAN, ↓ 13%, resp. AUC, Cmax modification; DDI. A = DDI EC way crossover absorption RAN in RAN ↓ 16%, ↔, resp. buffer

Clin Pharmacokinet 2003;42(3) presence of formulation antacid DDI adequate protection RAN T DLV, IDV ↑ gastric pH by ↓ absorption DLV, IDV Clinical Long-term use 28 RAN significance RAN with DLV,

unknown IDV not de Maatet al. recommended. TDM DLV/IDV recommended Drug InteractionswithAntiretrovirals © Adis International Limited. Allrights reserved. RAN 150mg 2 doses S 12 vol SQV-HGC single ? AUC, Cmax SQV ↑ TDM SQV 45,48 dose 600mg 67%, 74%, resp. recommended Ribavirin (RIB) T AZT Interference with Conc. triphosphate Avoid where 25,182 phosphorylation anabolite-AZT ↓ (active) possible, monitor by RIB blood counts regularly RIB 2, 20 µmol/L In vitro AZT 10, 100 ↑ formation dTTP ↓ phosphorylation AZT; Concentration µmol/L by RIB → ↓ effect primarily on AZT- dependent; ↓ activity thymidine MP rather than active AZT-MP, thus kinase AZT-TP ↓ toxicity RIB T DDC, D4T Similar toxicity Peripheral neuropathy Avoid where 24 profile possible, monitor for peripheral neuropathy RIB 6 months Case reports 3 HIV+, DDI 400mg qd RIB promotes Moderate Avoid where 20,21,183 800–1200 mg/day male phosphorylation hyperlactacidaemia, possible, dosage by inhibition of IMP severe clinical reduction DDI symptoms; ↑ may be needed intracellular/mitochondrial conc. of ddATP (suggested) RIB T DDI Similar toxicity Peripheral neuropathy profile

Rifabutin (RFB) Open-label, 12 vol AMP 10 days Inhibition CYP3A4 AUC, Cmax, Cmin RFB ↑ Combination Monitor 36,184 10 days 300mg qd randomised, 1200mg bid by AMP 2.9-, 2.2-, 3.7-fold, poorly neutrophil counts parallel-group, resp. AUC, Cmax, Cmin tolerated: only regularly, dosage 3-period 25-O-desacetyl-RFB 6 evaluable, reduction RFB ↑ 13.35-, 7.39-, 32.9- PK AMP? >50%. TDM AMP fold, resp. recommended RFB T AZT Similar toxicity Haematological toxicity Avoid where 4,25 profile possible, monitor blood counts regularly

RFB 14 days 300mg qd Open-label, 7, 5 HIV+ DLV 30 days Induction CYP3A CL DLV ↑ 445%, Cmin, Avoid where 28,185,186 ↓ Clin Pharmacokinet 2003;42(3) parallel-group, (controls) 400mg tid by RFB, inhibition Cmax DLV 95%, 75%, possible, monitor multiple-dose, CYP3A by DLV resp. Cmax RFB ↑ 20%, neutrophil counts randomised Ctrough, CL RFB ↓ 40%, regularly. 20%, resp. TDM DLV recommended, DLV 600mg tid

RFB 30 days 300mg S 6 HIV+ DLV 14 days Inhibition hepatic AUC, Cmin RFB ↑ RFB compared 400mg tid CYP3A by DLV 242%, 455%, resp. with historical AUC DLV ↓ 80% data RFB 300mg qd S 7 HIV+ DLV 400mg tid AUC RFB ↑ 100% 261 Continued over page 262 © Adis International Limited. Allrights reserved. Table III. Contd Coadministered agent Type of study Subjects Antiretroviral agent Interaction Effect of interaction Comments Advice References and dosage involved (n) and dosage mechanism

RFB 7 days 300mg qd (see Sequential, 8- 10 HIV+ D4T 7 days Inhibition Cmax D4T ↓ 35% when Significance? 81 also clarithromycin + D4T part, multiple- 40mg bid absorption by combined with CLA + and fluconazole + D4T) dose, RFB? RFB + FLU non-blinded, randomised RFB 14 days 300mg qd S EFV 14 days Induction CYP3A Conc. RFB ↓, PK EFV? Increase dose 30,187 600mg qd by EFV RFB to 450– 600mg/day. TDM EFV recommended RFB (1) 300mg qd, S IDV 800mg tid Inhibition CYP3A (1) AUC IDV ↓ 32%, AUCs Reduce dosage 37,188 (2) 150mg qd by IDV, induction AUC RFB ↑ 204%. compared with RFB >50% CYP3A by RFB (2) AUC IDV ↓ 31%, RFB 300mg qd (300mg qd 2–3 AUC RFB ↑ 60% without IDV times/week), monitor neutrophil counts regularly RFB 150mg qd when + IDV, A: multiple- ? 1000mg tid when A: AUC RFB 150mg qd Sequential IDV 1000mg tid, 300mg qd when alone dose, 3-period, + RFB, 800mg tid + IDV 1000mg tid = administration TDM IDV randomised when alone 60% ↑ than AUC RFB = simultaneous recommended crossover. B: 300mg qd. B: AUC IDV administration multiple-dose, 1000mg tid + RFB when RFB PK 2-period 150mg qd = AUC IDV were compared sequential 800mg tid RFB 10 days 150mg qd S 14 vol LPV/RTV 20 days Inhibition CYP3A AUC RFB + 25-O- Maximum dose 39 400/100mg bid by LPV/RTV desacetyl-RFB ↑ 5.7- RFB 150mg fold. AUC LPV ↑ 17% every other day or 3× per week. Monitor neutrophil counts regularly. TDM LPV/RTV

Clin Pharmacokinet 2003;42(3) recommended

RFB 8 days 150mg qd S 12 vol NFV 7/8 days Inhibition CYP3A AUC, Cmax RFB ↑ 83%, NFV 1250mg Reduce dosage 41 750mg tid by NFV, induction 19%, resp. AUC, Cmin bid shows no RFB >50% CYP3A by RFB NFV ↓ 23%, 18%, resp. change in (300mg qd 2–3 PK when times/week),

combined with monitor de Maatet al. RFB 150mg qd neutrophil counts regularly Drug InteractionswithAntiretrovirals © Adis International Limited. Allrights reserved. RFB 8 days 300mg qd S 10 vol NFV 7/8 days AUC, Cmax RFB ↑ TDM NFV 750mg tid 207%, 146%, resp. recommended, AUC, Cmin NFV ↓ 32%, preferred dosage 25%, resp. NFV 1250mg bid

RFB S 19 NVP Induction CYP3A Ctrough ss NVP ↓ 16% Avoid where 33 by RFB possible, TDM NVP recommended

RFB 24 days 150mg qd Multiple-dose, 5, 11 RTV 10 days Inhibition CYP3A AUC, Cmax, Cmin RFB ↑ 8 patients RTV/SQV 189,190 randomised, (control) vol 500mg bid (intestinal, 4-, 2.5-, 6-fold, resp. discontinued 400/400mg bid + parallel-group, (escalation hepatic, or combi) AUC, Cmax, Cmin 25-O- because of AE RFB double-blind scheme) by RTV desacetyl-RFB ↑ 35-, (1 control, 300mg/week or 16-, 200-fold, resp. 7 case). 150mg every 3 days, monitor neutrophil counts regularly. TDM RTV/SQV recommended RFB S SQV AUC SQV ↓ 45% RTV/SQV 45,48,190 400/400mg bid + RFB 300mg/week or 150mg every 3 days, monitor neutrophil counts regularly.

RFB 14 days 300mg qd Preliminary 12 HIV+ SQV-HGC 14 days Induction CYP3A AUC, Cmax SQV ↓ TDM RTV/SQV data 600mg tid by RFB 43%, 30%, resp. recommended

Rifampicin (RIF) 10 days Open-label, 12 vol AMP 10 days Induction AUC, Cmax, Cmin, CL Combination CI; A = AMP + 36,184 600mg qd randomised, 1200mg bid hepatic/intestinal AMP ↓ 82%, 70%, poorly RFB reduced parallel-group, CYP3A4 by RIF 92%, ↑ 5.45-fold resp. tolerated: only dose > 50% 3-period 6 evaluable

RIF 14 days 600mg qd 2-treatment, 8 HIV+ AZT 14 days Induction AUC, Cmax AZT ↓ 47%, No dosage 25,191,192 3-period, single 200mg tid glucuronidation, 43%, resp. AUC: adjustment sequence, amination by RIF; GAZT/AZT ↑ 99%; necessary

Clin Pharmacokinet 2003;42(3) repeated induction AMT AMT/AZT ↑ 36% measures formation RIF 600mg qd S 10 AZT 200mg qd AUC AZT ↓ 48% RIF 600mg qd 4 HIV+, AZT 200–500mg AUC normalised AZT ↓ AUC AZT ↔ male bid/tid > 50%; t1⁄2β for n = 3 compared with AUC AZT of population not using RIF 263 Continued over page 264 © Adis International Limited. Allrights reserved. Table III. Contd Coadministered agent Type of study Subjects Antiretroviral agent Interaction Effect of interaction Comments Advice References and dosage involved (n) and dosage mechanism RIF 600mg qd S 7 HIV+ DLV 400mg tid Induction CYP3A AUC DLV ↓ 96%; CL Conc. RIF ↑ (T) CI; A = NVP 28,193 by RIF, inhibition DLV ↑ 27-fold + RFB CYP3A by DLV RIF 15 days 600mg qd S 7, 5 HIV+ DLV 30 days Metabolite Virtually 400mg tid formation/metabolite negligible ss elimination ↑ 16-fold Ctrough DLV

RIF 7 days 600mg qd S 12 vol EFV 14 days Induction CYP3A AUC, Cmax EFV ↓ 13%, 2 patients had A = RFB 450– 30,194,195 600mg qd by RIF, induction 14%, resp. n = 10: ↑ AUC, Cmax 600mg/day. CYP3A by EFV AUC, Cmax EFV ↓ 33%, EFV. Clinical Increase dose 23%, resp. significance EFV to 800mg unknown qd. TDM EFV recommended.

RIF 7 days Randomised, 24 HIV+ EFV 600mg 7/8 (600mg qd) Cmax, Conc. RIF ↓ (T) 3-group qd/800mg qd Cmin, AUC EFV ↓ 30%, 24%, 22%, resp. EFV 800mg qd: conc. in therapeutic range RIF 7 days 600mg qd S IDV 7 days Induction CYP3A4 AUC IDV ↓ 89% Avoid 14,37,196 800mg tid by RIF, inhibition combination; IDV CYP3A4 by IDV 1000mg tid + reduced dose RFB (>50%), TDM IDV recommended

RIF single dose 600mg S 11 HIV+ IDV 14 days AUC24 RIF ↑ 73% A = 9-month 800mg tid streptomycin- based regimen

RIF 10 days 600mg qd S 22 vol LPV/RTV 20 days Induction CYP3A AUC, Cmax, Cmin LPV ↓ Conc. RIF ↑ (T) CI. A = RFB 39,167 400/100mg bid by RIF, inhibition 75%, 55%, 99%, resp. maximum CYP3A by dosage 150mg LPV/RTV every other day ×

Clin Pharmacokinet 2003;42(3) or 3 per week. TDM LPV/RTV recommended

RIF 7 days 600mg qd Randomised 12 vol NFV 6 days Induction CYP3A AUC8, Cmax NFV ↓ Conc. RIF ↑ (T) CI; A = RFB 130,197 crossover 750mg tid ss by RIF, inhibition 82%, 76% reduced dosage CYP3A by NFV >50% + NFV de Maatet al. 1250mg bid Drug InteractionswithAntiretrovirals © Adis International Limited. Allrights reserved. RIF 7 days 600mg qd Case report 1 HIV+ NFV ss 27 mg/kg Blocking RIF- AUC24 (NFV + M8), Addition of TDM NFV (+ M8) 2 infant bid (+ 380mg/m induced Cmin (NFV + M8) ↑ RTV resulted in recommended RTV bid) metabolism NFV 130%, 142% compared highly elevated by addition RTV with population values M8 conc.

RIF 43 days 600mg qd Open-label, 22 HIV+ NVP 28 days Induction CYP3A4 Average conc., Cmin RIF 600mg Consider NVP 33,198,199 single arm 200mg bid by RIF, NVP NVP ↓ 58%, 68%, twice weekly 300mg bid, TDM resp. n= 3: Ctrough ss less marked NVP NVP ↓ 37% drug interaction recommended. than with daily A = RFB RIF. Conc. RIF ↓ (T)

RIF 10 days Parallel design 7 / 9 RTV 20 days Induction CYP3A AUC, Cmax RTV ↓ Conc. RIF ↑ (T) A = RFB 150mg 43,200 600mg/300mg qd 500mg bid by RIF, inhibition 35%, 25%, resp. every other day. CYP3A by RTV TDM RTV recommended

RIF 28 weeks 600mg qd Pilot, non- 18 HIV+ RTV 28 weeks n = 8: median Cmin RTV 6 discontinued randomised, 600mg bid 2.22 mg/L, > IC90 at because of open-label most time-points. RIF intolerance to level within normal limits RTV liquid

RIF 7 days 600mg qd S 12 vol SQV-HGC 14 days Induction CYP3A AUC, Cmax SQV ↓ Conc. RIF ↑ (T) Avoid 45,48,88, 600mg tid by RIF, inhibition 84%, 79%, resp. combination or 101,201 CYP3A by SQV use SQV combined with RTV, TDM RTV/SQV recommended

RIF Retrospective AUC, Cmax SQV ↓ review 70%, 65%, resp.

RIF 14 days 600mg qd Open-label, 14 vol SQV-SGC AUC, Cmax SQV ↓ SQV plasma randomised, 2- 1200mg tid ss 70%, 65%, resp. concentrations way crossover < EC50 SQV

RIF 14 days 600mg qd Open-label, 11 HIV+ SQV-SGC AUC, Cmax SQV ↓ substudy 1200mg tid ss 46%, 43%, resp. Risperidone (RIS) Case report 1 HIV+, RTV/IDV Inhibition CYP2D6 Neuroleptic malignant Avoid combination 12,43,202 1.5mg daily female by RTV and syndrome: persistent Clin Pharmacokinet 2003;42(3) CYP3A4 by fever, rigidity, tremor, RTV/IDV autonomic instability, ↑ CPK. AUC RIS ↑ 1. 5–3-fold by RTV 265 Continued over page 266 © Adis International Limited. Allrights reserved. Table III. Contd Coadministered agent Type of study Subjects Antiretroviral agent Interaction Effect of interaction Comments Advice References and dosage involved (n) and dosage mechanism Roxithromycin Open-label, 6 HIV+ NFV Protein (AAG) 3/6 no baseline TDM NFV 203 (ROX) 300 or 600mg/day randomised binding resistance to NFV: recommended displacement by median ↑ HIV-RNA ROX? 0.96 log after 1 week. 3/6 baseline resistance to NFV: transient/no virological response Salicylic acid (SAC) In vitro AZT Inhibition 0.5 mmol/L 99.7% Conc. AZT Monitor blood 57 (human liver glucuronidation enzyme activity probably ↑. counts regularly microsomes) by SAC remained; 10 mmol/L Significance? 52.2% emzyme activity remained Selective serotonin T RTV Inhibition CYP3A Conc. SSRI ↑ Use lowest dose 12,43 reuptake inhibitors (SSRI) and/or CYP2D6 SSRI possible [see also fluoxetine] by RTV and titrate Sildenafil (SIL) T AMP, DLV, Inhibition CYP3A Conc. SIL ↑ Based on Starting dose SIL 28,36,39,41 LPV/RTV, NFV by PI/DLV studies with 25mg in 48h, other PIs monitor for AEs

SIL single dose 25mg S 6 HIV+ IDV 800mg tid ss Inhibition CYP3A4 AUC8, Cmax IDV ↑ PD effect >72h Starting dose SIL 204 IDV/SIL 11%, 48%, resp. post ingestion 25mg in 48h Headache, flushing, dyspepsia, rhinitis, blood pressure ↓ SIL 25mg Case report 1 HIV +, RTV/SQV Inhibition CYP3A4 Severe central Starting dose SIL 43,205,206 male 400/400mg bid (first-pass)/2C9 chest pain 25mg in 48h (systemic CL) by RTV

SIL single dose 100mg Independent, 28 vol RTV 8 days AUC, Cmax SIL ↑ 11-, open, 500mg bid 3.9-fold randomised, (escalation placebo- scheme) controlled, Clin Pharmacokinet 2003;42(3) parallel-group

SIL 100mg Independent, 27 vol SQV-SGC 7 days Inhibition CYP3A4 AUC, Cmax SIL ↑ 3.1-, See also case Starting dose SIL 45,48,206 open, 1200mg tid (both intestinal 2.4-fold report 25mg in 48h randomised, and hepatic) RTV/SQV placebo- by SQV de Maatet al. controlled, parallel-group Drug InteractionswithAntiretrovirals © Adis International Limited. Allrights reserved. Simvastatin (SIM) T AMP, DLV, IDV, Inhibition CYP3A Conc. SIM ↑ Based on Combination not 36,37,39,45, LPV/RTV, SQV by PI/DLV interaction with recommended. 48,207 atorvastatin, CI (AMP), risk for A = fluvastatin, myopathy pravastatin SIM Case report 1 HIV+, IDV/RTV Inhibition CYP3A RTV was added to IDV male by PI/DLV and SIM → rhabdomyolysis, renal failure

SIM 14 days 20mg qd Open-label, 16 vol NFV 14 days Inhibition CYP3A AUC, Cmax SIM ↑ Risk for CI; A = 41,66 sequential, 1250mg bid by NFV 505%, 517%, resp. myopathy, pravastatin multiple-dose including rhabdomyolysis SIM 4 days 40mg qd Randomised, 14 vol RTV/SQV-SGC 14 Inhibition CYP3A AUC SIM ↑ 30-fold Risk for CI; A = 43,68 open label, days 400/400mg by RTV/SQV myopathy, fluvastatin, multiple dose bid including pravastatin rhabdomyolysis Sirolimus (SIR) T AMP, DLV, IDV, Inhibition CYP3A Conc. SIR ↑ TDM SIR Monitor blood 36,39 LPV/RTV, NFV, by PI/DLV recommended. counts regularly. RTV, SQV Risk for TDM SIR anaemia, recommended thrombo- cytopenia St John’s wort (SJW) T AMP, DLV, EFV, Induction CYP3A Conc. PI/NNRTI ↓ Coadministration 36,39,41,43 LPV/RTV, NFV, by SJW not RTV, SQV recommended. TDM PI/NNRTI recommended

SJW 14 days 300mg tid Open-label 8 vol, male IDV 800mg tid Induction CYP3A4 AUC8, Cmin, Cmax IDV ↓ After 4th dose Coadministration 37,208 by SJW, maybe 57%, 49–99%, 28%, IDV PK not effect on P-gp resp. recommended. TDM IDV recommended SJW Population 5 HIV+ NVP Induction CYP3A4 CL NVP ↑ 35% Coadministration 33,209 PK data (n = 176) by SJW not

Clin Pharmacokinet 2003;42(3) recommended. TDM NVP recommended Sulfadiazine (SUF) T AZT Similar toxicity Haematological toxicity Avoid where 4,25 profile possible, monitor blood counts regularly 267 Continued over page 268 © Adis International Limited. Allrights reserved. Table III. Contd Coadministered agent Type of study Subjects Antiretroviral agent Interaction Effect of interaction Comments Advice References and dosage involved (n) and dosage mechanism Tacrolimus (TAC) T AMP, DLV, IDV, Inhibition CYP3A Conc. TAC ↑ Monitor blood 36,39,41,43 LPV/RTV, RTV, by PI/DLV counts regularly. SQV TDM TAC recommended TAC 0.5mg weekly Case report 1 HIV+, NFV 500mg tid Inhibition CYP3A Conc. TAC 5–15µg/L. Monitor blood 41,210 male by NFV Conc. NFV slightly ↑ counts regularly. than normal TDM TAC recommended TAC Case report 1 HIV+, (1) RTV/SQV Inhibition CYP3A (1) Conc. TAC ↑ 120 Monitor blood 41,43,211 female 400/400mg bid. by PI µg/L, severe prolonged counts regularly. (2) NFV toxicity. (2) Confusion, TDM TAC lethargy, delusional recommended Tamoxifen (TAM) T RTV Inhibition CYP3A Conc. TAM ↑ Monitor for by RTV neurotoxicity, dosage reduction TAM may be needed Terfenadine (TER) T, in vitro AMP, DLV, EFV, Inhibition CYP3A4 Conc. TER ↑ Risk for cardiac CI; A = cetirizine, 28,36,37,39, (AMP) IDV, LPV/RTV, by PI/NNRTI arrhythmias acrivastine 43,63 RTV, SQV-HGC (see also TER + SQV-SGC) TER single dose 60mg S 12 vol NFV 7 days Inhibition CYP3A4 Conc. TER alone <5 Risk for cardiac CI; A = cetirizine, 130 750mg tid by NFV µg/L. Cmax TER + NFV arrhythmias acrivastine 5–15 µg/L

TER 11 days 60mg bid S 12 vol SQV-SGC 4 days Inhibition CYP3A4 AUC, Cmax TER ↑ Risk for cardiac CI; A = cetirizine, 45,48,89 1200mg tid by SQV 368%, 253%, resp. arrhythmias acrivastine AUC, Cmax TER acid metabolite ↑ 120%, 93%, resp. Tetracyclines (TET) T DDI Chelation with ↓ absorption TET TET > 2h prior to 92 Clin Pharmacokinet 2003;42(3) cations in DDI DDI or 6h after tablets DDI; A = DDI EC Thalidomide (THA) T RTV Inhibition CYP by Conc. THA ↑ Monitor for RTV neurotoxicity THA, dosage reduction THA de Maatet al. may be needed Drug InteractionswithAntiretrovirals © Adis International Limited. Allrights reserved. Theophylline (THE) Placebo- 13, 11 RTV 10 days Induction CYP1A2 AUC, Cmax, Cmin THE ↓ TDM THE 43,212 5 days 3 mg/kg tid controlled (control) 500mg bid by RTV? 43%, 32%, 57%, resp. recommended (escalation scheme) Thioridazine (THI) T RTV Inhibition CYP2D6 Conc. THI potential ↑. Based on Dosage reduction 12,43 by RTV, THI Conc. RTV potential ↑ interaction with THI may be perphenazine needed Timolol (TIM) T RTV Inhibition CYP2D6 Conc. TIM ↑↑ risk for Dosage reduction 43 by RTV bradycardia TIM (>50%) may and be needed hypotension Tiotixene (TIO) T RTV Inhibition CYP2D6 Conc. TIO ↑↑ risk for Dosage reduction by RTV sedation TIO may be needed Tramadol (TRM) T RTV Inhibition CYP3A Conc. TRM ↑↑ risk for GI Dosage reduction 43 by RTV toxicity TRM (>50%) may be needed

Trazodone (TRA) T, in vitro IDV, RTV Inhibition CYP3A IC50 IDV 0.63 µmol/L, Monitor for 12,213 (human liver (2D6) by IDV, RTV IC50 RTV 0.30 µmol/L, increased microsomes) conc. TRA potential ↑ sedation. Dosage reduction may be needed Triazolam (TRI) T AMP, DLV, EFV, Inhibition CYP3A Conc. TRI ↑ Risk for CI; A = 28,30,36,37, IDV, LPV/RTV, by PI/NNRTI prolonged or ↑ oxazepam, 39,41,45,48 NFV, SQV sedation, lorazepam respiratory depression ↑ TRI Single dose 0.125mg Double-blind, 6 vol, male RTV 200mg bid Initial inhibition of AUC, t1⁄2β, Cmax TRI Probably CI; A = 43,59,60 randomised, 5- (4 doses) CYP3A by RTV 19-, 13-fold, 87%, resp. induction from oxazepam, way crossover (presystemic) CL TRI ↓ 96%. PD: long-term lorazepam ↑ sedation exposure will offset inhibition due to short- term exposure Tricyclic antidepressants T AMP, RTV Inhibition CYP2D6 Conc. TRC ↑ TDM TRC 12,36,43 Clin Pharmacokinet 2003;42(3) (TRC) [see also and/or CYP3A recommended, desipramine] by PI dosage reduction TRC may be needed 269 Continued over page 270 © Adis International Limited. Allrights reserved. Table III. Contd Coadministered agent Type of study Subjects Antiretroviral agent Interaction Effect of interaction Comments Advice References and dosage involved (n) and dosage mechanism Trifluoperazine (TRF) T RTV Inhibition CYP2D6 Conc. TRF ↑. Conc. Based on Dosage reduction by RTV. TRF RTV ↑ interaction with TRF, RTV may perphenazine be needed. TDM RTV recommended

Triflupromazine (TRP) T RTV Inhibition CYP2D6 Conc. TRP ↑. Based on Dosage reduction by RTV. TRP Conc. RTV ↑ interaction with TRP, RTV may perphenazine be needed. TDM RTV recommended

Trimethoprim (TMP) 8 Open, 8 HIV+ AZT single dose Competition by CLR AZT ↓ 58% Only 20% of Monitor blood 4,25,214 days 200mg bid randomised, 200mg TMP at the renal CL/F AZT by counts regularly crossover tubular site CLR, thus probably not significant TMP/sulfamethoxazole T AZT Similar toxicity Haematological toxicity (SUL) [cotrimoxazole] profile

TMP S ? HIV+ DDC Inhibition renal CLR DDC ↓ Clinical 215 tubular secretion significance unknown

TMP/SUL 5 days Randomised, 2- 14 HIV+ 3TC single dose Competitive AUC 3TC ↑ 44%, CLR No intervention Stop 3TC during 4,22, 800/160mg qd way crossover 300mg inhibition renal 3TC ↓ 30%, CL 3TC when high dose 216-218 tubular secretion ↓ 29% TMP/SUL is therapy with by TMP used to prevent TMP/SUL (>960 PCP (480mg mg/day) qd) TMP/SUL T 3TC Similar toxicity Pancreatitis Monitor for profile pancreatitis TMP/SUL T DDI, D4T Similar toxicity Pancreatitis Monitor for 4 profile pancreatitis Clin Pharmacokinet 2003;42(3) TMP/SUL 7 days S ? IDV 400mg qid Inhibition CYP AUC TMP ↑ 19% No dosage 37 400/80mg bid by IDV adjustment necessary de Maatet al. Drug InteractionswithAntiretrovirals © Adis International Limited. Allrights reserved. TMP/SUL single dose Open-label 15 vol RTV 12 days Induction N- AUC, Cmax SUL ↓ 20%, Not clinically No dosage 43,219 800/160mg 500mg bid glucuronidation, ↔, resp. AUC, Cmax relevant adjustment (escalation inhibition CYP TMP ↑ 20%, ↔, resp. necessary scheme) by RTV

Valproic acid (VAL) 4 days S 6 HIV+ AZT 4 days Inhibition AUC, Cmax, CL AZT ↑ Clinical Monitor blood 25,220 250mg tid 100mg tid glucuronidation, 80%, 41%, ↓ 38%, significance counts regularly first-pass resp. AUC, Cmax GAZT unknown metabolism by ↓ 22%, 36%, resp. VAL GAZT/AZT urinary excretion ratio ↓ 58% VAL Case report 1 HIV+, RTV/SQV ↑ risk carnitine Headache, nausea, Levocarnitine Replacement of 221 male 400/400mg bid, depletion, vomiting, anorexia, 1g tid carnitine is followed by NVP accumulation fevers etc. → hepatitis administered recommended 200mg bid toxic VAL metabolites by CYP-inducing agents RTV, NVP Verapamil (VER) T AMP, DLV, IDV, Inhibition CYP3A Conc. VER ↑ Risk for Dosage reduction 36,43 LPV/RTV, NFV, by PI/DLV hypotension, VER may be RTV, SQV bradycardia etc. needed Vincristine (VIN) T DDC, DDI, D4T Similar toxicity Peripheral neuropathy Avoid where 20,21,24 profile possible, monitor for peripheral neuropathy Warfarin (WAR) T AMP, DLV, EFV, Inhibition CYP3A Conc. WAR ↑ (or ↓ in Monitor INR 28,30,36,39 LPV/RTV, NFV by PI/DLV, case of EFV) induction CYP3A by EFV WAR 5mg/day Case report 1 HIV+, IDV 800mg tid, Induction Both regimens ↑ PCA Monitor INR 43,222 male followed by RTV metabolism by → dosage WAR ↑ 600mg bid RTV/IDV 8.75mg/day WAR Case reports 3 HIV+ NVP 200mg bid Induction of CYP Dosage increase WAR Monitor INR 223 by NVP was needed to stabilise Quick time and INR within therapeutic Clin Pharmacokinet 2003;42(3) range 271 Continued over page 272 © Adis International Limited. Allrights reserved. Table III. Contd Coadministered agent Type of study Subjects Antiretroviral agent Interaction Effect of interaction Comments Advice References and dosage involved (n) and dosage mechanism

WAR 12.5mg qd Case report 1 HIV+, RTV 400mg bid ↓ anticoagulant Paradoxical effect: Comedication Monitor INR 43,224,225 female effect, results of INR↓, WAR dosage ↑, CLA, TMP/SUL RTV effect on RTV discontinued: TMP-SUL INR ↑ 3-fold interaction/RTV affected WAR directly WAR 10mg/day Case report 1 HIV+, RTV 400mg bid, Inhibition CYP2C9 INR ↑ 4-fold male NFV 750mg tid by RTV (switch from EFV 600mg qd)

WAR Case report 1 HIV+, SQV 600mg tid Inhibition CYP3A4 INR ↑ slowly → Monitor INR 226 male by SQV hypoprothrombinaemia Zolpidem (ZOL) T AMP, DLV, IDV, Inhibition CYP3A Conc. ZOL ↑ Based on Dosage reduction LPV/RTV, NFV, by PI/DLV interaction with ZOL may be SQV RTV needed. A = oxazepam, lorazepam ↑ ZOL single dose 5mg Double-blind, 6 HIV+ RTV 200mg bid Initial inhibition AUC, t1⁄2β, Cmax ZOL Probably Dosage reduction 43,227 randomised, 5- (4 doses) CYP3A by RTV 28%, 20%, 22%, resp. induction from ZOL may be way crossover CL ZOL ↓ 26% long-term needed. A = exposure will oxazepam, overcome lorazepam inhibition due to short-term exposure

A = alternative; AAG = α1-acid glycoprotein; ABC = abacavir; ADH = alcohol dehydrogenase; AE = adverse events; AMP = amprenavir; AMT = 3 -amino-3 -deoxythymidine; ARV = antiretroviral; AUC = area under the plasma concentration-time curve; AZT = zidovudine; BA = bioavailability; bid = twice daily; C = controls; CI = contraindicated; CL Clin Pharmacokinet 2003;42(3) = apparent (‘oral’) systemic clearance; CLCR = creatinine clearance; CLR = renal clearance; Cmax = maximum plasma concentration; Cmin = minimum plasma concentration; CNS = central nervous system; Conc. = plasma concentration; CPK = creatinine phosphokinase; CRABP-1 = cellular retinoic acid-binding protein-1; CSF = cerebrospinal fluid; Ctrough = trough plasma concentration; CYP = cytochrome P450; dd = times per day; DDC = zalcitabine; DDI = didanosine; DLV = delavirdine; dTTP = deoxythymidine triphosphate; D4T = stavudine; EC = enteric coated; EFV = efavirenz; F = oral bioavailability; GAZT = 3 -azido-3 -deoxy-5 -O-β-D-glucopyranuronosylthymidine; GI = gastrointestinal; HC = historical controls; HGC = hard gel capsule; IC50 = concentration giving 50% inhibition; IDV = indinavir; IMP = inosine monophosphate dehydrogenase; INR = international normalised ratio; IV = intravenous; Ki = inhibitory constant; LEs = liver enzymes; LPV/RTV = lopinavir/ritonavir; NFV = nelfinavir; NNRTI = non-nucleoside reverse transcriptase inhibitors; NO = ; NVP = nevirapine; PCA = prothrombin complex activity; PCP = Pneumocystis carinii pneumonia; PD = pharmacodynamic; de Maatet al. PEP = post-exposure prophylaxis; PHN = postherpetic neuralgia; PI = protease inhibitor; PK = pharmacokinetic; PO = oral; P-gp = P-glycoprotein; qd = once daily; qid = four times daily; ref. = reference population; resp. = respectively; RTV = ritonavir; S = study, design not specified; seq = sequential; SGC = soft gel capsule; sim = simultaneous;

SQV = saquinavir; ss = steady state; T = theoretical; TDM = therapeutic drug monitoring; tid = three times daily; tmax = time to Cmax; TSH = thyroid stimulating hormone; t1⁄2β = elimination half-life; UDPGT = uridine diphosphate glucuronosyltransferase; vol = healthy volunteers; 3TC = lamivudine;↑ indicates increase; ↓ indicates decrease. Drug Interactions with Antiretrovirals 273

the liver, the kidney, the blood-brain barrier and in digoxin plasma concentration was 2.5 times the CD4+ lymphocytes. Kim et al. demonstrated in upper limit of normal and inhibition of P-glycopro- Mdr1a knockout mice that P-glycoprotein has a tein in the small intestine or renal proximal tubules role in the absorption, distribution and elimination by RTV was suspected as the cause of this drug of PIs,[231] indicating that P-glycoprotein may interaction (table III).[96] affect these processes in humans too. Moreover, PIs and NNRTIs are substrates of CYP3A4 and data indicate that modulation of P-glycoprotein P-glycoprotein and can modulate their function. function plays an important role in drug interac- Therefore, these drugs are expected to have con- tions.[54,232] Many substrates metabolised by CYP- siderable effects on coadministered agents that are 3A4 are also substrates for P-glycoprotein. The also using this metabolic pathway. Coadminis- spatial relationship of P-glycoprotein traversing tered drugs may, however, also influence the phar- the plasma membrane and CYP3A inside the cell macokinetics of PIs and NNRTIs by modulation of on the endoplasmic reticulum suggests that P- CYP enzymes or drug transporters. Furthermore, glycoprotein may act to control exposure of sub- besides the influence of drug-drug interactions on strates to metabolism by CYP3A enzymes.[233] the pharmacokinetics of the antiretroviral drugs Induction of CYP3A and/or P-glycoprotein was and comedicated agents, polymorphism of several suggested in the interaction of St John’s wort and CYP enzymes (e.g. CYP3A4/5, CYP2D6 and IDV, in which St John’s wort reduced the AUC of CYP2C19) and P-glycoprotein may also result in IDV by 57% (table III).[208,234] That herbal agents large interindividual differences in plasma con- [235] are not as harmless as generally thought is also centrations. illustrated by clinically important interactions ob- 3.1.3 Protein Binding served with garlic supplements and grapefruit Following absorption, drugs are rapidly distrib- juice (table III). In a study in healthy volunteers, uted by the body circulation. Most drugs are partly garlic supplements administered twice daily for 20 protein-bound, particularly to albumins and α - days resulted in a 51% reduction in the AUC of 1 [119] acid glycoprotein (AAG). In contrast to the SQV, probably by induction of CYP enzymes. NNRTIs, which are predominantly bound to albu- After a 10-day washout the AUC of SQV was still min, PIs are mostly bound to AAG.[6,7] Only the only 60–70% of the AUC at baseline. The effect of unbound fraction is considered to have pharmaco- grapefruit juice on the pharmacokinetics of prote- logical activity. Variations in plasma albumin ase inhibitors appears unpredictable. Grapefruit and/or AAG levels may alter free drug fractions juice reduced the AUC of IDV by 26%, while the and may, therefore, influence activity. On the other AUC of SQV increased, depending on the dose of hand, changes in unbound fraction will generally [122,123] grapefruit juice, by 39–121%. Grapefruit not lead to changes in free drug concentrations due juice was thought to exert these effects by modu- to other equilibrium processes. Protein binding lation of the function of P-glycoprotein and/or displacement of one drug by another may increase CYP3A. Based on these results and the fact that the free plasma concentration of the former drug, the interacting potential for most of these herbal and hence the effect of that drug. For drugs with a agents has not been completely elucidated, one high hepatic extraction ratio, the free plasma con- should always be aware of possible interactions centration determines the elimination rate. How- with herbal agents. ever, for drugs with a low hepatic extraction ratio, Modulation of P-glycoprotein function was also an increase in the free plasma concentration will suggested in an HIV-infected patient who received not lead to a proportional increase in clearance. digoxin and started with IDV and RTV as part of This type of interaction mostly has minor effects the antiretroviral regimen. This patient experi- on drug exposure and is, therefore, in general not enced nausea, vomiting and mild dehydration. The clinically relevant.[236]

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3.1.4 Excretion signs of these adverse effects. In addition, drugs Drug interactions based on alterations in renal with adverse events similar to those of PIs and elimination mainly involve changes in tubular se- NNRTIs should be added with caution to a PI- or cretion or changes in kidney function. Drugs that NNRTI-containing antiretroviral regimen. use the same active transport system in the kidney tubules can compete for this excretory system. Pro- 4. Practical Issues for Use of benecid and trimethoprim are known inhibitors of Interactions Table tubular secretion,[237] and the observation that the AUC of AZT increased 80–115% when concomi- In table III we have defined nine areas that are tantly used with probenecid can partly be ex- considered essential for overviewing drug interac- plained by this effect (table III).[175-177] Aminogly- tions between antiretroviral drugs and com- cosides are nephrotoxic drugs[238] and the use of edicated agents: this class of drugs might lead to a decreased renal 1. The first column (‘Co-administered agent and clearance, as demonstrated for DDC (table III).[24] dosage’) is presented in alphabetical order, either for the individual drug or the drug class (see table 3.2 Pharmacodynamic Interactions II). The dosage of the coadministered drug is given when available from the cited interaction study. 3.2.1 Efficacy 2. The second column describes ‘Type of An example of a synergistic pharmacodynamic study’. As can be observed from the table, most interaction is combination treatment with hy- drug interactions are based on theoretical consid- droxycarbamide (hydroxyurea) and DDI. By erations ( = T), e.g. because it is known that the adding hydroxycarbamide to the regimen, levels drugs are metabolised by the same CYP isoen- of deoxyadenosine triphosphate (dATP; cellular zymes. competitor) decrease, favouring incorporation of 3. In the third column, the ‘Number of subjects’ dideoxyadenosine triphosphate (ddATP; DDI is [239] involved in the interaction study is mentioned. In the precursor of ddATP) into proviral DNA. case of an interaction based on theoretical grounds, This combination provides a simultaneous inhibi- this field is empty. Whenever possible, the type of tion of a cellular protein (by hydroxycarbamide) subjects (healthy volunteers, HIV-infected pa- and a viral protein (by DDI), which should result tients, gender) is presented. in a sustained suppression of HIV-1. However, in 4. The fourth column includes ‘Antiretroviral practice it appears that a higher rate of toxicity was agent and dosage’. For one comedicated agent, encountered without increased efficacy.[240,241] more than one row can be presented. This occurs 3.2.2 Toxicity when information on a drug interaction with one Combinations of drugs may lead to an increased specific drug or drug group includes more than just toxicity compared with administration of the single theoretical information. Antiretroviral drugs are drugs. For example, both AZT and ganciclovir then presented in different rows for that com- used as single agents show bone marrow suppres- edicated agent. The antiretroviral drugs are in al- sion.[25,242] When these drugs are used concomi- phabetical order per row and per comedicated tantly, this toxic effect is enhanced and increased agent. incidence of severe neutropenia and anaemia are 5. In the section ‘Interaction mechanism’, the found. DDI, D4T and DDC are associated with the most plausible mechanism is given. When a ques- development of peripheral neuropathy,[20,21,23,24] tion mark is given, it is possible, but not completely and DDI and 3TC are associated with the develop- certain, that the interaction is caused by the men- ment of pancreatitis.[20-22] Patients using these tioned mechanism. drugs and other agents with a similar toxicity pro- 6. The column ‘Effect of interaction’ includes file should be monitored closely and frequently for the effect of the increase or decrease in plasma con-

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centration of the antiretroviral drug and/or com- number of factors such as the role of metabolites edicated agent. In addition, other observations and interindividual differences in clearance.[58] made during the observation of drug interaction Case reports should also be interpreted with cau- (increase in adverse events, change in Interna- tion as they usually provide limited information tional Normalised Ratio) are presented. and can be outliers in a population. 7. In the column ‘Comments’, additional infor- For some drug combinations, well-designed mation on the drug interaction that cannot be clas- drug interaction studies have been performed, but sified into another category is presented. not all involve HIV-infected patients. Pharmaco- 8. The section ‘Advice’ suggests how to deal kinetic studies are often performed in healthy vol- with the interaction. Therapeutic drug monitoring unteers who are exposed to two-drug combina- (TDM) of PIs and NNRTIs is currently valued as tions, whereas in the treatment of HIV infection an additional clinical tool in HIV care, since rela- more complex multidrug regimens are used. In ad- tionships have been described between plasma dition, CYP3A4 activity appears to be more vari- concentrations and efficacy and/or toxicity.[4,8-11] able in HIV-positive patients than in non-infected When TDM of drugs is suggested, the plasma con- subjects.[243] Moreover, Lee et al. demonstrated centration needs to be quantified with a validated method and interpretation of the result should be that AIDS patients with acute illnesses had altered [244] performed by a qualified person (e.g. clinical phar- patterns of drug metabolism. Data collected macologist). When TDM of RTV is recommended, from studies performed in healthy volunteers this only refers to RTV used as an antiviral rather should thus be extrapolated carefully to HIV- than a pharmacoenhancer. Management of interac- infected individuals. tions with drugs that have a similar toxicity profile The use of a single dose in some studies is also will include regular monitoring of the most fre- an important factor to consider. Some drugs must quent and prominent toxicity, although other ad- be administered for longer times before the effect verse events may occur. The frequency of moni- of an interaction can be observed. An example is toring is dependent on hospital procedures and the interaction between RTV and alprazolam, in needs to be judged by the treating physician. which opposite effects of RTV on alprazolam 9. The last column (‘Reference’) provides the clearance were found with short and extended ad- literature source that describes the drug interac- ministration of RTV.[59,60] During initial exposure tion. It could be that a presented drug interaction to RTV, inhibition of CYP3A may predominate, is not supported by a literature reference. In this while during extended exposure induction may case, an interaction can be based on another drug offset this inhibition. interaction with a comedicated agent that is struc- Special care should also be addressed to the ef- turally similar. In addition, the drug interaction can fect of a drug interaction when an enzyme-induc- be based on knowledge of the metabolic pathway ing agent is discontinued. Toxicity may then occur of the drugs involved and/or the capacity to inhibit due to continuation of the high dose of the drug or induce this metabolic pathway by one of the that was formerly needed to offset the inducing implicated drugs. effect. In this overview, the aim was to provide a com- 5. Conclusions plete overview about drug interactions between When using this overview in the management antiretroviral drugs and comedicated agents. New of drug interactions, it should be kept in mind that information in this field, however, emerges rap- most information is based on theoretical consider- idly. An excellent review on drug interactions ations and in vitro data. Extrapolating in vitro data among drugs for HIV and opportunistic infections to the in vivo situation requires consideration of a was published in 2001 in which some web sites

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were suggested for the most recent information on 13. Barry M, Mulcahy F, Merry C, et al. Pharmacokinetics and [15] potential interactions amongst antiretroviral agents used to this subject. treat patients with HIV infection. Clin Pharmacokinet 1999; Overall, this overview may be a further aid in 36: 289-304 understanding and addressing drug interactions 14. Malaty LI, Kuper JJ. Drug interactions of HIV protease inhibi- tors. Drug Saf 1999; 20: 147-69 that can be encountered in the treatment of HIV- 15. Piscitelli SC, Gallicano KD. Interactions among drugs for HIV infected persons. Awareness of the mechanisms of and opportunistic infections. N Engl J Med 2001; 344: 984-96 16. Lipsky JJ. Antiretroviral drugs for AIDS. Lancet 1996; 348: drug interactions and clinical consequences, as 800-4 well as interventions to minimise these interac- 17. Hoetelmans RMW. Clinical pharmacokinetics of antiretroviral tions, are pivotal in the optimisation of treatment drugs. AIDS Rev 1999; 1: 167-78 18. ZiagenTM (abacavir sulfate) tablets, oral solution [product in- of HIV-infected individuals. formation]. Research Triangle Park (NC): GlaxoWellcome, 1998 Dec Acknowledgements 19. Hervey PS, Perry CM. Abacavir: a review of its clinical poten- tial in patients with HIV infection. Drugs 2000; 60: 447-79 ® No sources of funding were used to assist in the prepara- 20. Videx (didanosine) chewable/dispersible buffered tablets, buffered powder for oral solution, pediatric powder for oral tion of this manuscript. There are no conflicts of interest solution [product information]. Princeton (NJ): Bristol-Myers directly relevant to the content of this review. Squibb, 2000 Dec 21. Videx® EC (didanosine) delayed-release capsules enteric- References coated beadlets [product information]. Princeton (NJ): Bris- 1. Ledergerber B, Egger M, Opravil M, et al. Clinical progression tol-Myers Squibb, 2000 Dec ® ® and virological failure on highly active antiretroviral therapy 22. Epivir Tablets (lamivudine tablets), Epivir Oral solution in HIV-1 patients: a prospective cohort study. Lancet 1999; (lamivudine oral solution) [product information]. Research 353: 863-8 Triangle Park (NC): GlaxoWellcome, 2001 ® 2. Berrey MM, Schacker T, Collier AC, et al. Treatment of pri- 23. Zerit (stavudine) capsules and for oral solution [product infor- mary human immunodeficiency virus type 1 infection with mation]. Princeton (NJ): Bristol-Myers Squibb, 2000 Dec ® potent antiretroviral therapy reduces frequency of rapid pro- 24. Hivid (zalcitabine) tablets [product information]. New Jersey: gression to AIDS. J Infect Dis 2001; 183: 1466-75 F. Hoffman-La Roche, 2000 ® 3. Vittinghoff E, Scheer S, O’Malley P, et al. Combination anti- 25. Retrovir (zidovudine) tablets, capsules, syrup [product infor- retroviral therapy and recent declines in AIDS incidence and mation]. Research Triangle Park (NC): GlaxoWellcome, mortality. J Infect Dis 1999; 179: 717-20 1998 May 4. Yeni PG, Hammer SM, Carpenter CCJ, et al. Antiretroviral 26. Hoetelmans RMW, Burger DM, Meenhorst PL, et al. Pharma- treatment for adult HIV infection in 2002. Updated recom- cokinetic individualisation of zidovudine therapy: current mendations of the International AIDS Society-USA Panel. state of pharmacokinetic-pharmacodynamic relationships. JAMA 2002; 288: 222-35 Clin Pharmacokinet 1996; 30: 314-27 5. Moyle G. The role of combinations of HIV protease inhibitors 27. Sperling R. Zidovudine. Infect Dis Obstet Gynecol 1998; 6: in the management of persons with HIV infection. Exp Opin 197-203 Invest Drugs 1998; 7: 413-26 28. Rescriptor (brand of delavirdine mesylate tablets) [product in- 6. Smith PF, Dicenzo R, Morse GD. Clinical pharmacokinetics of formation]. Detroit (MI): Pharmacia & Upjohn, 1999 Jul non-nucleoside reverse transcriptase inhibitors. Clin Phar- 29. Tran JQ, Gerber JG, Kerrs BM. Delavirdine: clinical pharma- macokinet 2001; 40: 893-905 cokinetics and drug interactions. Clin Pharmacokinet 2001; 7. Sommadossi J-P. HIV protease inhibitors: pharmacologic and 40: 207-26 metabolic distinctions. AIDS 1999; 13 Suppl. 1: S29-40 30. SustivaTM (efavirenz) capsules [product information]. Wil- 8. Veldkamp AI, Weverling GJ, Lange JM, et al. High exposure mington (DE): DuPont Pharma, 2000 Feb to nevirapine in plasma is associated with an improved viro- 31. Veldkamp AI, Harris M, Montaner JSG, et al. The steady-state logical response in HIV-1-infected individuals. AIDS 2001; pharmacokinetics of efavirenz and nevirapine when used in 15: 1089-95 combination in human immunodeficiency virus type 1- 9. Murphy RL, Sommadossi J-P, Lamson M, et al. Antiviral effect infected persons. J Infect Dis 2001; 184: 37-42 and pharmacokinetic interaction between nevirapine and in- 32. Adkins JC, Noble S. Efavirenz. Drugs 1998; 56: 1055-64 dinavir in persons infected with human immunodeficiency 33. Viramune® (nevirapine) tablets and oral suspension [product virus type 1. J Infect Dis 1999; 179: 1116-23 information]. Columbus (OH): Roxane Laboratories Inc, 10. Marzolini C, Telenti A, Decosterd LA, et al. Efavirenz plasma 2000 Nov levels can predict treatment failure and central nervous sys- 34. Van Heeswijk RPG, Veldkamp AI, Mulder JW, et al. The tem side effects in HIV-1- infected patients. AIDS 2001; 15: steady-state pharmacokinetics of nevirapine during once 71-5 daily and twice daily dosing in HIV-1-infected individuals. 11. Dieleman JP, Gijssens IS, van der Ende ME, et al. Urological AIDS 2000; 14: F77-82 complaints in relation to indinavir plasma concentration in 35. Riska P, Lamson M, MacGregor T, et al. Disposition and bio- HIV-infected patients. AIDS 1999; 13: 473-8 transformation of the antiretroviral drug nevirapine in hu- 12. Tseng AL, Foisy MM. Significant interactions with new anti- mans. Drug Metab Dispos 1999; 27: 895-901 retrovirals and psychotropic drugs. Ann Pharmacother 1999; 36. Agenerase® (amprenavir) [product information]. Research Tri- 33: 461-73 angle Park (NC): GlaxoWellcome, 2000

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37. Crixivan® (indinavir sulfate) capsules [product information]. 59. Greenblatt DJ, von Moltke LL, Daily JP, et al. Extensive Westpoint (PA): Merck & Co, 2000 impairment of triazolam and alprazolam clearance by 38. Plosker GL, Noble S. Indinavir: a review of its use in the man- short-term low-dose ritonavir: the clinical dilemma of con- agement of HIV infection. Drugs 1999; 58: 1165-203 current inhibition and induction. J Clin Psychopharmacol 39. Kaletra(lopinavir/ritonavir) capsules, (lopinavir/ritonavir) 1999; 19: 293-6 oral solution [product information]. North Chicago (IL): Ab- 60. Greenblatt DJ, von Moltke LL, Harmatz JS, et al. Alprazolam- bott Laboratories, 2000 ritonavir interaction: implications for product labeling. Clin 40. Hurst M, Faulds D. Lopinavir. Drugs 2000; 60: 1371-9 Pharmacol Ther 2000; 67: 335-41 41. Viracept® (nelfinavir mesylate) tablets and oral powder [prod- 61. Frye R, Bertz R, Granneman GR, et al. Effect of ritonavir on uct information]. La Jolla (CA): Agouron Pharmaceuticals the pharmacokinetics and pharmacodynamics of alprazolam Inc, 2000 May [abstract A-59]. 37th Interscience Conference on Antimicro- 42. Bardsley-Elliot A, Plosker GL. Nelfinavir: an update on its use bial Agents and Chemotherapy; 1997; Toronto (ON) in HIV infection. Drugs 2000; 59: 581-620 62. Lohman JJHM, Reichert LJM, Degen LPM. Antiretroviral ther- 43. Norvir® (ritonavir capsules) soft gelatin, ritonavir oral solution apy increases serum concentrations of amiodarone. Ann [product information]. North Chicago (IL): Abbott Labora- Pharmacother 1999; 33: 645-6 tories, 2000 63. Decker DJ, Latinen LM, Bridson GW, et al. Metabolism of 44. Lea AP, Faulds D. Ritonavir. Drugs 1996; 52: 541-6 amprenavir in liver microsomes: role of CYP3A4 inhibition 45. Invirase® (saquinavir mesylate) capsules [product informa- for drug interactions. J Pharm Sci 1998; 87: 803-7 tion]. Nutley (NJ): F. Hoffman-La Roche, 2000 64. Castro JG, Gutierrez L. Rhabdomyolysis with acute renal fail- 46. Hoetelmans RMW, Meenhorst PL, Mulder JW, et al. Clinical ure probably related to the interaction of atorvastatin and pharmacology of HIV protease inhibitors: focus on saqui- delavirdine [letter]. Am J Med 2002; 112: 505 navir, indinavir, and ritonavir. Pharm World Sci 1997; 19: 65. Carr RA, Andre AK, Bertz RJ, et al. Concomitant administra- 159-75 tion of ABT-378/ritonavir (ABT-378/r) results in a clinically 47. Regazzi MB, Villani P, Maserati R, et al. Pharmacokinetic vari- important pharmacokinetic (PK) interaction with atorvastatin ability and strategy for therapeutic drug monitoring of (ATO) but not pravastatin (PRA) [abstract 1644]. 40th Inter- saquinavir (SQV) in HIV-1 infected individuals. Br J Clin science Conference on Antimicrobial Agents and Chemother- Pharmacol 1999; 47: 379-82 apy; 2000 Sep 17-20; Toronto (ON) 48. Fortovase® (saquinavir) soft gelatine capsules [product infor- 66. Hsyu PH, Schultz-Smith MD, Lillibridge JH, et al. Pharmaco- mation]. Nutley (NJ): F. Hoffman-La Roche, 2001 kinetic interactions between nelfinavir and 3-hydroxy-3- 49. Hugen PWH, Burger DM, Koopmans PP, et al. Differences in methylglutaryl coenzyme A reductase inhibitors atorvastatin pharmacokinetics (PK) of saquinavir soft-gel capsules (SQV- and simvastatin. Antimicrob Agents Chemother 2001; 45: sgc, Fortovase) after a normal and high fat breakfast [abstract 3445-50 7.3]. First International Workshop on Clinical Pharmacology; 67. Barry M, Belz G, Roll S, et al. Interaction of nelfinavir with 2000 Mar 30-31; Noordwijk, The Netherlands atorvastatin and pravastatin in normal healthy volunteers [ab- 50. Joly V, Yeni P. Non nucleoside reverse transcriptase inhibitors. stract P260]. 5th International Congress on Drug Therapy in AIDS Rev 1999; 1: 37-44 HIV Infection; 2000 Oct 22-26; Glasgow 51. Kohl NE, Emini EA, Schleif WA, et al. Active human immu- 68. Fichtenbaum C, Gerber J, Rosenkranz S, et al. Pharmacokinetic nodeficiency virus protease is required for viral infectivity. interactions between protease inhibitors and statins in HIV Proc Natl Acad Sci U S A 1988; 85: 4686-90 seronegative volunteers: ACTG Study A5047. AIDS 2002; 52. McDonald CK, Kuritzkes DR. Human immunodeficiency virus 16: 569-77 type 1 protease inhibitors. Arch Intern Med 1997; 157: 951-9 69. Lee BL, Täuber MG, Sadler B, et al. Atovaquone inhibits the 53. Srinivas RV, Middlemas D, Flynn P, et al. Human immunode- glucuronidation and increases the plasma concentrations of ficiency virus protease inhibitors serve as substrates for multi- zidovudine. Clin Pharmacol Ther 1996; 59: 14-21 drug transporter proteins MDR1 and MRP1 but retain 70. Amsden GW, Nafziger AN, Foulds G, et al. A study of the antiviral efficacy in cell lines expressing these transporters. pharmacokinetics of azithromycin and nelfinavir when Antimicrob Agents Chemother 1998; 42: 3157-62 coadministered in healthy volunteers. J Clin Pharmacol 2000; 54. Huisman MT, Smit JW, Schinkel AH. Significance of P-glyco- 40: 1522-7 protein for the pharmacology and clinical use of HIV protease 71. Hesse LM, von Moltke LL, Shader RI, et al. Ritonavir, efa- inhibitors. AIDS 2000; 14: 237-42 virenz, and nelfinavir inhibit CYP2B6 activity in vitro: po- 55. Profit L, Eagling VA, Back DJ. Modulation of P-glycoprotein tential drug interactions with bupropion. Drug Metab Dispos function in human lymphocytes and Caco-2 cell monolayers 2001; 29: 100-2 by HIV-1 protease inhibitors. AIDS 1999; 13: 1623-7 72. Greenwood I, Heylen R, Zakrzewska JM. Anti-retroviral 56. Bouscarat F, Certain A, Picard C, et al. Pharmacological inter- drugs: implications for dental prescribing. Br Dent J 1998; action between acenocoumarol and ritonavir [abstract 459]. 184: 478-82 6th European Conference on Clinical Aspects and Treatment 73. Hugen PWH, Burger DM, Brinkman K, et al. Carbamazepine- of HIV-Infection; 1997 Oct 11-15; Hamburg indinavir interaction causes antiretroviral failure. Ann Phar- 57. Sim SM, Back DJ, Breckenridge AM. The effect of various macother 2000; 34: 465-70 drugs on the glucuronidation of zidovudine (azidothymidine; 74. Berbel Garcia A, Latorre Ibarra A, Porta Etessam J, et al. Pro- AZT) by human liver microsomes. Br J Clin Pharmacol 1991; tease inhibitor-induced carbamazepine toxicity. Clin Phar- 32: 17-21 macol 2000; 23: 216-8 58. Bertz RJ, Granneman GR. Use of in vitro and in vivo data to 75. Burman W, Orr L. Carbamazepine toxicity after starting com- estimate the likelihood of metabolic pharmacokinetic inter- bination antiretroviral therapy including ritonavir and actions. Clin Pharmacokinet 1997; 32: 210-58 efavirenz. AIDS 2000; 14: 2793-4

 Adis International Limited. All rights reserved. Clin Pharmacokinet 2003; 42 (3) 278 de Maat et al.

76. Sahai J, Gallicano K, Oliveras L, et al. Cations in the didanosine 92. Perry CM, Balfour JA. Didanosine: an update on its antiviral, tablet reduce ciprofloxacin bioavailability. Clin Pharmacol pharmacokinetic properties and therapeutic efficacy in the Ther 1993; 53: 292-7 management of HIV disease. Drugs 1996; 52: 928-62 77. Knupp CA, Barbhaiya RH. A multiple-dose pharmacokinetic 93. Huengsberg M, Castelino S, Sherrard J, et al. Does drug inter- interaction study between didanosine (Videx®) and cipro- action cause failure of PCP prophylaxis with dapsone? [let- floxacin (Cipro®) in male subjects seropositive for HIV but ter]. Lancet 1993; 341: 48 asymptomatic. Biopharm Drug Dispos 1997; 18: 65-77 94. Von Moltke LL, Greenblatt DJ, Duan SX, et al. Inhibition of 78. Mummaneni V, Damle B, Kaul S, et al. Lack of effect of desipramine hydroxylation (cytochrome P450-2D6) in vitro didanosine encapsulated enteric coated beadlet formulation by quinidine and by viral protease inhibitors: relation to drug on the pharmacokinetics of indinavir, ketoconazole, and interactions in vivo. J Pharm Sci 1998; 87: 1184-9 ciprofloxacin in healthy subjects [abstract 1629]. 40th Inter- 95. Bertz RJ, Cao G, Cavanaugh JH, et al. Effect of ritonavir on the science Conference on Antimicrobial Agents and Chemother- pharmacokinetics of desipramine [abstract Mo.B.1201]. 11th apy; 2000 Sep 17-20; Toronto (ON) International Conference on AIDS; 1996 Jul 7-12; Vancou- 79. Brophy DF, Israel DS, Pastor A, et al. Pharmacokinetic inter- ver (BC) action between amprenavir and clarithromycin in healthy 96. Phillips EJ, Rachlis AR. Digoxin toxicity and ritonavir: a drug male volunteers. Antimicrob Agents Chemother 2000; 44: interaction mediated through P-glycoprotein? [abstract 1.9]. 978-84 Second International Workshop on Clinical Pharmacology; 80. Polis MA, Piscitelli SC, Vogel S, et al. Clarithromycin lowers 2001 Apr 2-4; Noordwijk, The Netherlands plasma zidovudine levels in persons with human immunode- 97. Rosenthal E, Sala F, Chichmanian R-M, et al. Ergotism related ficiency virus infection. Antimicrob Agents Chemother 1997; to concurrent administration of ergotamine tartrate and in- 41: 1709-14 dinavir [letter]. JAMA 1999; 281: 987 81. Piscitelli SC, Kelly G, Walker RE, et al. A multiple drug inter- 98. Mortier E, Pouchot J, Vinceneux P, et al. Ergotism related to action study of stavudine with agents for opportunistic infec- interaction between nelfinavir and ergotamine [letter]. Am J tions in human immunodeficiency virus-infected patients. Med 2001; 110: 594 Antimicrob Agents Chemother 1999; 43: 647-50 99. Montero A, Giovannoni AG, Tvrde PL. Leg ischemia in a pa- 82. Benedek IH, Joshi A, Fiske WD, et al. Pharmacokinetic (PK) tient receiving ritonavir and ergotamine. Ann Intern Med 1999; 130: 329-30 interaction studies in healthy volunteers with efavirenz (EFV) and the macrolide antibiotics, azithromycin (AZM) and clar- 100. Liaudet L. Severe ergotism associated with interaction between ithromycin (CLR) [abstract 347]. 5th Conference on Retro- ritonavir and ergotamine [letter]. BMJ 1999; 318: 771 viruses and Opportunistic Infections; 1998 Feb 1-5; Chicago (IL) 101. Grub S, Bryson H, Goggin T, et al. The interaction of saquinavir 83. Boruchoff SE, Sturgill MG, Grasing KW, et al. The steady-state (soft gelatin capsule) with ketoconazole, erythromycin and ri- fampicin: comparison of the effect in healthy volunteers and in disposition of indinavir is not altered by the concomitant ad- HIV-infected patients. Eur J Clin Pharmacol 2001; 57: 115-21 ministration of clarithromycin. Clin Pharmacol Ther 2000; 102. McDowell JA, Chittick GE, Stevens CP, et al. Pharmacody- 67: 351-9 namic interaction of abacavir (1592U89) and ethanol in hu- 84. Mirochnick M, Clarke DF, Dorenbaum A. Nevirapine. Pharma- man immunodeficiency virus-infected adults. Antimicrob cokinetic considerations in children and pregnant women. Agents Chemother 2000; 44: 1686-90 Clin Pharmacokinet 2000; 39: 281-93 103. Ravitch JR, Bryant BJ, Reese MJ, et al. In vivo and in vitro 85. Robinson P, Gigliotti M, Lamson M, et al. Effect of the reverse studies of the potential for drug interactions involving the transcriptase inhibitor, nevirapine, on the steady-state phar- anti-retroviral 1592 in humans [abstract 634]. 5th Conference macokinetics of clarithromycin in HIV-positive patients [ab- on Retroviruses and Opportunistic Infections; 1998 Feb 1-5; stract 374]. 6th Conference on Retroviruses and Opportunistic Chicago (IL) Infections; 1999 Jan 31-Feb 4; Chicago (IL) 104. Olkkola KT, Palkama VJ, Neuvonen PJ. Ritonavir s role in 86. Prime K, French P. Neuropsychiatric reaction induced by clar- reducing fentanyl clearance and prolonging its half-life. An- ithromycin in a patient on highly active antiretroviral therapy esthesiology 1999; 91: 681-5 (HAART). Sex Transm Infect 2001; 77: 297-8 105. Sahai J, Gallicano K, Pakuts A, et al. Effect of fluconazole on 87. Ouellet D, Hsu A, Granneman GR, et al. Pharmacokinetic in- zidovudine pharmacokinetics in patients infected with human teraction between ritonavir and clarithromycin. Clin Phar- immunodeficiency virus. J Infect Dis 1994; 169: 1103-7 macol Ther 1998; 64: 355-62 106. Wit S de, Smet M de, McCrea J, et al. Effect of fluconazole on 88. Jorga K, Buss NE, F. Hoffman-La Roche Ltd., Basel, Switzer- indinavir pharmacokinetics in human immunodeficiency vi- land. Pharmacokinetic (PK) drug interaction with saquinavir rus-infected patients. Antimicrob Agents Chemother 1998; soft gelatin capsule [abstract 339]. 39th Interscience Confer- 42: 223-7 ence on Antimicrobial Agents and Chemotherapy; 1999, San 107. Jackson KA, Rosenbaum SE, Kerr BM, et al. A population phar- Francisco (CA) macokinetic analysis of nelfinavir mesylate in human immu- 89. Buss N, Fortovase® Study Group. Saquinavir Soft Gel Capsule nodeficiency virus-infected patients enrolled in a phase III (Fortovase®): pharmacokinetics and drug interactions [ab- clinical trial. Antimicrob Agents Chemother 2000; 44: 1832-7 stract 354]. 5th Conference on Retroviruses and Opportunistic 108. Cato III A, Cao G, Hsu A, et al. Evaluation of the effect of Infections; 1998 Feb 1-5; Chicago fluconazole on the pharmacokinetics of ritonavir. Drug Metab 90. Tseng A, Nguyen ME, Cardella C, et al. Probable interaction Dispos 1997; 25: 1104-6 between efavirenz and cyclosporine. AIDS 2002; 16: 505-6 109. Koks CHW, Crommentuyn KML, Hoetelmans RMW, et al. The 91. Brinkman K, Huysmans F, Burger DM. Pharmacokinetic inter- effect of fluconazole on ritonavir and saquinavir pharmacoki- action between saquinavir and cyclosporine. Ann Intern Med netics in HIV-1-infected individuals. Br J Clin Pharmacol 1998; 129: 914-5 2001; 51: 631-5

 Adis International Limited. All rights reserved. Clin Pharmacokinet 2003; 42 (3) Drug Interactions with Antiretrovirals 279

110. DeSilva KE, Le Flore DB, Marston BJ, et al. Serotonin syn- 127. Polk RE, Crouch MA, Israel DS, et al. Pharmacokinetic inter- drome in HIV-infected individuals receiving antiretroviral action between ketoconazole and amprenavir after single therapy and fluoxetine. AIDS 2001; 15: 1281-5 doses in healthy men. Pharmacotherapy 1999; 19: 1378-84 111. Ouellet D, Hsu A, Qian J, et al. Effect of fluoxetine on pharma- 128. Sadler B, Gillotin C, Chittick GE, et al. Pharmacokinetic drug cokinetics of ritonavir. Antimicrob Agents Chemother 1998; interactions with amprenavir [abstract 12389]. 12th World 42: 3107-12 AIDS Conference; 1998 Jun 29-Jul 3; Geneva 112. Clevenbergh P, Corcostegui M, Gérard D, et al. Iatrogenic 129. Knupp CA, Brater DC, Relue J, et al. Pharmacokinetics of Cushing’s syndrome in a HIV-infected patient treated with didanosine and ketoconazole after coadministration to pa- inhaled corticosteroids and low dose ritonavir enhanced PI tients seropositive for the human immunodeficiency virus. J containing regimen [abstract 1.8]. Second International Clin Pharmacol 1993; 33: 912-7 Workshop on Clinical Pharmacology; 2001 Apr 2-4; 130. Kerr B, Yuen G, Daniels R, et al. Strategic approach to Noordwijk, The Netherlands nelfinavir mesylate (NFV) drug interactions involving 113. Khaliq Y, Gallicano K, Leger R, et al. A drug interaction be- CYP3A metabolism [abstract 429]. 4th Conference on Retro- tween fusidic acid and a combination of ritonavir and viruses and Opportunistic Infections; 1997 Jan 22-26; Wash- saquinavir. Br J Clin Pharmacol 2000; 50: 81-3 ington, DC 114. Harrington RD, Woodward JA, Hooton TM, et al. Life-threat- 131. Lee CA, Liang B-H, Wu EY, et al. Prediction of nelfinavir ening interactions between HIV-1 protease inhibitors and the mesylate (VIRACEPT) clinical drug interactions based on in illicit drugs MDMA and γ-hydroxybutyrate. Arch Intern Med vitro human P450 metabolism studies [abstract 523]. 4th 1999; 159: 2221-4 Conference on Retroviruses and Opportunistic Infections; 115. Burger DM, Meenhorst PL, ten Napel CHH, et al. Pharmacoki- 1997 Jan 22-26; Washington, DC netic variability of zidovudine in HIV-infected individuals: sub- 132. Lamson M, Robinson P, Gigliotti M, et al. The pharmacokinetic group analysis and drug interactions. AIDS 1994; 8: 1683-9 (PK) interactions of nevirapine (NVP) and ketoconazole 116. Cimoch PJ, Lavelle J, Pollard R, et al. Pharmacokinetics of oral (Keto) [abstract 12218]. 12th World AIDS Conference; 1998 ganciclovir alone and in combination with zidovudine, didanos- Jun 29-Jul 3; Geneva ine, and probenecid in HIV-infected subjects. J Acquir Immune 133. Khaliq Y, Gallicano K, Venance S, et al. Effect of ketoconazole Defic Syndr Hum Retrovirol 1998; 17: 227-34 on ritonavir and saquinavir concentrations in plasma and ce- rebrospinal fluid from patients infected with human immuno- 117. Jung D, AbdelHameed MH, Teitelbaum P, et al. The pharmaco- deficiency virus. Clin Pharmacol Ther 2000; 68: 637-46 kinetics and safety profile of oral ganciclovir combined with zalcitabine or stavudine in asymptomatic HIV- and CMV-sero- 134. Schutz M, Nangah S, Merry C. The effect of gastric proton positive patients. J Clin Pharmacol 1999; 39: 505-12 pump inhibitors on delavirdine absorption: four case reports [abstract 1.15]. Second International Workshop on Clinical 118. Jung D, Griffy K, Dorr A, et al. Effect of high-dose oral Pharmacology; 2001 Apr 2-4; Noordwijk, The Netherlands ganciclovir on didanosine disposition in human immunodefi- 135. Caparros-Lefebvre D, Lannuzel A, Tiberghien F, et al. Protease ciency virus (HIV)-positive patients. J Clin Pharmacol 1998; inhibitors enhance levodopa effects in Parkinson’s disease 38: 1057-62 [letter]. Mov Disord 1999; 14: 535 119. Piscitelli SC, Burstein AH, Welden N, et al. The effect of garlic 136. Nerad JL, Kessler HA. Hypercholesterolemia in a health care supplements on the pharmacokinetics of saquinavir. Clin In- worker receiving thyroxine after postexposure prophylaxis fect Dis 2002; 34: 234-8 for human immunodeficiency virus infection. Clin Infect Dis 120. Miller J, Carey D, Ray J, et al. Potential interaction with prote- 2001; 32: 1635-6 ase inhibitors and gemfibrozil [abstract 2.11]. First Interna- 137. Tseng A, Fletcher D. Interaction between ritonavir and tional Workshop on Clinical Pharmacology; 2000 Mar 30-31; levothyroxine. AIDS 1998; 12: 2235-6 Noordwijk, The Netherlands 138. Tayrouz Y, Ganssmann B, Ding R, et al. Ritonavir increases 121. Shelton MJ, Wynn HE, Hewitt RG, et al. Effects of grapefruit loperamide plasma concentrations without evidence for P- juice on pharmacokinetic exposure to indinavir in HIV-posi- glycoprotein involvement. Clin Pharmacol Ther 2001; 70: tive subjects. J Clin Pharmacol 2001; 41: 435-42 405-14 122. Fuhr U. Drug interactions with grapefruit juice. Extent, prob- 139. Khaliq Y, Gallicano K, Tisdale C, et al. Pharmacokinetic inter- able mechanism and clinical relevance. Drug Saf 1998; 18: action between mefloquine and ritonavir in healthy volun- 251-72 teers. Br J Clin Pharmacol 2001; 51: 591-600 123. Kupferschmidt HHT, Fattinger KE, Ha HR, et al. Grapefruit 140. Piscitelli SC, Rock Kress D, Bertz RJ, et al. The effect of juice enhances the bioavailability of the HIV protease inhib- ritonavir on the pharmacokinetics of meperidine and itor saquinavir in man. Br J Clin Pharmacol 1998; 45: 355-9 normeperidine. Pharmacotherapy 2000; 20: 549-53 124. Piscitelli SC, Vogel S, Figg WD, et al. Alteration in indinavir 141. Hendrix C, Wakeford J, Wire MB, et al. Pharmacokinetic (PK) clearance during interleukin-2 infusions in patients infected and pharmacodynamic (PD) evaluation of methadone (MD) with the human immunodeficiency virus. Pharmacotherapy enantiomers following co-administration with amprenavir 1998; 18: 1212-6 (APV) in opioid-dependent subjects [abstract]. 40th Intersci- 125. Padberg J, Schürmann D, Grobusch M, et al. Drug interaction ence Conference on Antimicrobial Agents and Chemother- of isotretinoin and protease inhibitors: support for the cellular apy; 2000 Sep 17-20; Toronto (ON) retinoic acid-binding protein-1 theory of lipodystrophy? 142. Bart P-A, Rizzardi PG, Gallant S, et al. Methadone concentra- AIDS 1999; 13: 284-5 tions are decreased by the administration of abacavir plus 126. Damle BD, Mummaneni V, Kaul S, et al. Lack of effect of amprenavir. Ther Drug Monit 2001; 23: 553-5 simultaneously administered didanosine encapsulated enteric 143. McCance-Katz EF, Rainey PM, Jatlow P, et al. Methadone ef- bead formulation (Videc EC) on oral absorption of indinavir, fects on zidovudine disposition (AIDS Clinical Trials Group ketoconazole, or ciprofloxacin. Antimicrob Agents Chemo- 262). J Acquir Immune Defic Syndr Hum Retrovirol 1998; ther 2002; 46: 385-91 18: 435-43

 Adis International Limited. All rights reserved. Clin Pharmacokinet 2003; 42 (3) 280 de Maat et al.

144. Rainey PM, Friedland G, McCance-Katz EF, et al. Interaction order: an open trial of nefazodone. J Clin Psychiatry 1999; 60: of methadone with didanosine and stavudine. J Acquir Im- 226-31 mune Defic Syndr 2000; 24: 241-8 163. Penzak SR, Lawhorn WD, Hon YY, et al. Influence of ritonavir 145. Marzolini C, Troillet N, Telenti A, et al. Efavirenz decreases and CYP1A2 genotype on olanzapine disposition in healthy methadone blood concentrations. AIDS 2000; 14: 1291-2 subjects. 41th Interscience Conference on Antimicrobial 146. Pinzani V, Faucherre V, Peyriere H, et al. Methadone with- Agents and Chemotherapy [abstract A-493]. 2001 Dec 16-19; drawal symptoms with nevirapine and efavirenz. Ann Phar- Toronto (ON) macother 2000; 34: 405-7 164. Burger DM, Hugen PWH, Kroon FP, et al. Pharmacokinetic 147. Clarke SM, Mulcahy FM, Tjia J, et al. The pharmacokinetics of interaction between the proton pump inhibitor omeprazole methadone in HIV-positive patients receiving the non-nucle- and the HIV protease inhibitor indinavir. AIDS 1998; 12: oside reverse transcriptase inhibitor efavirenz. Br J Clin Phar- 2080-2 macol 2001; 51: 213-7 165. Hugen PWH, Burger DM, ter Hofstede HJM, et al. Concomitant 148. Beauverie P, Taburet A-M, Dessalles M-C, et al. Therapeutic use of indinavir and omeprazole: risk of antiretroviral sub- drug monitoring of methadone in HIV-infected patients re- therapy. 4th International Congress on Drug Therapy in HIV ceiving protease inhibitors. AIDS 1998; 12: 2510-1 Infection [abstract P46]; 1998; Glasgow 149. Hsyu PH, Lillibridge JH, Maroldo L, et al. Pharmacokinetic 166. Joshi AS, Fiske WD, Benedek IH, et al. Lack of a pharmacoki- (PK) and pharmacodynamic (PD) interactions between netic interaction between efavirenz (DMP 266) and ethinyl nelfinavir and methadone [abstract 87]. 7th Conference on estradiol in healthy female volunteers. 5th Conference on Retroviruses and Opportunistic Infections; 2000 Jan 31-Feb Retroviruses and Opportunistic Infections [abstract 348]; 2; San Francisco (CA) 1998 Feb 1-5; Chicago (IL) 150. Smith PF, Booker BM, Difrancesco R, et al. Effect of 167. Bertz R, Hsu A, Lam W, et al. Pharmacokinetic interactions methadone or LAAM on the pharmacokinetics of nelfinavir between lopinavir/ritonavir (ABT-378r) and other non-HIV and M8 [abstract A-491]. 41th Interscience Conference on drugs. 5th International Congress on Drug Therapy in HIV Antimicrobial Agents and Chemotherapy; 2001 Dec 16-19; Infection; [abstract P291]; 2000 Oct 22-26; Glasgow Toronto (ON) 168. Ouellet D, Hsu A, Qian J, et al. Effect of ritonavir on the phar- 151. Altice FL, Friedland GH, Cooney EL. Nevirapine induced opi- macokinetics of ethinyl oestradiol in healthy female volun- ate withdrawal among injection drug users with HIV infection teers. Br J Clin Pharmacol 1998; 46: 111-6 receiving methadone. AIDS 1999; 13: 957-62 169. Mildvan D, Yarrish R, Marshak A, et al. Pharmacokinetic in- 152. Heelon MW, Meade LB. Methadone withdrawal when starting teraction between nevirapine and ethinyl estradiol/norethin- an antiretroviral regimen including nevirapine. Pharmaco- drone when administered concurrently to HIV-infected therapy 1999; 19: 471-2 women. J Acquir Immune Defic Syndr 2002; 29: 471-7 153. Otero M-J, Euertes A, Sánchez R, et al. Nevirapine-induced 170. Mole L, Israelski D, Bubp J, et al. Pharmacokinetics of zidovud- withdrawal symptoms in HIV patients on methadone mainte- ine alone and in combination with oxazepam in the HIV in- nance programme: an alert. AIDS 1999; 13: 1004-5 fected patient. J Acquir Immune Defic Syndr Hum Retrovirol 154. Hsu A, Grannemann GR, Carothers L, et al. Ritonavir does not 1993; 6: 56-60 increase methadone exposure in healthy volunteers [abstract 171. Nannan Panday VR, Hoetelmans RMW, Heeswijk RPG van, et 342]. 5th Conference on Retroviruses and Opportunistic In- al. Paclitaxel in the treatment of human immunodeficiency fections; 1998 Feb 1-5; Chicago (IL) virus 1-associated Kaposi s sarcoma: drug-drug interactions 155. Geletko SM, Erickson AD. Decreased methadone effect after with protease inhibitors and a nonnucleoside reverse trans- ritonavir initiation. Pharmacotherapy 2000; 20: 93-4 criptase inhibitor: a case report study. Cancer Chemother 156. Gerber JG, Rosenkranz S, Segal Y, et al. Effect of ritonavir/- Pharmacol 1999; 43: 516-9 saquinavir on stereoselective pharmacokinetics of metha- 172. Schwartz JD, Howard W, Scadden DT. Potential interaction of done: results of AIDS Clinical Trials Group (ACTG) 401. J antiretroviral therapy with paclitaxel in patients with AIDS- Acquir Immune Defic Syndr 2001; 27: 153-60 related Kaposi s sarcoma. AIDS 1999; 13: 283-4 157. Henry JA, Hill IR. Fatal interaction between ritonavir and 173. Shelton MJ, Cloen D, Becker M, et al. Evaluation of the phar- MDMA. Lancet 1998; 352: 1751-2 macokinetic (PK) interaction between phenytoin (Phen) and 158. Hales G, Roth N, Smith D. Possible fatal interaction between nelfinavir (NFV) in healthy volunteers at steady state. 40th protease inhibitors and methamphetamine [letter]. Antivir Interscience Conference on Antimicrobial Agents and Che- Ther 2000; 5: 19 motherapy [abstract 426]. 2000 Sep 17-20; Toronto (ON) 159. Gastaldo JM, Neidig JL, Para MF, et al. The clinical signifi- 174. Honda M, Yasuoka A, Aoki M, et al. A generalized seizure cance of the drug interaction between protease inhibitors and following initiation of nelfinavir in a patient with human im- midazolam. 40th Interscience Conference on Antimicrobial munodeficiency virus type 1 infection, suspected due to inter- Agents and Chemotherapy [abstract 422]; 2000 Sep 17-20; action between nelfinavir and phenytoin. Intern Med 1999; Toronto (ON) 38: 302-3 160. Merry C, Mulcahy F, Barry M, et al. Saquinavir interaction with 175. Kornhauser DM, Hendrix CW, Nerhood LJ, et al. Probenecid midazolam: pharmacokinetic considerations when prescrib- and zidovudine metabolism. Lancet 1989; II: 473-5 ing protease inhibitors for patients with HIV disease. AIDS 176. Hedaya MA, Elmquist WF, Sawchuk RJ. Probenecid inhibits 1997; 11: 268-9 the metabolic and renal clearances of zidovudine (AZT) in 161. Palkama VJ, Ahonen J, Neuvonen PJ, et al. Effect of saquinavir human volunteers. Pharm Res 1990; 7: 411-7 on the pharmacokinetics and pharmacodynamics of oral and 177. Miranda P de, Good SS, Yarchoan R, et al. Alteration of intravenous midazolam. Clin Pharmacol Ther 1999; 66: 33-9 zidovudine pharmacokinetics by probenecid in patients with 162. Elliott AJ, Russo J, Bergam K, et al. Antidepressant efficacy AIDS or AIDS-related complex. Clin Pharmacol Ther 1989; in HIV-seropositive outpatients with major depressive dis- 46: 494-500

 Adis International Limited. All rights reserved. Clin Pharmacokinet 2003; 42 (3) Drug Interactions with Antiretrovirals 281

178. Petty BG, Kornhauser DM, Lietman PS. Zidovudine with pro- 196. Jaruratanasirikul S, Sriwiriyajan S. Effect of indinavir on the benecid: a warning. Lancet 1990; 335: 1044-5 pharmacokinetics of rifampicin in HIV-infected patients. J 179. Massarella JW, Nazareno LA, Passe S, et al. The effect of pro- Pharm Pharmacol 2001; 53: 409-12 benecid on the pharmacokinetics of zalcitabine in HIV-posi- 197. Bergshoeff AS, Wolfs TFW, Geelen SPM, et al. Favourable tive patients. Pharm Res 1996; 13: 449-52 nelfinavir pharmacokinetics (PK) during rifampin use by 180. Peloquin CA, Nitta AT, Burman WJ, et al. Low antituberculosis coadministration of ritonavir-case report. Second Interna- drug concentrations in patients with AIDS. Ann Phar- tional Workshop on Clinical Pharmacology [abstract 1.13]; macother 1996; 30: 919-25 2001 Apr 2-4; Noordwijk, The Netherlands 181. Knupp CA, Graziano FM, Dixon RM, et al. Pharmacokinetic- 198. Robinson P, Lamson M, Gigliotti M, et al. Pharmacokinetic interaction study of didanosine and ranitidine in patients se- (PK) interaction between nevirapine (NVP) and rifampin ropositive for human immunodeficiency virus. Antimicrob (RMP). 12th World AIDS Conference [abstract 60623]; 1998 Agents Chemother 1992; 36: 2075-9 Jun 29-Jul 3; Geneva 182. Sim SM, Hoggard PG, Sales SD, et al. Effect of ribavirin on 199. Dean GL, Back DJ, De Ruiter A. Effect of tuberculosis therapy on nevirapine trough plasma concentrations. AIDS 1999; 13: zidovudine efficacy and toxicity in vitro: a concentration-de- 2489-90 pendent interaction. AIDS Res Hum Retroviruses 1998; 14: 200. Moreno S, Podzamcer D, Blázquez R, et al. Treatment of tuber- 1661-7 culosis in HIV-infected patients: safety and antiretroviral ef- 183. Kakuda TN, Brinkman K, Salmon-Céron D, et al. Mitochon- ficacy of the concomitant use of ritonavir and rifampin. AIDS drial toxic effects and ribavirin. Lancet 2001; 357: 1802-4 2001; 15: 1185-7 184. Polk RE, Brophy DF, Israel DS, et al. Pharmacokinetic interac- 201. Veldkamp AI, Hoetelmans RMW, Beijnen JH, et al. Ritonavir tion between amprenavir and rifabutin or rifampin in healthy enables combined therapy with rifampin and saquinavir [let- males. Antimicrob Agents Chemother 2001; 45: 502-8 ter]. Clin Infect Dis 1999; 29: 1586 185. Borin MT, Chambers JH, Carel BJ, et al. Pharmacokinetic study 202. Lee SI, Klesmer J, Hirsch BE. Neuroleptic malignant syndrome of the interaction between rifabutin and delavirdine mesylate associated with use of risperidone, ritonavir, and indinavir: a in HIV-1 infected patients. Antiviral Res 1997; 35: 53-63 case report. Psychosomatics 2000; 41: 453-4 186. Cox SR, Herman BD, Batts DH, et al. Delavirdine (D) and 203. Murphy R, Katlama C, Bonmarchand M, et al. Roxithromycin rifabutin (R): pharmacokinetic (PK) evaluation in HIV-1 pa- pharmacodynamic interaction and effect on nelfinavir-based tients with concentration-targeting of delavirdine. 5th Con- antiretroviral therapy. 8th European Conference on Clinic ference on Retroviruses and Opportunistic Infections Aspects and Treatment of HIV-Infection [abstract 251]; 2001 [abstract 344]; 1998 Feb 1-5; Chicago (IL) Oct 28-31; Athens 187. Kuper JJ, D Aprile M. Drug-drug interactions of clinical signif- 204. Merry C, Barry MG, Ryan M, et al. Interaction of sildenafil and icance in the treatment of patients with Mycobacterium avium indinavir when co-administered to HIV-positive patients. complex disease. Clin Pharmacokinet 2000; 39: 203-14 AIDS 1999; 13: S101-7 188. Hamzeh F, Benson C, Gerber J, et al. Steady-state pharmaco- 205. Hall MCS, Ahmad S. Interaction between sildenafil and HIV-1 kinetic (PK) interaction of modified-dose indinavir (IDV) and combination therapy. Lancet 1999; 353: 2071-2 rifabutin (RBT). Second International Workshop on Clinical 206. Muirhead GJ, Wulff MB, Fielding A, et al. Pharmacokinetic Pharmacology [abstract 1.4]; 2001 Apr 2-4; Noordwijk, The interactions between sildenafil and saquinavir/ritonavir. Br J Netherlands Clin Pharmacol 2000; 50: 99-107 189. Cato III A, Cavanaugh J, Shi H, et al. The effect of multiple 207. Martin CM, Hoffman V, Berggren RE. Rhabdomyolysis in a doses of ritonavir on the pharmacokinetics of rifabutin. Clin patient receiving simvastatin concurrently with highly active Pharmacol Ther 1998; 63: 414-21 antiretroviral therapy. 40th Interscience Conference on Anti- 190. Gallicano K, Khaliq Y, Carignan G, et al. A pharmacokinetic microbial Agents and Chemotherapy [abstract 1297]; 2000 study of intermittent rifabutin dosing with a combination of Sep 17-20; Toronto (ON) ritonavir and saquinavir in patients infected with human im- 208. Piscitelli SC, Burstein AH, Chaitt D, et al. Indinavir concentra- munodeficiency virus. Clin Pharmacol Ther 2001; 70: 149-58 tions and St John’s wort. Lancet 2000; 355: 547-8 191. Gallicano KD, Sahai J, Shukla VK, et al. Induction of zidovud- 209. de Maat MMR, Hoetelmans RMW, Mathôt RAA, et al. Drug interaction between St Johns wort and nevirapine. AIDS ine glucuronidation and amination pathways by rifampicin in 2001; 15: 420-1 HIV-infected patients. Br J Clin Pharmacol 1999; 48: 168-79 210. Schvarcz R, Rudbeck G, Söderdahl G, et al. Interaction between 192. Burger DM, Meenhorst PL, Koks CHW, et al. Pharmacokinetic nelfinavir and tacrolimus after orthoptic liver transplantation interaction between rifampin and zidovudine. Antimicrob in a patient coinfected with HIV and hepatitis C (HCV). Agents Chemother 1993; 37: 1426-31 Transplantation 1999; 69: 2194-5 193. Borin MT, Chambers JH, Carel BJ, et al. Pharmacokinetic study 211. Sheikh AM, Wolf DC, Lebovics E, et al. Concomitant human of the interaction between rifampin and delavirdine mesylate. immunodeficiency virus protease inhibitor therapy markedly Clin Pharmacol Ther 1997; 61: 544-53 reduces tacrolimus metabolism and increases blood levels. 194. Benedek I, Joshi A, Fiske WD, et al. Pharmacokinetic interac- Transplantation 1999; 68: 307-9 tion between efavirenz (EFV) and rifampin (RIF) in healthy 212. Hsu A, Granneman GR, Witt G, et al. Assessment of multiple volunteers. 12th World AIDS Conference [abstract 42280]; doses of ritonavir on the pharmacokinetics of theophylline. 1998 Jun 29-Jul 3; Geneva 11th International Conference on AIDS [abstract Mo.B.1200]; 195. Lopez-Cortes LF, Ruiz R, Viciana P, et al. Pharmacokinetic 1996 Jul 7-12; Vancouver (BC) interactions between rifampin and efavirenz in patients with 213. Zalma A, Moltke LL von, Granda BW, et al. In vitro metabo- tuberculosis and HIV infection. 8th Conference on Retro- lism of trazodone by CYP3A: Inhibition by ketoconazole and viruses and Opportunistic Infections [abstract 32]; 2001 Feb human immunodeficiency viral protease inhibitors. Biol Psy- 4-8; Chicago (IL) chiatry 2000; 47: 655-61

 Adis International Limited. All rights reserved. Clin Pharmacokinet 2003; 42 (3) 282 de Maat et al.

214. Lee BL, Safrin S, Makrides V, et al. Zidovudine, trimethoprim, ies with liver microsomes of 30 Japanese and 30 Caucasians. and dapsone pharmacokinetic interactions in patients with hu- J Pharmacol Exp Ther 1994; 270: 414-23 man immunodeficiency virus infection. Antimicrob Agents 231. Kim RB, Fromm MF, Wandel C, et al. The drug transporter Chemother 1996; 40: 1231-6 P-glycoprotein limits oral absorption and brain entry of HIV- 215. Adkins JC, Peters DH, Faulds D. Zalcitabine: an update of its 1 protease inhibitors. J Clin Invest 1998; 101: 289-94 pharmacodynamic and pharmacokinetic properties and clini- 232. Malingré MM, Beijnen JH, Schellens JHM. Oral delivery of cal efficacy in the management of HIV infection. Drugs 1997; taxanes. Invest New Drugs 2001; 19: 155-62 53: 1054-80 233. Zhang Y, Benet LZ. The gut as a barrier to drug metabolism: 216. Moore KHP, Yuen GJ, Raasch RH, et al. Pharmacokinetics of combined role of cytochrome P450 3A and P-glycoprotein. lamivudine administered alone and with trimethoprim-sul- Clin Pharmacokinet 2001; 40: 159-68 famethoxazole. Clin Pharmacol Ther 1996; 59: 550-8 234. Hennessy M, Kelleher D, Spiers JP, et al. St Johns Wort in- 217. Hudson M, Nash C. Effect of trimethoprim on lamivudine bio- creases expression of P-glycoprotein: implications for drug availability [letter]. JAMA 1996; 276: 1140 interactions. Br J Clin Pharmacol 2002; 53: 75-82 218. Katlama C. Effect of trimethoprim on lamivudine bioavailabil- 235. Fellay J, Marzolini C, Meaden ER, et al. Response to anti- ity [letter]. JAMA 1996; 276: 1140 retroviral treatment in HIV-1-infected individuals with allelic 219. Bertz RJ, Cao G, Cavanaugh JH, et al. Effect of ritonavir on the variants of the multidrug resistance transporter 1: a pharma- pharmacokinetics of trimethoprim/sulphamethoxazole. 11th cogenetics study. Lancet 2002; 359: 30-6 International Conference on AIDS [abstract Mo.B.1197]; 236. Sansom LN, Evans AM. What is the true significance of plasma 1996 Jul 7-12; Vancouver (BC) protein binding displacement interactions? Drug Saf 1995; 220. Lertora JJL, Rege AB, Greenspan DL, et al. Pharmacokinetic 12: 227-33 interaction between zidovudine and valproic acid in patients 237. Somogyi A. Renal transport of drugs: specificity and molecular infected with human immunodeficiency virus. Clin Phar- mechanisms. Clin Exp Pharmacol Physiol 1996; 23: 986-9 macol Ther 1994; 56: 272-8 238. Prins JM, Büller HR, Kuijper EJ, et al. Once versus thrice daily 221. Cozza KL, Swanton EJ, Humphreys CW. Hepatotoxicity with gentamicin in patients with serious infections. Lancet 1993; combination of valproic acid, ritonavir, and nevirapine: a case 341: 335-9 report. Psychosomatics 2000; 41: 452-3 239. Lori F, Malykh AG, Foli A, et al. Combination of a drug target- 222. Gatti G, Alessandrini A, Camera M, et al. Influence of indinavir ing the cell with a drug targeting the virus controls human and ritonavir on warfarin anticoagulant activity. AIDS 1998; immunodeficiency virus type 1 resistance. AIDS Res Hum 12: 825-6 Retroviruses 1997; 13: 1403-9 223. Dionisio D, Mininni S, Bartolozzi D, et al. Need for increased 240. Zala C, Salomon H, Ochoa C, et al. Higher rate of toxicity with dose of warfarin in HIV patients taking nevirapine. AIDS no increased efficacy when hydroxyurea is added to a regimen 2001; 15: 277-8 of stavudine plus didanosine and nevirapine in primary HIV 224. Knoell KR, Young TM, Cousins ES. Potential interaction in- infection. J Acquir Immune Defic Syndr 2002; 29: 368-73 volving warfarin and ritonavir. Ann Pharmacother 1998; 32: 241. Havlir DV, Gilbert PB, Bennett K, et al. Effects of treatment 1299-302 intensification with hydroxyurea in HIV-infected patients 225. Newshan G, Tsang P. Ritonavir and warfarin interaction. AIDS with virologic suppression. AIDS 2001; 15: 1379-88 1999; 13: 1788-9 242. Squires KE. Oral ganciclovir for cytomegalovirus retinitis in 226. Darlington MR. Hypoprothrombinemia during concomitant patients with AIDS: results of two randomized studies. AIDS therapy with warfarin and saquinavir [letter]. Ann Phar- 1996; 10 Suppl. 4: S13-8 macother 1997; 31: 647 243. Slain D, Pakyz A, Israel DS, et al. Variability in activity of 227. Greenblatt DJ, von Moltke LL, Harmatz JS, et al. Differential hepatic CYP3A4 in patients infected with HIV. Pharmaco- impairment of triazolam and zolpidem clearance by ritonavir. therapy 2000; 20: 898-907 J Acquir Immune Defic Syndr 2000; 24: 129-36 244. Lee BL, Wong D, Benowitz NL, et al. Altered patterns of drug 228. Rang HP, Dale MM. Absorption, distribution and fate of drugs. metabolism in patients with acquired immunodeficiency syn- In: Rang HP, Dale MM, editors. Pharmacology. 2nd ed. Ed- drome. Clin Pharmacol Ther 1993; 53: 529-35 inburgh: Churchill Livingstone, 1991: 72-109 229. Dresser GK, Spence JD, Bailey DG. Pharmacokinetic-pharma- codynamic consequences and clinical relevance of cyto- Correspondence and offprints: Dr Monique M.R. de Maat, chrome P450 3A4 inhibition. Clin Pharmacokinet 2000; 38: 41-57 Department of Pharmacy & Pharmacology, Slotervaart 230. Shimada T, Yamazaki H, Mimura M, et al. Interindividual vari- Hospital, Louwesweg 6, Amsterdam, 1066 EC, The Nether- ations in human liver cytochrome P-450 enzymes involved in lands. the oxidation of drugs, carcinogens and toxic chemicals: stud- E-mail: [email protected]

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