HIV Medicine 2006 | Drug-Drug Interactions, Introduction

HIV Medicine 2006
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Drug-Drug Interactions

Leonie Meemken and Laura Dickinson

In an attempt to predict or avoid drug-drug interactions, a complete medication history, including herbal remedies and recreational drug use is necessary. In particular, combinations involving inducers (e.g. rifampicin) and inhibitors (e.g. ketoconazole) can result in unfavorable plasma concentrations of antiretroviral agents. For example, inhibitors can increase concentrations of some drugs to such an extent that toxicity develops and inducers can reduce concentrations to a point where resistance can occur. If there are no clear clinical data about a specific drug-drug interaction, theoretical consideration can help to exclude severe drug-drug interactions. It is important to look at the bilateral effect of ART. ART can influence co-medication and vice versa. Dose adjustments of ARVs and/or co-medication may need to be considered. For further information on drug-drug interactions refer to the website www.hiv-druginteractions.org

Drug plasma concentrations can also be influenced by many different factors such as age, gender, liver disease and genetic polymorphism. Individualized dosing with the use of TDM is, in many cases, very important.

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Individual drugs Comment: plasma concentrations of drugs are affected by many factors: such as ethnicity, kidney and liver failure, age or sex. Prediction of possible interactions can be challenging and in a number of cases therapeutic drug monitoring (TDM) may be useful. Abbreviations used in the table: AUC = area under the curve, QD = once daily, BID = twice daily, TID = three times daily, ?? = AUC decreases or increases, TDM = therapeutic drug monitoring 3TC (Lamivudine, Epivir; in Combivir, Trizivir, Kivexa) Approved dose: 150 mg BID or 300 mg QD. Elimination: renal Drugs Interactions (IA) Comments NRTIs FTC [1-2] Antagonism Avoid combination NNRTIs [ 1-2] No clinically significant IA PIs [1-2] No clinically significant IA References 1. Tseng A. www.tthhivclinic.com, General Hospital, Toronto 2006 Clinical Pharmacology, Gold Standard Multimedia, 2004. http://www.gsm.com 2. US Department of Health and Human Services (DHHS) and National Institutes of Health (NIH). The living document: Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. Retrieved April 14, 2004. www.aidsinfo.nih.gov. Abacavir (ABC, Ziagen; also in Trizivir, Kivexa) Approved dose: 300 mg BID or 600 mg QD. Metabolism via alcohol dehydrogenase and glucuronidation pathway Drugs Interactions (IA) Comments Alcohol [1-3] ABC ? 41 % Clinically not significant NRTIs [1-2] No clinically significant IA NNRTIs [1-2] No clinically significant IA Caution when starting ABC and NNRTI (allergy/HSR) PIs TPV/r [4] ABC: 40 % ? Clinical relevance unknown. No dose adjustment at the moment * HSR = hypersensitivity reaction References 1. Tseng A. www.tthhivclinic.com, General Hospital, Toronto 2004. 2. Clinical Pharmacology, Gold Standard Multimedia, 2004. http://www.gsm.com 3. McDowell JA, Chittick GE, Pilati-Stevens C, et al. Pharmacokinetic interaction of abacavir and ethanol in HIV-infected adults. Antimicrob Agents Chemother 2000 ; 44: 1686-90. http://www.amedeo.com/lit.php?id=10817729 4. Aptivus, Boehringer Ingelheim. Atazanavir (ATV, Reyataz) Approved dose: ATV/RTV: 300/100 mg. Metabolism: atazanavir (ATV) is primarily metabolized by CYP3A4 and inhibits CYP3A4, CYP2C9, CYP1A2 and UDP-glucuronosyltransferase (UGT)-1A1 [1]. Drugs Interactions Comments NRTIs TDF [2,31] ATV 400 + TDF 300 QD [2]: ATV ? 25 % (Cmin 40 % ?) ATV/r 300/100 +TDF 300 QD: ATV ? 11 % (Cmin 20 % ?) TDF ? 37 % (Cmin 29 % ?) ATV/RTV 300/100 QD [2,3], taken with a light meal. Boosted ATV levels are 2-4-fold higher than unboosted ATV without TDF. NNRTIs EFV [3-5] ATV 400 + EFV 600 QD: ATV ? up to 74 % [4,5] ATV/RTV 400/100 QD [3], taken with a light meal. NVP [24] Theoretically: NVP ? No data. PIs IDV/r [3,6] Risk of hyperbilirubinemia Avoid combination. SQV/r [8,9] ATV 300 + SQV/r 1600/100 QD: SQV ? 60 %, RTV ? 41 % [9] ATV 200 + SQV 1500 BID: SQV: 75 % > 0.1 ug/ml [8] TDM. Synergistic effect [9]. NLF [26] NLF 1250 BID + ATV 400 QD: Cmin NLF: 57 % , M8: 124 % FPV/r [27,30] ATV 300 QD + FPV/r 700/100 BID: controversial data TDM. LPV/r [28,34,35] ATV 400 QD + LPV/r 400/100 BID: 1. LPV ? 16 % (Cmin 35 % ?) [28] 2. ATV (Cmin 45 % ?) [34] 3. ATV ? 38 % (Cmin 38 % ?) [35] Controversial data => TDM. 1. HIV-patients. 2. Healthy volunteers. 3. HIV-patients TPV/r [33] ATV 300 QD + TPV/r 500/100 BID: ATV ? 68 % (Cmin 81 % ?) TPV (Cmin 75 % ) Avoid combination. DNV (TMC 114)/r [36] ATV 300 QD + DNV/r 400/100 BID: ATV (Cmin 50 % ?) RTV ? 50-59 % Increased risk of hyperbiliru-binemia, icterus. Combination possible if necessary Antiarrhythmics Amiodarone, bepridil, quinidine, flecainide, lidocaine [3,11] Theoretically: antiarrhythmic drugs ? Avoid combination: bepridil, quinidine [3]. Possible: dose adjustment of antiarrhythmics Antibiotics Clarithromycin [12] Clarithromycin ? 1.9-fold (caution: QT-prolongation), active clarithromycin metabolite ? 70 %, ATV ? 30 % Avoid combination or 50 % dose reduction of clarithromycin. Theoretical alternative: azithromycin. Erythromycin [13] Theoretically: ATV ? Anticoagulants Warfarin Theoretically: warfarin ? Check INR Antidepressants Tricyclic antidepressants [14] Theoretically: tricyclic antidepressants ? Monitor for anticholinergic effects. St. John's Wort [3] Theoretically: ATV ? Avoid combination. Antiepileptics Carbamazepine, phenytoin, primidon [3] Theoretically: ATV ? Theoretical alternative: gabapentin, lamotrigine, valproic acid. Antifungal drugs Itra-, keto-, vori-conazole [18] Theoretically: ATV ? Theoretical alternative: fluconazole. Antihistamines Loratadine (> 20 mg), terfenadine [3,15,16] Theoretically: antihistamines ? risk of QT-prolongation ? Avoid combination: terfena-dine, loratadine (> 20 mg) [3]. Theoretical alternative: cetirizine, fexofenadine [15,16]. Antihypertensives Calcium channel blockers [17] such as bepridil, diltiazem, nifedipine, verapamil Bepridil, diltiazem ? 2-fold Theoretically: calcium channel blockers ? Theoretically: dose reduction of calcium channel blockers. 50 % dose reduction of diltiazem. Bosentan [11,23] Theoretically: ATV ? Avoid combination or TDM. Antipsychotics several neuroleptics Theoretically: antipsychotics ? Avoid combination with pi-mozide. Monitor for side-ef-fects. Prefer: atypical neuro-leptics (less anticholinergic) Antituberculosis drugs Rifampicin [21] 90 % AUC-reduction of PIs Avoid combination. Rifabutin [21] ATV 400 + rifabutin 150 QD: rifabutin ? 2-fold ATV 400 QD + rifabutin 150 mg 3 times a week. Cytotoxic drugs Paclitaxel, vinca-alkaloids [22], irinotecan [3] Theoretically: cytotoxic drugs ? Monitor for side-effects. Gastritis-/ Ulcer healing drugs Proton pump inhibitors (PPIs) H2-receptor antagonists, antacids [25,29] Omeprazole 40 + ATV/r 300/100: ATV ? 76 % (Cmin 78 % ?) Famotidin + 1. ATV 400 QD = ATV 40-50 % ¯ 2. ATV/r 300/100 QD = ATV-level of ATV/TDF 3. ATV/r 400/100 QD = ATV-level = ATV 300/100 QD Avoid combination: PPIs are not recommended. At least 12h time-lag: H2-receptor antagonists, antacids. ATV/r + H2-receptor antagonists: concurrent intake could be possible. Hypnotics Barbexaclone, phenobarbital Theoretically: ATV ? Avoid combination or TDM. Benzodiazepines, zolpidem [10] Theoretically: benzodiazepines ? Avoid combination: midazolam, triazolam. Alternatives: oxazepam, lorazepam, temazepam. Immunosuppressants Cylosporine, siroli-mus, tacrolimus [11] Theoretically: immunosuppressants ? Dose adjustment of immunosuppressants with TDM. Lipid-lowering drugs Atorvastatin, lovastatin, simvastatin [19] Theoretically: statins ? Avoid combination: lovastatin, simvastatin. Alterna-tives: pravastatin, fluvastatin, rosuvastatin. Oral contraceptives [11] ATV: ethinyl estradiol ? 48 %, norethindrone ? 110 % RTV: ethinyl estradiol ? Monitor for side-effects, when necessary, reduce dose. PDE5 inhibitors Sildenafil, tadalafil vardenafil [11] Theoretically: PPH ? Start with lowest dose. Substitution Methadone [32] No interaction Others Ergot alkaloids [11] Theoretically: ergotamines ? Avoid combination: Theoretical alternative: triptans. References 1. Tseng A. www.tthhivclinic.com, General Hospital, Toronto; 2004. 2. Kaul S, Bassi K, Damle BD, et al. Pharmacokinetic evaluation of the combination of atazanavir, enteric coated didanosine, and tenofovir disoproxil fumarate for a once daily antiretroviral regimen. Abstract A-1616, 43rd ICAAC 2003, Chicago. 3. Atazanavir. Bristol Myers-Squibb. 4. Preston S, Piliero P, OŽMara E, et al. Evaluation of steady-state interaction between atazanavir and efavirenz. Abstract 443, 9th CROI 2002, Seattle. http://63.126.3.84/2002/Abstract/13543.htm 5. Tackett D, Child M, Agarwala S, et al. Atazanavir: A summary of two pharmacokinetic drug interaction studies in healthy volunteers. Abstract 543, 10th CROI 2003, Boston. 6. Robinson BS, Riccardi KA, Gong YF, et al. BMS- 232632, a highly potent HIV protease inhibitor that can be used in in combination with other available antirtroviral agents. Antimicrob Agents Chemother 2000; 44: 2093-9. http://www.amedeo.com/lit.php?id=10898681 7. King J, Paul Lundy S, Kakuda TN et al. Pharmacokinetics of saquinavir with low-dose ritonavir or atazanavir twice daily in seronegativ volunteers. ASPIRE II. Abstract 586. 13th CROI 2006, Denver. 8. DeJesus E, Grinsztejn B, Rodriguez C, et al. Efficacy and safety of atazanavir with ritonavir or saquinavir vs lopinavir/ritonavir in patients who have experienced virologic failure on multiple HAART regimens: 48-Week results from BMS A1424-045. Abstract 54, 11th CROI 2004, San Francisco. http://www.retroconference.org/2004/cd/Abstract/547.htm 9. Boffito M, Kurowski M, Kruse G, et al. Atazanavir enhances saquinavir hard gel concentration in a ritonavir boosted once daily regimen. AIDS 2004; 18: 1292-7. http://www.amedeo.com/lit.php?id=15362661 10. Agarwala S, Russo R, Mummanemi V, et al. Steady-state pharmacokinetic interaction study of atazanavir with ritonavir in healthy subjects. Abstract H1716, 42nd ICAAC 2002, San Diego. 11. Clinical Pharmacology, Gold Standard Multimedia, 2004. http://www.gsm.com 12. Mummaneni V, Randall D, Chabuel D, et al. Steady-state pharnacokinetic interaction study of atazanavir with clarithromycin in healthy subjects. Abstract H1717, 42nd ICAAC 2002, San Diego. 13. Benedek ICH, Joshi A, Fiske WD, et al. Pharmacokinetic studies in healthy volunteers with efavirenz and the macrolide antibiotics, azithromycin and chlarithromycin. Abstract 347, 5th CROI 1998, Chicago. 14. Richelson E. Pharmacokinetic interactions of antidepressiva. J Clin Psychiatry 1998; 59: 22-6. http://www.amedeo.com/lit.php?id=9720479 15. Pratt CM, Mason J, Russell T. Cardiovascular safety of fexofenadine HCL. Am J Cardiol 1999; 84: 278-9. http://www.amedeo.com/lit.php?id=10444240 16. Abernethy DR, Barbey JT. Loratadine and terfenadine interaction with nefazodone: Both antihistamines are associated with QT-prolongation. Clin Pharmacol Ther 2001; 69: 96-103. http://www.amedeo.com/lit.php?id=11240972 17. Rossi DR, Rathbun C, Slater LD. Symptomatic ortostasis with extended-release nifedipine and protease inhibitors. Ann Pharmacother 2002; 22: 1312-6. http://www.amedeo.com/lit.php?id=12389881 18. OŽMara E, Randall D, Uderman H, et al. Steady-state pharmacokinetics interaction study between BMS-232632 and ketoconazole in healthy subjects. Abstract 1646, 40th ICAAC 2000, Toronto. 19. Fichtenbaum CJ, Gerber JG, Rosenkranz S. Pharmacokinetic interaction between protease inhibitors and statins in HIV seronegative volunteers: ACTG Study A5047. AIDS 2002; 16: 569-77. http://www.amedeo.com/lit.php?id=11873000 20. Antoniou T, Lin-in Tseng. Interactions between recreational drugs and antiretroviral agents. Annals Pharmacother 2002; 36: 1598-613. http://www.amedeo.com/lit.php?id=12243611 21. CDC. Notice to Readers: Updated guidelines for the use of rifamycins for the treatment of tuberculosis among HIV-infected patients taking protease inhibitors or nonnucleoside reverse transcriptase inhibitors. MMWR 2004; 53:37. http://www.amedeo.com/lit.php?id=11795500 22. Lam M, Ignoffo R, Meibohm B. Ein Leitfaden für klinisch-relevante Arzneimittel-Interaktionen in der Onkologie. 23. Ghofrani HA, Olschewski H, Seeger W, et al. Sildenafil for treatment of severe pulmonary hypertension and commencing right-heart failure. Pneumologie 2002; 56: 665-72. http://amedeo.com/lit.php?id=12442206 24. Alexander CS, Montaner JG, Langridge S, et al. Interaction between atazanavir/Ritonavir (ATV/r) and nevirapine (NVP) is observed in a clinical setting. Abstract P275, 7th Int Congr Drug Ther HIV Inf 2004, Glasgow. 25. Roter Hand Brief, Bristol Myers-Squibb, December 2004 26. Kurowski M, Breske A, Kruse G, et al. Atazanavir (ATV) enhances through concentrations of nelfinavir (NFV) and its M8 metabolite in a treatment regimen without ritonavir (RTV). Abstract 90, 6th Int Worksh Clin Pharmacol HIV Ther 2005, Quebec. 27. Guttanti M, Raffaella de Pascalis C, Seminari E, et al. Pharmacokinetics of amprenavir given once or twice a day when combined with atazanavir in heavily pre-treated patients. AIDS 2003, 17: 2669-70. http://www.amedeo.com/lit.php?id=14685066 28. Colombo S, Buclin T, Franc C. Ritonavir-boosted atazanavir-lopinavir combination: a pharmacokinetic interaction study of total, unbound plasma and cellular exposures. Antivir Ther. 2006;11:53-62. 29. Agarwala S, Child M, Wang Y et al. Pharmacokinetic effect of famotidine on atazanavir with and without ritonavir in healthy subjects. Abstract 11, 6th Int Worksh Clin Pharmacol HIV Ther 2005, Quebec. 30. Wire MB et al. The pharmacokientic interaction between fosamprenavir/ritonavir and atazanavir in healthy adult subjects (APC 10018). Abstract 4.3/9. 10th EACS Conference 2005, Dublin. 31. Agarwala S, Eley T, Villegas C, et al. Pharmacokinetic interaction between tenofovir and atazanavir co-administered with ritonavir in healthy subjects. Abstract 16, 6th Int Worksh Clin Pharmacol HIV Ther 2005, Quebec. 32. Friedland G, Andrews L, Schreibman T et al. Lack of an effect of atazanavir on steady-state pharmcokinetics of methadone in patients chronically treated for opiate addiction. AIDS 2005; 19:1635-41. http://amedeo.com/lit.php?id=16184033 33. Sekar V, De Marez T, Spinosa-Guzman S et al. Pharmacokinetic Interaction between TMC114/RTV and Atazanavir in healthy volunteers. Abstract PE4/3.4, 10th EACS Conference 2005, Dublin. 34. Pham P, Parson T, Flexner C et al. Beneficial Pharmacokinetic Interaction between Atazanavir and Lopinavir/r. 13th CROI Denver 2006, abstract 585. 35. Vezina HE, Tschampa JM, Jennings C et al. Steady-state pharmacokinetic of lopinavir/ritonavir coadministered with atazanavir in HIV-infected subjects. Abstract 48. 7th Int Worksh Clin Pharmacol HIV Ther 2005, Lissabon. 36. Sabo JP, Elgadi M, Wruck J et al. The pharmacokinetic interaction between atazanavir/ritonavir and steady-state tipranavir/ritonavir in healthy volunteers. Abstract 41, 7th Int Worksh Clin Pharmacol HIV Ther 2005, Lissabon. AZT (Zidovudine, Retrovir; also in Trizivir, Combivir) Approved dose: 250 or 300 mg BID. Metabolism: glucuronidation pathway, elimination: renal Drugs Interactions Comments NRTIs d4T [1-3] Antagonism Avoid combination. NNRTIs No significant interaction PIs TPV/r [15] AZT ? 33-43 % Avoid comb. if possible. Antibiotics Atovaquone AZT ? 35 % ± 23 % Monitor for AZT side-effects. Clarithromycin [4] AZT ? 10-25 % Take 2 - 4 h apart Cotrimoxazol [2] Haematotoxicity ? Dapsone [5] Haematotoxicity ? Antiepileptics (Fos-)Phenytoin [2] Clearance of AZT ? 30 % and phenytoin ?? Monitor for AZT side-effects, TDM of phenytoin. Valproic acid [2] AZT ? 79 % Monitor for AZT side-effects. Antifungal drugs Fluconazole [2] AZT ? 74 % Monitor for AZT side-effects. Antimalarials Pyrimethamine [2] Increased hematotoxicity ? Antiviral Drugs Acyclovir [7] Case report: profound lethargy Cidofovir [8] Increased hematotoxicity ? See: probenecid. Foscarnet [6] Increased risk of anaemia ? (less risky than with ganciclovir) Ganciclovir [9-10], Valganciclovir Increased hematotoxicity ? Avoid combination. Th. alternatives: foscarnet + AZT, ganciclovir + ddI. Interferon [11] Increased hematotoxicity ? Avoid combination. Ribavirin [12] Increased hematotoxicity and mitochondrial toxicity (lactic acidosis), AZT-antagonism Avoid combination. Cytotoxic drugs Doxorubicin [2] among many others Increased hematotoxicity ? Avoid combination or control blood counts closely. Substitution Methadone [14] AZT ? 41 % Monitor for AZT side-effects. Uricosuric drug Probenecid [13] AZT ? 80 % Monitor for AZT side-effects. Take 50 % of AZT dose when combined with cidofovir and probenecid. References 1. Tseng A. www.tthhivclinic.com, General Hospital, Toronto, 2006. 2. Clinical Pharmacology, Gold Standard Multimedia, 2004. http://www.gsm.com 3. Product information: Retrovir. Glaxo Smithkline. 4. Polis MA, Piscitelli SC, Vogel S, et al. Chlarithromycin lowers plasma zidovudine levels in persons with HIV-infection. Antimicrob Agents Chemother 1997; 41: 1709-14. http://www.amedeo.com/lit.php?id=9257746 5. US Department of Health and Human Services (DHHS) and National Institutes of Health (NIH). The living document: Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. Retrieved April 14, 2004. www.aidsinfo.nih.gov. 6. Foscavir. Astra Zeneca. 7. Cooper DA, Pehrson PO, Pedersen C, et al. The efficacy and safety of zidovudine alone or as co-therapy with acyclovir for the treatment of AIDS and AIDS-related complex: a double-blind randomized trial. European-Australian Collaborative Group. AIDS 1993; 7: 197-207. http://www.amedeo.com/lit.php?id=8096703 8. Bach MC. Possible drug interaction during therapy with azidothymidine and acyclovir for AIDS [letter]. N Engl J Med 1987; 317: 547. http://www.amedeo.com/lit.php?id=3468354 9. Hochster H, Dieterich D, Bozzette S, et al. Toxicity of combined ganciclovir and zidovudine for cytomegalovirus disease associated with AIDS. Ann Intern Med 1990; 113: 111-7. http://www.amedeo.com/lit.php?id=2163228 10. Cimoch PJ, Lavelle J, Pollard R, et al. Pharmacokinetics of oral ganciclovir alone and in combination with zidovudine, didanosine and probenecid in HIV-infected subjects. JAIDS 1998; 17: 227-34. http://www.amedeo.com/lit.php?id=9495222 11. Ruedy J, Schlechter M, Montaner JS. Zidovudine for early HIV-infection: who, when, and how? Ann Intern Med 1990; 112: 721-3. 12. Sim SM, Higgard PG, Sales SD, et al. Effect of ribavirin on zidovudine efficacy and toxicity in vitro: a concentration-dependent interaction. AIDS Res Hum Retr 1998; 14: 1661-7. 13. Kornhauser DM, Petty BG, Hendrix CW, et al. Probenecid and zidovudine metabolism. Lancet 1989; 2: 473-5. http://www.amedeo.com/lit.php?id=2570186 14. Antoniou T, Lin-in Tseng. Interactions between recreational drugs and antiretroviral agents. Ann Pharmacother 2002; 36: 1598-613. http://www.amedeo.com/lit.php?id=12243611 15. Roszko PJ, Curry K, Brazina B, et al. Standard doses of efavirenz, zidovudine, tenofovir, and didanosine may be given with tipranavir/ritonavir. Abstract 865, 2nd IAS 2003, Paris. http://www.aegis.com/conferences/2ndIASHIVPT /865.html d4T (Stavudine, Zerit) Approved dose: 30-40 mg BID (< 60 kg: 30 mg BID). Elimination: 34-43 % renal Drugs Interactions Comments NRTIs AZT Antagonism ddI [1] Risk of lactic acidosis, pancreatitis, neuropathy ? Not recommended for first line therapy. ddC [1] Risk of neuropathy ? Avoid combination. Co-medication Dapsone [1] Risk of neuropathy ? Avoid combination. Isoniazid Risk of neuropathy ? Avoid combination. Pentamidine [3] Additive pancreas toxicity when given i.v. Avoid combination. Start d4T after one week. Ribavirin [4-6] Increased risk of mitochondrial to-xicity (lactic acidosis), pancreatitis Closely monitor for amylase, lipase, lactate. Vinca Alcaloids [1] Risk of neuropathy ? Avoid combination. References 1. Tseng A. www.tthhivclinic.com, General Hospital, Toronto, 2004. 2. Clinical Pharmacology, Gold Standard Multimedia, 2004. http://www.gsm.com 3. Foisy MM, Slayter KL, Hewitt RG, et al. Pancreatitis during intravenous pentamidine therapy in an AIDS patient with prior exposure to didanosine. Ann Pharmacother 1994; 28: 1025-8. http://www.amedeo.com/lit.php?id= 7803875 4. Landau A, Batisse D, Piketty C, et al. Lack of interference between ribavirin and nucleoside analogues in HIV/HCV co-infected individuals undergoing concomitant antiretroviral and anti-HCV combination therapy. AIDS 2000; 14: 1857-8. http://www.amedeo.com/lit.php?id=10985327 5. Hittinger G. Mitochondrial toxicity in HIV/HCV co-infected patients treated with ribavirin, interferon alpha and antiretroviral therapy. Abstract TuPeB4516, XIV Int AIDS Conference 2002, Barcelona. 6. Smith DM, Puoti M, Sulkowski, et al. Symptomatic hyperlactatemia during a large hepatitis C treatment trial in HIV/HCV co-infected participants on stable antiretroviral therapy. Abstract MoOrB1059, XIV Int AIDS Conference 2002, Barcelona. Darunavir (DRV, TMC 114, PrezistaTM) Dose (approved in US): TMC 114/r: 600/100 mg BID taken with a meal [5]. Metabolism: TMC 114 is metabolized by the isoenzyme CYP3A4 [5]. By means of boostering with RTV, TMC 114 becomes to be an inhibitor of CYP3A4. Substance Interactions Comments NRTIs ddI [5] ddI 2h before or after TDF [1] TDF 300 QD + DRV/r 300/100 BID: TDF ? 22 % No dose adjustment. NNRTIs EFV [5] EFV 600 QD + DRV 300/100 BID: DRV ? 13 % (Cmin 31 % ?) EFV ? 21 % (Cmin 17 % ? ) Clinical relevance unclear. Combine with caution. NVP [5] NVP 200 BID + DRV 300/100 BID: NVP ? Combination possible. PIs ATV [2] ATV 300 QD + DRV/r 400/100 BID: ATV ? (Cmin 87 %?) RTV ? 50-59 % Increased incidence of hyperbilirubinemia, ocular icterus. IDV [5] IDV 800 BID + DRV/r 400/100 BID: IDV ?, DRV ? Combination possible, if clinically necessary. LPV/r [5] LPV/r 400/100 + DRV/r 300/100 BID: DRV ? 53 %, LPV/r ? Avoid combination. No appropriate dosages known as yet. SQV [5] SQV 1000 BID + DRV/r 400/100 BID: DRV ? 26 % Avoid combination. Antiarrhythmics Amiodarone, lidocai-ne, chinidine [5] Theoretically: antiarrhythmics ?, potential for severe arrhythmia Close monitoring. Antibiotics Clarithromycin [5] Clarithromycin 500 BID + DRV/r 400/100 BID: clarithromycin ? Only dose adjustment in renal failure. Antidepressants Trazodone sertraline, paroxetine [5] Trazodone side effects ?: syncope, sickness, hypotension sertraline 50 QD + DRV/r 400/100 BID: sertraline ?, paroxetine 20 QD + DRV/r 400/100 BID: paroxetine ? Caution. Possibly dose reduction. Start with low dose. Look out for antidepressive effects. Antihistamines Astemizole, terfenadine [5] Astemizole, terfenadine ? Avoid combination: astemizole, terfenadine. Antihypertensives Calcium channel blockers [5] Calcium channel blockers ? If necessary, dose reduction of calcium channel blockers. Antifungal drugs Ketoconazole, itraconazole, voriconazole [5] Ketoconazole 200 BID + DRV/r 400/100 BID: DRV ?, ketoconazole ?, itraconazole ?, voriconazole + RTV 100 BID: voriconazole ? 39 % Dose of ketoconazole, itraconazole: < 200 mg. Avoid combination. No data, apart from RTV. Antituberculosis drugs Rifampicin Rifabutin [5] DRV ? DRV ? Avoid combination. DRV + rifabutin 150 mg every other day. Corticoids Dexamethasone, fluticasone [5] Theoretically: dexamethasone + DRV: DRV ?, fluticasone + DRV: fluticasone ? Look for alternative by longtime use. Ergotamines [5] Theoretically: ergotamines ?. Possibly life-threatening ergotism Avoid combination. Gastritis-/ Ulcer healing drugs Ranitidine [3] Omeprazole [3] Cisapride [5] DRV/r 400/100 BID alone + rantidine 150 BID or omeprazole 20 QD: no level fluctuations No interaction. Avoid combination. Hypnotics Mida-, triazolam [5] Prolonged sedation. Avoid combination. Immunosuppressants Ciclosporine, sirolimus tacrolimus [5] Immunosuppressants ? TDM of immunosuppressants. Lipid-lowering drugs Atorvastatin [4] Atorvastatin 10 + DRV/r 300/100 BID versus atorvastatin 40 alone: atorvastatin 10 ? 15 % Start with a low initial dose of 10 mg atorvastatin. Avoid combination: lovastatin, simvastatin. Neuroleptics Pimozide [5] Potential for severe, life-threatening cardiac arrhythmia. Avoid combination. Oral contraceptives [5] Ethinyl estradiol ? Norethindrone ? Use additional contraceptive method. PDE5 inhibitors Sildenafil, tadalafil, vardenafil [5] PDE5 inhibitors ?, sildenafil 100 QD+ DRV/r 400/100 BID: sildenafil ? Sildenafil 25 mg in 48h. Tadalafil 10 mg in 72h. Vardenafil 2.5 mg in 72h. Substitution Methadone [5] Methadone ? Monitor f. withdr. symptoms. Others [5] St. John's Wort Warfarin DRV ? Warfarin ? Avoid combination. Check for INR levels. References 1. Hoetelmans R, Marien K, De Pauw M et al. Pharmacokinetic Interaction between TMC114/RTV and Tenofovir in healthy volunteers. XVth World AIDS Conference 2004, Bangkok. 2. Sekar V, De Marez T, Spinosa-Guzman S et al. Pharmacokinetic Interaction between TMC114/RTV and Atazanavir in healthy volunteers. Abstract PE4/3.4, 10th European AIDS Conference 2005, Dublin. 3. Sekar VJ , Hoetelmans R , De Marez T et al. Pharmakokinetics of TMC114: Effect of Omeprazole and Ranitidin. Poster 2.10, 6th Inter Worksh on Clin Pharmacol of HIV-Ther 2005, Quebec 4. Hoetelmans R, Lasure A, Koester A et al. The effect of TMC114, a potent next generation HIV Protease Inhibitor with low-dose Ritonavir on Atorvastatin Pharmakokinetics. Abstract H-885, 44th ICAAC 2004, Washington 5. US product information on Prezista®. ddI (Didanosine, Videx) Approved dose: < 60 kg: 250 mg QD, > 60 kg: 400 mg QD. Metabolism: Hypoxanthine-oxidase; elimination: 30-50 % renal Drugs Interactions Comments NRTIs d4T [1-3] Risk of lactic acidosis, pancreatitis, neuropathy ? Not recommended for first line therapy. TDF [3-5] ddI EC 250 QD + 300 TDF QD has equivalent ddI AUC compared to ddI 400 mg alone. Dose recommendation: Patients > 60 kg: ddI 250 mg Patients < 60 kg: ddI 200 mg Despite dose reduction increased risk of lactic acidosis/pancreatitis Probably unfavourable combination. Virological failure in patients with high viral load and low CD4 cells [4]. Closely monitor for amylase, lipase, lactate. Take ddI and TDF together with food. PIs ATV [1,3] ddI tablets: ATV ? 87 %, ddI-EC: no data Take ddI 2 h apart from ATV. Co-medication Allopurinol [6] ddI ? 122 % (Cmax ? 116 %) Avoid combination. Cimetidine [1] Theoretically: ddI ? Monitor for side-effects. Dapsone [7] Increased risk of neuropathy ? Avoid combination. Ganciclovir (GCV), Valganciclovir (VGCV) [8-10] Risk of lactic acidosis and pancreatitis ? GCV i.v.: ddI ? 70 % Closely monitor for amylase, lipase, lactate. Isoniazid Risk of neuropathy ? Avoid combination. Methadone [11] ddI 41 % ? Not clinically significant. Pentamidine [12] Additive pancreas toxicity when given i.v. Avoid combination. Ribavirin [13] ddI + metabolite ?, risk of lactic acidosis, pancreatitis, neuropathy ? Avoid combination. Never combine ddI and RBV! Vinca Alcaloids [1] Risk of neuropathy ? Vinblastine: less neurotoxic than vincristine. References 1. Tseng A. www.tthhivclinic.com, General Hospital, Toronto, 2004. 2. US Department of Health and Human Services (DHHS) and National Institutes of Health (NIH). The living document: Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. Retrieved April 14, 2004. 3. Clinical Pharmacology, Gold Standard Multimedia, 2004. http://www.gsm.com 4. Moyle G, Maitland D, Hand J, et al. Early virological failure in persons with viral loads > 100.000 cps/ml and CD4 counts < 200/mm3 receiving DDI/tenofovir/ efavirenz as initial therapy: Results from a randomised comparative trial. Abstract H-566, 44th ICCAC 2004, Washington. 5. Kearney BP, Isaacson E, Sayre J, et al. Didanosine and tenofovir DF drug-drug interaction: assessment of didanosine dose reduction. Abstract 533, 10th CROI 2003, Boston. 6. Liang D, Breaux K, Rodriguez-Barradas M, et al. Allopurinol increases didanosine adsorption in HIV-infected patients. Abstract A498, 41st ICAAC 2001, Chicago. 7. Sahai J, Garber G, Gallicano K, et al. Effects of the antacids in didanosine tablets on dapsone pharmacokinetics. Ann Intern Med 1995; 123: 584-7. http://www.amedeo.com/lit.php?id=7677298 8. Cimoch PJ, Lavelle J, Pollard R, et al. Pharmacokinetics of oral ganciclovir alone and in combination with zidovudine, didanosine and probenecid in HIV-infected subjects. JAIDS 1998; 17: 227-34. http://www.amedeo.com/lit.php?id=9495222 9. Jung D, Griffy K, Dorr A, et al. Effect of high dose oral ganciclovir on didansosine disposition in HIV-positive patients. J Clin Pharmacol 1998; 38: 1057-62. http://www.amedeo.com/lit.php?id=9824788 10. Frascino RJ, Gaines Griffy K, Jung D, et al. Multiple dose crossover study of IV ganciclovir induction dose (5 mg/kg IV q12h) and didanosine (200 mg po q12h) in HIV-infected persons. Abstract A-27, 3th CROI 1995, San Francisco. 11. Rainey PM, Friedland G, McCance-Katz EF, et al. Interaction of Methadone with didanosine and stavudine. JAIDS 2000; 24: 241-8. http://www.amedeo.com/lit.php?id=10969348 12. Foisy MM, Slayter KL, Hewitt RG, et al. Pancreatitis during intravenous pentamidine therapy in an AIDS patient with prior exposure to didanosine. Ann Pharmacother 1994; 28: 1025-8. http://www.amedeo.com/lit.php?id=7803875 13. Product nformation: Videx, Bristol Myers-Squibb. 14. Roszko PJ, Curry K, Brazina B, et al. Standard doses of efavirenz, zidovudine, tenofovir, and didanosine may be given with tipranavir/ritonavir. Abstract 865, 2nd IAS 2003, Paris. http://www.aegis.com/conferences/2ndIASHIVPT /865.html Efavirenz (EFV, Sustiva, Stocrin) Approved dose: 600 mg QD. Metabolism: efavirenz is mainly metabolized by CYP2B6 and minor by CYP3A4 and CYP1A2. In vitro EFV is an inducer of CYP3A4 and a poor inhibitor of CYP3A4, -2C9 and -2C19 [1]. Note: wrong positive Cannabinoid urine result with CEDIA DAU multilevel THC assay [2] possible. Drugs Interactions (IAs) Comments NRTIs No clinically significant IAs [1] NNRTIs Nevirapine NVP [3,34] NVP 400 QD + EFV [3]: EFV ? 22 % (Cmin 36 % ?) Unfavourable combination. Less efficacy, increased toxicity [33]. PIs FPV/r [4] FPV/r 700/100 BID + EFV: no clinically significant IA Off label use: when use FPV/r QD, increase RTV to 300 mg. ATV [7,8] ATV 400 QD + EFV: ATV ? up to 74 % ATV/r: 300/100 QD. IDV/r [9,10] IDV/r 800/100 BID + EFV: IDV ? 19 % (Cmin 48 % ?) [9] IDV/r 800/100, probably higher doses for pre-treated patients are necessary [10]. LPV/r [1,5, 11]] Capsules: LPV/r 400/100 + EFV: LPV ? 25 % (Cmin 44 % ?) Tablets: LPV/r 600/150 BID + EFV: LPV ? 35 %, RTV ? 56-92 % Capsules: LPV/r: 533/133 BID. TDM Tablets: LPV/r 400/100 BID: may be used in ART-naive patients. LPV/r 600/150 BID: recommended for pretreated pts [1]. SQV/r [12-15] SQV 1200 TID + EFV: SQV ? 62 % [12,13] SQV/r 400/400 BID or SQV/r 1200/100 QD [14,15]. No data with new SQV tablets (TDM) NFV [6,16] NFV 1250 BID + EFV: NFV ? 38 % (Cmin 65 % ?) [16] TDM. TPV/r [34] EFV ? 1-31 % TPV ? (Cmax ?, Cmin ?) Limited data. No dose adjustment necessary as yet. TMC/r [32] TMC/r 300/100 BID + EFV: TMC ? 13 % (Cmin 31 %) EFV ? 21 % (Cmin 17 %) Limited data. Use combination with caution. TMC/r 300/100 BID + EFV: TMC ? 13 % (Cmin 31 %) EFV ? 21 % (Cmin 17 %) Antiarrhythmics Amiodarone,quinidineflecainide, lidocaine Theoretically: antiarrhythmic ? ? Avoid combination. Antibiotics Clarithromycin [2,17,18] CLM 500 BID + EFV 400 QD: CLM metabolite ? 34 % (Cmax 49 % ?), 46 % exanthema [2,18] Theoretical alternative: azithromycin [17]. Erythromycin [17] Theoretically: EFV ? Monitor for EFV side-effects. Th. alternative: azithromycin. Antiepileptics Carbamazepine, phenytoin primidone [2] Theoretically: EFV ? Avoid combination or TDM. Theoretical alternative: gabapentin, valproic acid, lamotrigine. Antifungal drugs Itraconazole, ketoconazole, voriconazole [2,21] Theoretically: EFV ?, azole ? Voriconazole + EFV: voriconazole 77 % ? (Cmax 61 % ?) EFV ? 44 % (Cmax 38 % ?) Avoid combination: voriconazole. Itra-/ketoconazole: no data. Theoretical alternative: fluconazole [1]. Antihistamines Astemizole, loratadine (> 20 mg), terfenadine [1,2,19,21] Theoretically: antihistamines ?? Risk of QT-prolongation [1,21] Avoid combination: Terfenadine. Th. alternative: ceti-rizine, fexofenadine [2,19]. Antihypertensives Calcium channel bl. felodipine, nifedipine, verapamil [23] Theoretically: calcium channel blockers ? ? Perhaps reduce dose of calcium channel blockers. Bosentan [18,31] Theoretically: EFV ? [18] Avoid combination or TDM. Off label use sildenafil [31]. Antipsychotics Several drugs [2,18,28] 1. Theoretically: antipsychotics ?? 2. Clozapine (active metabolite ?) 3. QT-prolongation of pimozide Avoid combination with pimozide. Prefer atypical neu-roleptics (less anticholinergic) Antituberculosis drugs Rifabutin [2,16,29] Rifabutin ? 38 % (Cmax 32 % ?) Rifabutin 450 mg QD or 600 mg two or three times/week Rifampicin [2,29, 36,37] EFV ? 26 % (Cmax 20 % ?) EFV 800 QD; EFV 600 for pts < 50 kg only with TDM. Cytotoxic drugs Cyclophosphamide [18,30] Theoretically: neurotoxic metabolite ? Avoid additional neurotoxic drugs. Hypnotics Barbexaclone, phenobarbital Theoretically: EFV ? Avoid combination or TDM. Benzodiazepines, zol-pidem [2,22] Theoretically: benzodiazepines ? Avoid combination: mida-, triazolam [2]. Th. alternative: lora/oxa/tema-zepam [22]. Immunosuppressants Cylosporine, sirolimus, tacrolimus Dose reduction of cylosporine when combined with EFV [35]. Dose adjustment of immunosuppressants via TDM. Herbals St. John's Wort [2] Theoretically: EFV ? Avoid combination. Lipid-lowering drugs Ator-, lo-, sim-vastatin [24-26] Atorvastatin 48 % ? and simvastatin 58 % ? Th. alternative: Pravastatin, fluvastatin, rosuvastatin. Oral contraceptives [2] Oestrogen ?, ethinylestradiol ? 37 % Use additional contraception method. Not enough data. PDE5 inhibitors (PPHs) Sildenafil, tadalafil, vardenafil Theoretically: PPHs ? ? Caution: low initial dose. Recreational drugs Cocaine [27] Theoretically: norcocaine ? Caution: liver toxicity. Substitution Methadone [27] Methadone: 60 % ? If necessary, increase methadone dose up to 100 %. Dose reduction of methadone when stopping EFV therapy. References 1. Tseng A. www.tthhivclinic.com, General Hospital, Toronto, 2004. 2. Sustiva, Bristol-Myers Squibb. 3. Veldkamp AI, Harris M, Montaner JSG, et al. The steady-state pharmacokinetics of efavirenz und nevirapine when used in HIV-1 infected patients. J Infect Dis 2001; 184: 37-42. http://www.amedeo.com/lit.php?id=11398107 4. Wire MB, Ballow C, Preston SL, et al. Pharmacokinetics and safety of GW433908 and ritonavir, with and without efavirenz, in healthy volunteers. AIDS 2004, 18: 897-907. http://www.amedeo.com/lit.php?id=15060437 5. Klein C, ZHU T, Chiu YL et al. Effect of efavirenz on lopinavir/ritonavir pharmacokinetics from a new tablet formulation. Abstract 4.3/2, 10th EACS 2005, Dublin. 6. Alvarez-Amao D, Pace W, Gold M. Switch from high to low dose amprenavir in combination with efavirenz and ritonavir. Abstract 2.7, 3rd Int Worksh Clin Pharmacol HIV Ther 2002, Washington. 7. Preston S, Piliero P, OŽMara E, et al. Evaluation of steady-state interaction between atazanavir and efavirenz. Abstract 433, 9th CROI 2002, Seattle. 8. Reyataz, Bristol-Myers Squibb. 9. Aarnoutse RE, Grintjes KJT, Telgt DS, et al. The influence of efavirenz on the pharmacokinetics of a twice daily combination of indinavir and low-dose ritonavir in healthy subjects. JAIDS 2003; 34: 134-9. http://www.amedeo.com/lit.php?id=11823758 10. Boyd MA, Aarnoutse RE, Ruxrungtham K, et al. Pharmacokinetics of indinavir/ritonavir (800/100 mg) in combination with efavirenz (600 mg) in HIV-infected subjects. JAIDS 2003; 34: 134-9. http://www.amedeo.com/lit.php?id=14526202 11. Bertz R, Lam W, Hsu A, et al. Assessment of the pharmacokinetic interaction between ABT - 378/r and efavirenz in healthy volunteers and in HIV+subjects. Abstract 424, 40th ICAAC 2000, Toronto. 12. Jorga K, Buss NE. Pharmacokinetic drug interaction with saquinavir sgc. Abstract 339, 39th ICAAC 1999, San Francisco. 13. Hendrix CW, Fiske WD, Fuchs EJ, et al. Pharmacokinetics of the triple combination of saquinavir, ritonavir and efavirenz in HIV+subjects. Abstact 424, 11th CROI 2000, San Francisco. 14. van Heeswijk RP, Cooper C, Gallicano A, et al. The pharmacokinetics of SQV/RTV 400/400 mg BID before, and after short- and long term co-administration of efavirenz 600 mg QD. Abstract 7.4, 3rd Int Worksh Clin Pharmacol HIV-Ther 2002, Washington. 15. Lopez-Cortes LF, Viciana P, Ruiz-Valderas R, et al. Pharmacokinetics, efficacy and safety of once-daily saquinavir-sgc plus low-dose ritonavir (1200/100 mg) in combination with efavirenz in HIV-pretreated patients. Abstract 441, 9th CROI 2002, Seattle. 16. Fiske WD, Benedek IH, White SJ, et al. Pharmacokinetic interaction between efavirenz and nelfinavir mesylate in healthy volunteers. Abstract 349, 5th CROI 1998, Chicago. 17. Benedek ICH, Joshi A, Fiske WD, et al. Pharmacokinetic studies in healthy volunteers with efavirenz and the macrolide antibiotics, azithromycin and clarithromycin. Abstract 347, 5th CROI 1998, Chicago. 18. Clinical Pharmacology, Gold Standard Multimedia, 2004. http://www.gsm.com 19. Pratt CM, Mason J, Russell T. Cardiovascular safety of fexofenadine HCL. Am J Cardiol 1999; 84: 278-9. http://www.amedeo.com/lit.php?id=10335761 20. Abernethy DR, Barbey JT. Loratadine and terfenadine interaction with nefazodone: Both antihistamines are associated with QT-prolongation. Clin Pharmacol Ther 2001; 69: 96-103. http://www.amedeo.com/lit.php?id=11240972 21. Vfend, Pfizer. 22. Michalets E: Update: Clinically Significant Cytochrome P-450 Drug Interaction. Ann Pharmacother 1998; 18: 84-112. http://www.amedeo.com/lit.php?id=9469685 23. Rossi DR, Rathbun C, Slater LD. Symptomatic ortostasis with extended-release nifedipine and protease inhibitors. Ann Pharmacother 2002; 22:1312-16. http://www.amedeo.com/lit.php?id=12389881 24. Gerber JG, Fichtenbaum CJ, Rosenkranz S, et al. Efavirenz is a significant inducer of simvastatin and atorvastatin metabolism: results of ACTG A5108 study. Abstract 603, 11th CROI 2004, San Francisco. 25. Fichtenbaum CJ, Gerber JG, Rosenkranz S. Pharmacokinetic interaction between protease inhibitors and statins in HIV seronegative volunteers: ACTG Study A5047. AIDS 2002; 16: 569-77. http://www.amedeo.com/lit.php?id=11873000 26. Doser N, Kubli S, Telenti A. Efficacy and safety of fluvastatin in hyperlipidemic protease inhibitor-treated HIV-infected patients. AIDS 2002; 16: 1982-3. http://www.amedeo.com/lit.php?id=12351967 27. Antoniou T, Lin-in Tseng. Interactions between recreational drugs and antiretroviral agents. Ann Pharmacother 2002; 36: 1598-613. http://www.amedeo.com/lit.php?id=12243611 28. Tseng AL, Foisy MM. Significant interactions with new antiretrovirals and psychotropic drugs. Ann Pharmacother 1999; 33: 461-73. http://www.amedeo.com/lit.php?id=10332538 29. Centers for Disease Control and Prevention (CDC). Notice to Readers: Updated guidelines for the use of rifamycins for the treatment of tuberculosis among HIV-infected patients taking protease inhibitors or nonnucleoside reverse transcriptase inhibitors. MMWR; 2004; 53: 37. http://www.cdc.gov/mmwr/preview/mmwrhtml/mm4909a4.htm 30. Lam M, Ignoffo R, Meibohm B. Ein Leitfaden für klinisch-relevante Arzneimittel-Interaktionen in der Onkologie, Institute for Applied Healthcare Science. 31. Ghofrani HA, Olschewski H, Seeger W, et al. Sildenafil for treatment of severe pulmonary hypertension and commencing right-heart failure. Pneumologie 2002; 56: 665-72. http://www.amedeo.com/lit.php?id=12442206 32. Sekar V, DePauw M, Marien K et al. No clinically significant pharmacokinetic drug-drug interaction is observed between the HIV protease inhibitor TMC 114 and the NNRTI Efavirenz. Abstract 55. 7th Int Worksh Clin Pharmacol HIV Ther 2005, Lissabon. 33. van Leth F, Phanuphak P, Ruxrungtham K, et al. Comparison of first-line antiretroviral therapy with regimens including nevirapine, efavirenz, or both drugs, plus stavudine and lamivudine: a randomised open-label trial, the 2NN Study. Lancet 2004, 363:1253-63. http://www.amedeo.com/lit.php?id=15094269 34. Roszko PJ, Curry K, Brazina B, et al. Standard doses of efavirenz, zidovudine, tenofovir, and didanosine may be given with tipranavir/ritonavir. Abstract 865, 2nd IAS 2003, Paris. 35. Tseng A, Nguyen ME, Cardella C, et al. Probable interaction between efavirenz and Cylosporine. AIDS 2002,16:505-6. 36. Sheehan NL, Richter C, Koopmans P et al. Efavirenz is not associated with subtherapeutic EFV concentrations whem given concomitantly with rifampin. Abstract 28. 6th Int Worksh Clin Pharmacol HIV Ther 2005, Quebec. 37. Almond L, Gibbons S, Davies G et al. A retrospective survey of the Liverpool TDM service: Factors influencing Efavirenz concentrations in patients taking Rifampicin. Abstract 19. 6th Int Worksh Clin Pharmacol HIV Ther 2005, Quebec. Emtricitabine (FTC, Emtriva; also in Truvada) Approved dose: 200 mg QD. Elimination: renal Drugs Interactions Comments NRTIs 3TC Antagonism Avoid combination. NNRTIs No significant interaction PIs No significant interaction Fosamprenavir (FPV, Lexiva, Telzir) Approved dose: FPV/r: 700/100 mg BID. Metabolism: FPV is a prodrug of amprenavir (APV) and is hydrolysed in the gut epithelium by cellular phosphatases during absorption to the active compound. APV is metabolized by CYP3A4 and is an inhibitor of CYP3A4 (as potent as indinavir and nelfinavir). Additionally, there are reports suggesting that APV is also an inducer of CYP3A4 [35]. Except the drug interaction between APV and LPV/r, the inducing effect may not be seen with the dose commonly used for boosting. Drugs Interactions (IAs) Comments NRTIs [3,30,31] No significant IAs NNRTIs EFV [4-6] EFV 600 QD + FPV/r: no clinically significant IAs Off label use FPV/r QD: increase RTV to 300/d [6]. NVP [7,8] NVP 200 BID + FPV/r: no clinically significant IAs In this study, no dose adjustment was necessary. PIs ATV [17,18] ATV 300 QD + FPV/r: 1. ATV ? 22 % (Cmin 24 % ?) [17] 2. Adequate levels of both dr. [18] Controversial data => TDM. IDV [19] APV 800 + IDV 800 TID: APV ? 33 %, IDV ? 38 % (Cmin 27 % ?) In this study, no dose adjustment was necessary. LPV/r [9-16] FPV/r 700/100 + LPV/r 400/100 BID: APV ? 63 % (Cmin 65 % ?) LPV ? 37 % (Cmax 30 % ?) [10] FPV 700 + LPV/r 400/100 BID: APV ? 64 % (Cmin 69 % ? ) LPV ? 48 % (Cmin 61 % ? ) [9] FPV 700 + LPV/r 533/133 BID: APV ? 26 % (Cmin 42 % ?) LPV: adequate concentrations [10] Avoid combination or TDM. [5]. Dose separation corrected LPV-levels, but not APV plasma concentrations [11] NFV [2,19] APV 800 + NFV 750 TID [19]: APV: Cmin 3-fold ?, NFV ? 15 % In this study, no dose adjustment was necessary [2]. SQV/r [20,21] FPV 700 + SQV/r 1000/100 BID: FPV not affected, SQV ? 14 % (Ctrough SQV 24 % ?) FPV 700 + SQV/r 1000/200 BID: FPV not affected, SQV ? 12 % FPV + SQV + RTV 100: unsafe => TDM of SQV. FPV + SQV + RTV 200: safe. TPV/r [34] TPV/r 500/200 + APV 600 BID: APV ? 44 % ( Cmin ? 56 %) Avoid combination. Antiarrhythmics Amiodarone, flecaini-de, lidocaine [3] Theoretically: antiarrhythmics ? Avoid combination. Antibiotics Clari-, erythromycin [2,3] Theoretically: APV ?, erythromycin, clarithromycin ? Dose reduction of clarithromycin in pts with renal failure Anticoagulants Warfarin [3] Theoretically: warfarin ?? Check INR. Antidepressants Tricyclic antidepressants [2,3] Paroxetin [33] Theoretically: APV and tricyclic antidepressants ? FPV 700/100 BID + Paroxetin 20 QD: paroxetin ¯ 60 % ¯ Monitor for side-effects of both drugs. Dose adjustment if necessary. St. John's Wort [2,3] Theoretically: APV ? Avoid combination. Antiepileptics Carbamazepine, Phen-toin [2,3,27] Theoretically: APV ?, antiepileptics ? Th. alternatives: gabapentin, lamotrigine, valproic acid. Antifungal drugs Itra-, Keto-conazole, voriconazole [1,2] Theoretically: APV ?, azole ? [2]. Caution: toxicity of both drugs [1] Theoretical alternative: fluconazole [1]. Antihistamines Astemizole, loratadine (> 20 mg), terfenadine [3,28,29] Theoretically: antihistamines ? and risk of QT-prolongation ? Avoid combination: terfenadine [2,3], loratadine > 20 mg. Th. alternatives: cetirizine, fexofenadine [28,29]. Antihypertensives Calcium channel blo-ckers felodipine, nife-dipine, verapamil [2] Theoretically: calcium channel blockers ? Avoid combination or reduce dose of calcium channel blockers if necessary. Bosentan [26] Theoretically: APV ? Avoid combination or TDM. Antipsychotics several drugs [2] Theoretically: antipsychotic drugs ? Avoid combination: pimozide, clozapine. Prefer: atypical neuroleptics (less anticholinergic effects). Antituberculosis drugs Rifampicin [2,25] APV + rifampicin 600 QD APV ? 82 % (Cmin 92 % ?) Avoid combination. Rifabutin [6,25] Rifabutin ? 200 % Rifabutin: 150 mg 3x/week. Monitor for side-effects. Gastritis-/ Ulcer healing drugs PPIs [32] Antacids [22] Esomeprazole + FPV/+r: adequate steady-steady APV-levels FPV/r: adequate absorption H2-blockers Cimetidine [3,22] theoretically: cimetidine ? weak interaction with ranitidine APV ? 18-30 % (Cmin unchanged, Cmax 35-51 % ?) Higher potential for drug-interaction with cimetidine. Prefer: ranitidine. Hypnotics Barbexaclone, phenobarbital Theoretically: APV ? Avoid combination or TDM. Benzodiazepines, zolpidem [1-3] Theoretically: benzodiazepines ? prolonged sedation Caution with all benzodiaze-pines. Lora-, oxa-, temazepam possible. Immunosuppressants Cylosporine, sirolimus, tacrolimus Theoretically: immunosuppressants ? Dose adjustment of immunosuppressants via TDM. Lipid-lowering drugs Atorvastatin, lovastatin, simvastatin [1,2,23] FPV/r 700/100 BID or FPV/r 1400/200 QD + 10 mg Atorvastatin QD [23] FPV/r ? 230 % (Cmax: 404 % ?) FPV ? 253 % (Cmax: 284 % ?) Avoid combination: simvastatin, lovastatin [1,2], atorvastatin > 20 mg. Th. alternatives: pravastatin, fluvastatin. Oral contraceptives [2] APV ? 22 % (Cmin 20 % ?) Ethinylestradiol (Cmin 32 % ?) Norethindrone ?18 % (Cmin 45 %?) Avoid combination or TDM of APV and use additional contraceptive methods. PDE5 inhibitors (PPHs) Sildenafil, tadalafil, vardenafil [6,26] Theoretically: PPHs ? [26] Sildenafil + FPV/r: Sildenafil ? 210 % [6] Not recommended: sildenafil, valdenafil, tadalafil: low initial dose. Substitution Methadone [2,24] Active methadone enantiomers: 13 % ? (Cmax 25 % ?) Comparison with historical studies: APV ? 30 % (Cmin 25 % ?) TDM of APV, if necessary, adjust dose of both drugs. Others Dexamethasone Theoretically: APV ? Ergotamines Theoretically: APV ? Avoid combination. Theoretical alternative: triptans. Theophylline Theoretically: theophylline ? TDM of theophylline. References 1. Tseng A. http://www.tthhivclinic.com/, General Hospital, Toronto, 2006. 2. Agenerase, GlaxoSmithKline. 3. Telzir, GlaxoSmithKline. 4. Piscitelli S, Bechtel C, Sadler B, et al. The addition of a second protease inhibitor eliminates amprenavir-efavirenz drug interaction and increases plasma amprenavir concentrations. Abstract 78, 7th CROI 2000, San Francisco. http://www.retroconference.org/2000/abstracts/78.htm 5. Alvarez-Amao D, Pace W, Gold M. Switch from high to low dose amprenavir in combination with efavirenz and ritonavir. Abstract 2.7, 3rd Int Worksh Clin Pharmacol HIV Ther, 2002, Washington. 6. Wire MB, Ballow C, Preston SL, et al. Pharmacokinetics and safety of GW433908 and ritonavir, with and without efavirenz, in healthy volunteers. AIDS 2004, 18: 897-907. http://www.amedeo.com/lit.php?id=15060437 7. Goujard C, Meynard JL, Choudet N, et al. Steady-state pharmacokinetics of amprenavir 600 mg BID and ritonavir 100 mg BID with or without NNRTI in HIV-1 infected patients. Abstract S92, 5th Int Congr Drug Ther HIV Inf 2000, Glasgow. http://www.aegis.com/conferences/hiv5/P268.html 8. DeJesus E, Piliero P, Summers K, et al. Evaluation of the pharmacokinetik drug interaction between fosamprenavir (FPV), FPV plus ritonavir (RTV) and nevirapine (NVP) in HIV-infected patients (APV10014). Abstract A447, 44th ICAAC 2004, Washington. 9. Kashuba ADM, Tierey C, Downey GF, et al. Combining fosamprenavir, 908 with lopinavir/ritonavir in HIV-1 infected adults in substantial reduction in amprenavir and lopinavir concentrations: pharmacokinetic results from Adult ACTG Protocol A5143. Abstract 855, 43rd ICAAC 2003, Chicago. 10. Wire MB, Naderer OJ, Masterman AL, et al. The pharmacokinetic interaction between GW433908 and lopinavir/ritonavir (APV10011 and APV 10012). Abstract 612, 11th CROI 2004, San Francisco. http://www.amedeo.com/lit.php?id=15060437 11. Corbett AH, Davidson L, Park JJ, et al. Dose separation strategies to overcome the pharmacokinetic interaction of a triple protease inhibitor regimen containing fosamprenavir, lopinavir and ritonavir. Abstract 611, 11th CROI 2004, San Francisco. 12. Khanlou H, Graham E, Brill M, et al. Drug interaction between amprenavir and lopinavir/ritonavir in salvage therapy. AIDS 2002; 16: 797-8. http://www.amedeo.com/lit.php?id=11964539 13. Bertz RJ, Foit C, Ashbrenner E, et al. Effect of amprenavir on the steady-state pharmacokinetics of lopinavir/ritonavir in HIV+ and healthy subjects. Abstract A1823, 42nd ICAAC 2002, San Diego. 14. Taburet AM, Raguin G, Le Tiec C, et al. Interaction between Amprenavir and lopinavir -ritonavir combination in heavily pretreated patients infected by HIV. Clin Pharmacol Ther 2004; 75: 310-23. http://www.amedeo.com/lit.php?id=15060509 15. Mauss S, Scholten S, Wolf E, et al. A prospective, controlled study assessing the effect of lopinavir on amprenavir concentrations boosted by ritonavir. HIV Med 2004; 5: 15-7. http://www.amedeo.com/lit.php?id=14731164 16. Wynn Vezina HE, Brundage RC, Bushman L, et al. Pharmacologic management of the drug-drug interaction between lopinavir/ritonavir and amprenavir. Abstract 609, 11th CROI 2004, San Francisco. http://www.retroconference.org/2004/cd/PDFs/609.pdf 17. Wire MB et al. The pharmacokientic interaction between fosamprenavir/ritonavir and atazanavir in healthy adult subjects (APC 10018). Abstract 4.3/9. 10th EACS Conference 2005, Dublin 18. Guttanti M, Raffaella de Pascalis C, Seminari E, et al. Pharmacokinetics of amprenavir given once or twice a day when combined with atazanavir in heavily pre-treated patients. AIDS 2003, 17: 2669-70. http://www.amedeo.com/lit.php?id=14685066 19. Sadler BM, Gillotin C, Lou Y, et al. Pharmacokinetic study of human immunodeficiency virus protease inhibitors used in combination with amprenavir. Antimicrob Agents Chemother 2001, 45: 3663-8. http://www.amedeo.com/lit.php?id=11709366 20. Boffito M, Dickinson L, Hill A, et al. Steady state pharmacokinetics of saquinavir hard gel/fosamprenavir 1000/700 plus 100 und 200 mg of Ritonavir twice daily in HIV+ Patients. Abstract 608, 11th CROI 2004, San Francisco. 21. Wolfe PR, Anderson PG, Gunawan S. Simultaneous administration of amprenavir and saquinavir does not appear to lower plasma levels of either agent when coadministered with low dose ritonavir. Abstract 7.11, 3rd Int Worksh Clin Pharmacol HIV Ther 2002, Washington. 22. Ford SL, Wire MB, Lou Y, et al. The effect of antacids and ranitidine on the pharmacokinetic of GW433908 (APV10007). Abstract A-1606, 43rd ICAAC 2003, Chicago. 23. Wire MB, Baker KL, Moore KHP, et al. The pharmacokinetic interaction of GW 433908 with atorvastatin and 908/ritonavir with atorvastatin (APV 10013). Abstract A1622, 43rd ICAAC 2003, Chicago. 24. Hendrix C, Wakeford J, Wire MB, et al. Pharmacokinetic and pharmacodynamic evaluation of methadone enantiomers following coadministration with amprenavir in opiod-dependent subjects. Abstract 1649, 40th ICAAC 2000, Toronto. 25. Centers for Disease Control and Prevention (CDC). Notice to Readers: Updated guidelines for the use of rifamycins for the treatment of tuberculosis among HIV-infected patients taking protease inhibitors or nonnucleoside reverse transcriptase inhibitors 2004. MMWR; 53: 37. http://www.amedeo.com/lit.php?id=11795500 26. Nandwani R, Gourlay Y. Possible Interaction between sildenafil and HIV combination therapy. Lancet 1999; 353: 840. http://www.amedeo.com/lit.php?id=10459981 27. Hugen PWH, Burger DM, Brinkman K, et al. Carbamazepine-indinavir interaction causes antiretroviral therapy failure. Ann Pharmacother 2000; 34: 465-70. http://www.amedeo.com/lit.php?id=10772431 28. Pratt CM, Mason J, Russell T. Cardiovascular safety of fexofenadine HCL. Am J Cardiol 1999; 84: 278-9. http://www.amedeo.com/lit.php?id=10335761 29. Abernethy DR, Barbey JT. Loratadine and terfenadine interaction with nefazodone: Both antihistamines are as sociated with QT-prolongation. Clin Pharmacol Ther 2001; 69: 96-103. http://www.amedeo.com/lit.php?id=11240972 30. Kurowski M, Walli R, Breske et al. Co-administration of tenofovir 300 mg QD with fosamprenavir/ritonavir 1400/100 mg QD or 1400/200 mg QD does not affect amprenavir pharmacokinetics. Abstract 10, 6th Int Worksh Clin Pharmacol HIV Ther 2005, Quebec. 31. Peytavin G, Rouault A, Agher R, et al. Plasma concentrations of amprenavir, ritonavir and tenofovir in HIV-infected patients treated with fosamprenavir / ritonavir (700 / 100 mg BID) and tenofovir (300 mg QD) containing regimen. Abstract 32, 6th Int. Worksh Clin Pharmacol HIV Ther 2005, Quebec. 32. Shelton MJ, Wire MB, Lou Y, et al. Co-administration of esomeprazole (ESO) with fosamprenavir (FPV) has no impact on steady-state plasma amprenavir (APV) pharmacokinetics (APV10031). Abstract 24, 6th Int Worksh Clin Pharmacol HIV Ther 2005, Quebec. 33. Blenke A, van der Lee M, Verweij-van Wissen C, et al. Combined use of paroxetine and fosamprenavir / ritonavir: a pharmacokinetic interaction study in healthy volunteers. Abstract 13, 6th Int Worksh Clin Pharmacol HIV Ther 2005, Quebec. 34. Leith J, Walmsley S, Katlama C, et al. Pharmacokinetics and safety of tipranavir/ritonavir alone or in combination with saquinavir, amprenavir, or lopinavir: interim analysis of BI1182.51. Abstract 34, 5th Int Worksh Clin Pharmacol HIV-Ther 2004, Rome. Indinavir (IDV, Crixivan) Approved dose: IDV: 800 mg TID, IDV/r: 800/100 mg BID. Metabolism: IDV is primarily metabolized by CYP3A4 and is an inhibitor of CYP3A4. For optimal adsorption an acidic gut ph is necessary. IDV should be taken with a light meal [1]. Drugs Interactions Comments NRTIs ddI [2-4] ddI EC + IDV: no interaction [4] Take ddI 1 h apart [2,3]. NNRTIs EFV [2,5-7] IDV/r 800/100 BID + EFV 600 QD: IDV ? 19 % (Cmin 48 % ?) [6] IDV/r 800/100, probably higher doses for pre-treated patients are necessary [6]. No QD-IDV [7]. NVP [2,5,8-9] IDV/r 800/100 BID + NVP: IDV: Cmin 57 % RTV: Cmin 59 % but IDV > 100 ng/ml [8] 1. IDV: 1000 TID [2] 2. IDV/r: 800/100 BID [8] Consider higher doses in pre-treated patients [8]. NVP QD may decrease IDV/r more than NVP BID [9]. PIs ATV [10] increased bilirubin levels Avoid combination. APV [11] IDV 800 + APV 800 TID APV ? 33 %, IDV ? 38 % (Cmin 27 % ?) In this study, no dose adjustment was necessary. LPV/r [16-21] IDV 800 BID + LPV/r 400/100 BID: PK-value of LPV insignificantly lower [16] TDM of both drugs. NFV [12] IDV 1200 + NFV 1250 BID In this study, no dose adjustment was necessary. Antiarrhythmics Amiodarone, bepridil, quinidine, flecainide, lidocaine, propafenone Theoretically: antiarrhythmics ? Avoid combination. If necessary, reduce dose of antiarrhythmic drugs. Antidepressants St. John's Wort [2] Theoretically: IDV ? Avoid combination. Trazodone [5] Theoretically: trazodone ? Avoid combination or possibly reduce trazodone dose. Antiepileptics Carbamazepine, Phe-nytoin, primidone [2,23] Theoretically: IDV ?, antiepileptics ? Theoretical alternative: gabapentin, lamotrigine, valproic acid. Antifungal drugs Itraconazol, ketoconazole, voriconazole [5,26] Theoretically: IDV and azole ? IDV 400 + Ketoconazole 400: IDV ? 68 % [5] IDV: 600 TID [5]. Theoretical alternative: fluconazole [26]. Antihistamines Astemizole, loratadine (> 20 mg), terfenadine [2,24,25] Theoretically: antihistamines and risk of QT-prolongation ? Avoid combination: terfenadine [2]. Theoretical alternative: cetirizine, fexofenadine [24,25]. Antihypertensives Calcium channel blockers such as felodipine, nifedipine, verapamil Theoretically: calcium channel blockers ? [2] Reduce dose of calcium channel blockers if necessary. Bosentan [5,32] Theoretically: IDV ? [5] Avoid combination or TDM. Off label use: sildenafil [32]. Antipsychotics Several drugs [2] Theoretically: IDV and antipsychotic drugs ? Avoid combination with pimozide. Monitor for side-effects. Prefer: atypical neuroleptics (less anticholinergic). Antituberculosis drugs Rifabutin [2,3,30] Rifabutin ? 173 % IDV ? 33 % [30] IDV: 1000 TID +Rifabutin: 150 mg/d [2]. IDV/r: 800/100 BID + Rifabutin: 150 mg 3x/week. Rifampicin [2] IDV ? 89 % Avoid combination [2]. Gastritis-/ Ulcer healing drugs Antacids [2] IDV requires acidic pH for adequate absorption, possible: IDV ? Antacids 1h apart from IDV. H2-blockers Theoretically: IDV ? TDM of IDV. Proton pump inhibitors (PPIs), e.g. omeprazole [5,22] TDM of IDV. Hypnotics Barbexaclone, phenobarbital Theoretically: IDV ? Avoid combination or TDM. Benzodiazepines, zolpidem [2,5] Prolonged sedation Avoid combination: Alpra-, mida-, triazolam [2]. Caution: clorazepate, diaze-pam, flurazepam [5]. Th. alternative: lorazepam, oxazepam, temazepam [5]. Immunosuppressants Cylosporine, siroli - mus, tacrolimus [27] Theoretically: immunosuppressants ? Dose adjustment of immunosuppressants by TDM. Lipid-lowering drugs Atorvastatin, lovastatin, simvastatin [2,5] Theoretically: Atorvastatin, lovastatin ? Avoid combination: simva-, lova-[2], atorvastatin [5]. Theoretical alternative: pravastatin [5], fluvastatin. Oral contraceptives [5] Estradiol ? 24 % Norethindrone ? 26 % No dose adjustment necessary. PDE5 inhibitors (PPHs) Sildenafil, tadalafil, vardenafil [5,31] Theoretically: PPHs ? IDV 800 TID + Sildenafil 25: Sildenafil ? 304 % [31] IDV + Vardenafil: Vardenafil ? 16-fold IDV ? 30 % (Cmax 40 % ?) [5] Sildenafil: 12.5 mg every 48h [5]. Avoid combination or TDM. Others Dexamethasone [2] Theoretically: IDV ? TDM of IDV. Ergotamine [2] Theoretically: IDV ? Avoid combination. Grapefruit juice [1] AUC of IDV: 26 % ? Avoid combination [1]. Interleukin [5,28] IL-2 + IDV: IDV ? 88 % TDM of IDV. L-Tyroxin [5,29] Thyroxin because IDV inhibits UDP-GT [29] Perhaps l-tyroxin dose could be reduced. Vitamine C [32] IDV 800 TID + 1 g vitamine C: Cmin IDV 32 % ? (not significant) Avoid high doses of vitamine C. References 1. Tseng A. http://www.tthhivclinic.com/, General Hospital, Toronto, 2004. 2. Crixivan, MSD. 3. Shelton MJ, Mei JH, Hewitt RG, et al. If taken 1 hour before indinavir, didanosine does not affect indinavir exposure, despite persistent buffering effects. Antimicrob Agents Chemother 2001; 45: 298-300. http://www.amedeo.com/lit.php?id=11120981 4. Damle BD, Mummaneni V, Kaul S, et al. Lack of effect of simultaneously administered didanosine encapsulated enteric coated formulation (Videx EC) on oral absorption of indinavir, ketoconazol or ciprofloxacin. Antimicrob Agents Chemother 2002; 46: 385-91. http://www.amedeo.com/lit.php?id=11796346 5. Clinical Pharmacology, Gold Standard Multimedia, 2004. http://www.gsm.com 6. Aarnoutse RE, Burger DM, Hugen PWH, et al. A Pharmacokinetic Study to investigate the influence of efavirenz on a BID indinavir 800 mg/ritonavir 100 mg in healthy volunteers. Abstract 423, 40th ICAAC 2000,Toronto. 7. Saah A, Winchell G, Rhodes R, et al. Multiple-dose pharmacokinetics and tolerability of indinavir with ritonavir and efavirenz combinations in a once daily regimen in healthy volunteers (Merck 093). Abstract 284, 5th Int Congr Drug Ther HIV Inf 2000, Glasgow. http://www.aegis.com/conferences/hiv5/P284.html 8. Burger DM, Prins JM, van der Ende ME, et al. The effect of nevirapine on the pharmakokinetics of indinavir/ritonavir 800/100 mg BID. JAIDS 2004; 35: 97-8. http://www.amedeo.com/lit.php?id=14707800 9. Crommentuyn KML, van Heeswijk RPG, Veldkamp AI, et al. Nevirapine once daily versus twice daily: implications for drug-drug interactions. Abstract 1.11, 2nd Int Worksh Clin Pharmacol HIV Ther 2001, Noordwijk. 10. Reyataz, Bristol Myers-Squibb. 11. Sadler BM, Gillotin C, Lou Y, et al. Pharmacokinetic study of human immunodeficiency virus protease inhibitors used in combination with amprenavir. Antimicrob Agents Chemother 2001; 45: 3663-8. http://www.amedeo.com/lit.php?id=11709366 12. Riddler S, Havlir D, Sqires KE, et al. Coadministration of indinavir and nelfinavir in human immunodeficiency virus type 1-infected adults: safety, pharmacokinetics and antiretroviral activity. Antimicrob Agent Chemother 2002; 46: 3877-82. http://www.amedeo.com/lit.php?id=12435691 13. Mc Crea J, Buss N, Stone J, et al. Indinavir-saqinavir single dose pharmacokinetic study. 4th CROI 1997, Washington. 14. Manion D, Merill DP, Hirsch MS. Combination drug regimens against multidrug resistant HIV-1 in vitro. 4th CROI 1997, Washington. 15. Buss N. Saquinavir soft gel capsule (Fortovase): Pharmacokinetics and drug interactions. Abstract 354, 5th CROI 1998, Chicago. 16. Tseng A, Phillips E, Antoniou A, et al. Steady-state pharmacokinetics and tolerability of indinavir when administered with lopinavir/r in antiretroviral-experienced subjects. Abstract 8.10, 4th Int Worksh Clin Pharmacol HIV Ther 2003, Cannes. 17. Bertz R, Foit C, Ashbrenner E, et al. Assessment of the steady-state pharmacokinetic interaction of lopinavir/ritonavir with either indinavir or saquinavir in healthy subjects. Abstract A1822, 42nd ICAAC 2002, San Diego. 18. Burger DM, Schmitz K, Schneider K, et al. Pharmacokinetics of lopinavir and reduced dose indinavir as a part of salvage therapy regimen. 4th Abstract 8.2, 4th Int Worksh Clin Pharmacol HIV Ther 2003, Cannes. 19. Harris M, Alexander C, Ting L, et al. Rescue therapy with indinavir 600 mg twice daily and lopinavir/ritonavir: baseline resistance, virologic response and pharmacokinetics. Abstract P170, 6th Int Congr Drug Ther HIV Inf 2002, Glasgow. 20. Isaac A, Taylor S, Rubin G, et al. Lopinavir /ritonavir combined with twice daily indinavir: pharmacokinetics in blood, CSF and semen (the Protect Study). Abstract 531, 10th CROI 2003, Boston. 21. DHHS: Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. Retrieved April 14, 2004. http://www.amedeo.com/lit.php?id=11364535 22. Burger DM, Hugen PW, Kroon FP, et al. Pharmacokinetic interaction between the proton pump inhibitor omeprazole and the HIV protease inhibitor indinavir. AIDS 1998; 12: 2080-2. http://www.amedeo.com/lit.php?id=9814882 23. Hugen PWH, Burger DM, Brinkmann K, et al. Carbamazepine-indinavir interaction causes antiretroviral failure. Ann Pharmacother 2000; 34: 465-70. http://www.amedeo.com/lit.php?id=10772431 24. Pratt CM, Mason J, Russell T. Cardiovascular safety of fexofenadine HCL. Am J Cardiol 1999; 84: 278-9. http://www.amedeo.com/lit.php?id=10335761 25. Abernethy DR, Barbey JT. Loratadine and terfenadine interaction with nefazodone: Both antihistamines are associated with QT-prolongation. Clin Pharmacol Ther 2001; 69: 96-103. http://www.amedeo.com/lit.php?id=11240972 26. Michalets E: Update: Clinically Significant Cytochrome P-450 Drug Interaction. Ann Pharmacother 1998; 18: 84-112. http://www.amedeo.com/lit.php?id=9469685 27. Brinkmann K, Huysmans F, Burger DM. Pharmacokinetic interaction between Saquinavir and Cyclosporine. Ann Intern Med 1998; 129: 914-5. http://www.amedeo.com/lit.php?id=9867740 28. Piscitelli SC, Vogel S, Figg WD, et al. Alteration in indinavir clearance during interleukin-2 infusions in patients infected with the human immunodeficieny virus. Ann Pharmacother 1998; 18: 1212-6. http://www.amedeo.com/lit.php?id=9855318 29. Lanzafame M, Trevenzoli M, Faggian F, et al. Interaction between levothyroxine and indinavir in a patient with HIV infection. Infection 2002; 30: 54-8. http://www.amedeo.com/lit.php?id=11876520 30. Centers for Disease Control and Prevention (CDC). Notice to Readers: Updated guidelines for the use of rifamycins for the treatment of tuberculosis among HIV-infected patients taking protease inhibitors or nonnucleoside reverse transcriptase inhibitors. MMWR; 2004; 53: 37. http://www.cdc.gov/mmwr/preview/mmwrhtml/mm4909a4.htm 31. Merry C, Barry MG, Ryan M, et al. Interaction of sildefanil and indinavir when coadministered to HIV-positive patients. AIDS 1999; 13: 101-7. http://www.amedeo.com/lit.php?id=10546851 32. Slain D, Amsden JR, Khakoo RA, et al. Effect of high-dose vitamin C on the steady-state pharmacokinetics of the protease inhibitor indinavir in healthy volunteers. Abstract A-1610, 43rd ICAAC 2003, Chicago. Lopinavir/r (LPV/r, Kaletra) Approved dose: LPV/r 400/100 mg BID. Metabolism: LPV is co-formulated with ritonavir and primarily metabolized by CYP3A4. LPV/r is a strong inhibitor of CYP3A4 and induces the glucuronidation pathway as well as CYP2C9 and CYP2C19 [1]. Drugs Interactions Comments NRTIs TDF [41,42] TDF ? 32 % (Cmax 15 % ?), LPV/r: Adequate plasma levels 18 heavily pre-treated patients: Cmin LPV 34 % ?, Cmin RTV 44 % ? [41] no increase in side-effects observed. LPV/r: TDM. NNRTIs EFV [2,3,50] Capsules: EFV 600 QD + LPV/r [3]: LPV ? 25 % (Cmin 44 % ?) Tablets: EFV 600 QD + LPV/r 600/150 BID: LPV ? 35 %, RTV ? 56-92 % [50] Capsules: LPV/r: 533/133 BID [2]. Tablets: LPV/r 400/100 BID: may be used in naive pts => TDM. LPV/r 600/150 BID: recommended in pre-treated pts [1]. NVP [2,4,45] NVP 200 BID + LPV/r: 1. Extensively pre-treated patients [4]: LPV/r ? 27 % (Cmin 51 % ?) 2. 31 patients with VL < 80 c/ml: adequate levels of both drugs [45] Clinical experiences: LPV/r: 533/133 BID [2]. PIs ATV [14,46,51] ATV400 QD + LPV/r 400/100 BID: 1. LPV ? 16 % (Cmin 35 % ?) [14] 2. ATV (Cmin 45 % ?) [51] 3. ATV ? 38 % (Cmin 38 % ?) [46] Controversial data. => TDM 1. HIV-patients. 2. Healthy volunteers. 3. HIV-patients. FPV/r [5-8] APV/r [9-13] 1. FPV/r 700/100 BID + LPV/r: APV ? 63 % (Cmin 65 % ?), LPV ? 37 % (Cmin 52 % ?) [6] 2. FPV/r 700/100 + LPV/r 533/133 BID [7]: APV ? 26 % (Cmin 42 % ?), LPV: adequate plasma levels 3. Dose separation corrects LPV concentration, but not APV plasma concentrations [8] Unfavourable combination, wide variability of concentrations => TDM. Tablets: LPV/r 400/100 BID in naïve, LPV/r 600/150 BID in pre-treated patients [1]. TDM. IDV/r [15-19] IDV 800 BID + LPV/r TDM. NFV [24] NFV 1000 BID + LPV/r: LPV/r ? 27 % (Cmin 33 % ?) TDM. Tablets: LPV/r 400/100 BID in naïve, LPV/r 600/150 BID in pre-treated patients [1]. TDM. SQV/r [20-23] SQV 1000 BID + LPV/r: adequate SQV- and LPV-levels Synergic effect, favourable combination: TDM. TPV/r [49] TPV 500 BID + LPV/r: LPV ? 55 % (Cmin ? 52-70 %) Avoid combination. TMC/r [52] TMC/r 300/100 BID + LPV/r: TMC ? 53 %, LPV/r ? Avoid combination. Antiarrhythmics Amiodarone, bepridil, quinidine, flecainide, lidocaine, propafenone Theoretically: antiarrhythmics ? Avoid combination: amiodarone [2]. Monitor for side-effects, dose reduction. Antibiotics Clarithromycin [25-27] Clarithromycin ? Dose reduction with patients of liver and renal failure [25] Dose reduction in liver and renal failure. Alternative: Azithromycin [26,27]. Anticoagulants Warfarin [25] Warfarin ? Monitor for INR. Antidepressants Nefazodone [28] Theoretically: LPV/r ? Monitor for side-effects. Th. alternative: SSRIs. St. John's Wort [2] Theoretically: LPV/r ? Avoid combination. Antiepileptics Carbamazepine, phenytoin, primidone, [2,25,40] Theoretically: LPV/r ? antiepileptics ? Theoretical alternative: gabapentin. Lamotrigine [47] Lamotrigine 100 QD + LPV/r 400/100 BID: lamotrigine Cmin: 56 % ¯ Dose adjustment of 200 % for lamotrigine, not for LPV/r. Antifungal drugs Itra-, keto-, vori-conazole [1,2,25] LPV/r and azole ? Caution: possible dose-related toxicity of both drugs. Avoid combination: Itra-, ketoconazole. Th. alternative: fluconazole [1]. Antihistamines Astemizole, loratadine (> 20 mg), terfenadine [2,29,30] Theoretically: antihistamines ? and increased risk of QT-prolongation Avoid combination: terfen-adine. Th. alternative: cetirizine, fexofenadine [29,30]. Antihypertensives Calcium channel blo-ckers [2,31] such as Amlodipine, nifedi-pine, verapamil Theoretically: calcium channel blockers ? Theoretically dose reduction of calcium channel blockers. Bosentan [25,39] Theoretically: LPV/r ? Avoid combination or TDM. Antipsychotics Several drugs[25,28] Theoretically: LPV/r and antipsychotic drugs ? Avoid combination with pimozide. Monitor for side-effects. Prefer: atypical neuroleptics (less anticholinergic). Antituberculosis drugs Rifabutin [2,37] Rifabutin: 303 % ?, rifabutin-metabolite ? 47.5-fold, no effect of LPV/r Rifabutin: 150 mg 3x/week. Monitor for side-effects. Rifampicin [2,37] LPV/r + rifampicin 600/QD: LPV/r ? 75 % (Cmin 99 % ?) Avoid combination. Cytotoxic drugs Docetaxel, etoposide, paclitaxel, tamoxifen, vinca alcaloida [38] Theoretically: cytotoxic drugs ? Monitor for side-effects of the cytotoxic drugs. Gastritis-/ Ulcer healing drugs Antacids, H2-blockers, proton pump inhibitors (PPIs) [44] No significant interactions after 48 week therapy Hypnotics Barbexaclone, Phenobarbital Theoretically: LPV ? Avoid combination or TDM. Benzodiazepines, zol-pidem [25] Theoretically: Benzodiazepines ? Prolonged sedation Avoid combination: midazolam, triazolam. Theoretical alternative: lorazepam, oxazepam, temazepam. Immunosuppressants Cylosporine, sirolimus tacrolimus [2,25,43,48] Theoretically: immunosuppressants ? Tacrolimus + LPV/r: (3 patients) Tacrolimus 10-20-fold ? [43] Dose adjustment of immunosuppressants with TDM. Lipid-lowering drugs Ator-, Lo-, Sim-vastatin [32-35] Atorvastatin, pravastatin + LPV/r: Atorvastatin ? 5.9-fold Pravastatin ? 30 % Low initial dose: atorva-statin. Alternatives: pravastatin, fluvastatin. Oral contraceptives [2,25] Ethinylestradiol ? 42 % Norethindrone ? 17 % Use additional contraceptive method. PDE5 inhibitors (PPHs) Sildenafil, tadalafil, vardenafil [2,25] Theoretically: PPHs ? Sildenafil 100 QD + RTV 500 BID: sildenafil ? 1000 % Sildenafil 25 mg every 48h. Substitution Methadone [36] Methadone ? 36 % (Cmax 44 % ?) Monitor for opiate withdrawal; if necessary, increase methadone dose. Others Atovaquone Theoretically: atovaquone ? If necessary, increase dose. Disulfiram [2] Kaletra liquid contains alcohol. Avoid combination. Dexamethasone [2] Theoretically: LPV/r ? Metronidazole [2] Kaletra liquid contains alcohol and can cause sickness when combined with metronidazole Avoid combination. Theophylline [2] Theoretically: theophylline ? TDM of theophylline. References 1. Tseng A. www.tthhivclinic.com, General Hospital, Toronto, 2006 2. Kaletra, Abbott. 3. Bertz R, Lam W, Hsu A, et al. Assessment of the pharmacokinetic interaction between ABT-378/ritonavir and efavirenz in healthy volunteers and in HIV + subjects. Abstract 424, 40th ICAAC 2000, Toronto. 4. Bertz R, Foit C, Burt D, et al. Assessment of the Effect of Nevirapine on the Pharmacokinetics of Lopinavir/Ritonavir after Multiple Dosing in HIV-infected Adults. Abstract TUPEB4565, XIV Int AIDS Conf 2002, Barcelona. 5. Telzir, GlaxoSmithKline. 6. Kashuba ADM, Tierey C, Downey GF, et al. Combining fosamprenavir, 908 with lopinavir/Ritonavir in HIV-1 infected adults in substantial reduction in Amprenavir and lopinavir concentrations: pharmakokinetic results from Adult ACTG Protocol A5143. Abstract H-855a , 43rd ICAAC 2003, Chicacgo. 7. Wire MB, Naderer OJ, Masterman AL, et al. The pharmacokinetic interaction between GW433908 and lopinavir/ritonavir (APV10011 and APV 10012). Abstract 612, 11th CROI 2004, San Francisco. http://www.retroconference.org/2004/cd/PDFs/612.pdf 8. Corbett AH, Davidson L, Park JJ, et al. Dose separation strategies to overcome the pharmacokinetic interaction of a triple protease inhibitor regimen containing fosamprenavir, lopinavir and ritonavir. Abstract 611, 11thŽCROI 2004, San Francisco. 9. Khanlou H, Graham E, Brill M, et al. Drug interaction between amprenavir and lopinavir/ritonavir in salvage therapy. AIDS 2002; 16: 797-8. http://www.amedeo.com/lit.php?id=11964539 10. Bertz RJ, Foit C, Ashbrenner E, et al. Effect of amprenavir on the steady-state pharmacokinetics of lopinavir/ritonavir in HIV+ and healthy subjects. Abstract A1823, 42nd ICAAC 2002, San Diego. 11. Taburet AM, Raguin G, Le Tiec C, et al. Interaction between Amprenavir and lopinavir - ritonavir combination in heavily pretreated patients infected by HIV. Clin Pharmacol Ther 2004; 75: 310-23. http://www.amedeo.com/lit.php?id=15060509 12. Mauss S, Scholten S, Wolf E, et al. A prospective, controlled study assessing the effect of lopinavir on amprenavir concentrations boosted by ritonavir. HIV Med 2004; 5: 15-7. http://www.amedeo.com/lit.php?id=14731164 13. Wynn Vezina HE, Brundage RC, Bushman L, et al. Pharmacologic management of the drug-drug interaction between lopinavir/ritonavir and amprenavir. Abstract 609, 11th CROI 2004, San Francicsco. 14. Colombo S, Buclin T, Franc C. Ritonavir-boosted atazanavir-lopinavir combination: a pharmacokinetic interaction study of total, unbound plasma and cellular exposures. Antivir Ther. 2006;11:53-62. 15. Tseng A, Phillips E, Antoniou A, et al. Steady-state pharmacokinetics and tolerability of indinavir when administered with lopinavir/r in antiretroviral-experienced subjects. Abstract 8.10, 4th Int Worksh Clin Pharmacol HIV Ther 2003, Cannes. 16. Bertz R, Foit C, Ashbrenner E, et al. Assessment of the steady-state pharmacokinetic interaction of lopinavir/ritonavir with either indinavir or saquinavir in healthy subjects. Abstract A1822, 42nd ICAAC 2002, San Diego. 17. Burger DM, Schmitz K, Schneider K, et al. Pharmacokinetics of lopinavir and reduced dose indinavir as a part of salvage therapy regimen. Abstract 8.2, 4th Int Worksh Clin Pharmacol HIV Ther 2003, Cannes. 18. Burger DM, Schmitz K, Schneider K, et al. Rescue therapy with indinavir 600 mg twice daily and lopinavir/ritonavir: baseline resistance, virologic response and pharmacokinetics. Abstract P170, 6th Int Congr Drug Ther HIV Inf 2002, Glasgow. 19. Isaac A, Taylor S, Rubin G, et al. Lopinavir /ritonavir combined with twice daily indinavir: pharmacokinetics in blood, CSF and semen (the Protect Study). Abstract 531, 10th CROI 2003, Boston. 20. La Porte CJ, Wasmuth JC, Schneider K, et al. Lopinavir/ritonavir plus saquinavir in salvage therapy; pharmacokinetics, tolerability and efficacy. AIDS 2003; 17: 1700-2. http://www.amedeo.com/lit.php?id=12853756 21. Ribera E, Diaz M, Pou L, et al. Steady-state pharmacokinetics of double boosting regimen of lopinavir, plus minidose Ritonavir, plus Saquinavir soft-gel in HIV-infected adults. Abstract TUPE4545, XIV Int AIDS Conf 2002, Barcelona. 22. Staszewski S, Dauer B, Von Hentig N, et al. The LopSaq study: 24 week analysis of the double protease inhibitor salvage regimen containing lopinavir plus saquinavir without any additional antiretroviral therapy. Abstract 583, 2nd IAS Conference on HIV Pathogenesis and Treatment 2003, Paris. 23. Stefan C, Von Hentig N, Kourbeti I, et al. Saquinavir drug exposure is not impaired by the boosted double protease inhibitor combination of lopinavir/Saquinavir. AIDS 2004; 18: 503-8. http://www.amedeo.com/lit.php?id=15090803 24. Klein C, Bertz R, Ashbrenner E, et al. Assessment of the multiple dose pharmacokinetic interaction of lopinavit/ritonavir with nelfinavir. Abstract 536, 10th CROI 2003, Boston. 25. Clinical Pharmacology, Gold Standard Multimedia, 2004. http://www.gsm.com 26. Michalets E. Update: Clinically Significant Cytochrome P-450 Drug Interaction. Ann Pharmacother 1998; 18: 84-112. http://www.amedeo.com/lit.php?id=9469685 27. Benedek ICH, Joshi A, Fiske WD, et al. Pharmacokinetic studies in healthy volunteers with efavirenz and the macrolide antibiotics, azithromycin and chlarithromycin. Abstract 347, 5th CROI 1998, Chicago. 28. Tseng AL, Foisy MM. Significant Interactions with New Antiretrovirals and Psychotropic Drugs. Ann Pharmacother 1999; 33: 461-73. http://www.amedeo.com/lit.php?id=10332538 29. Pratt CM, Mason J, Russell T. Cardiovascular safety of fexofenadine HCL. Am J Cardiol 1999; 84: 278-9. http://www.amedeo.com/lit.php?id=10335761 30. Abernethy DR, Barbey JT. Loratadine and terfenadine interaction with nefazodone: Both antihistamines are associated with QT-prolongation. Clin Pharmacol Ther 2001; 69: 96-103. http://www.amedeo.com/lit.php?id=11240972 31. Rossi DR, Rathbun C, Slater LD. Symptomatic ortostasis with extended-release nifedipine and protease inhibitors. Ann Pharmacother 2002; 22: 1312-6. http://www.amedeo.com/lit.php?id=12389881 32. Fichtenbaum CJ, Gerber JG, Rosenkranz S. Pharmacokinetic interaction between protease inhibitors and statins in HIV seronegative volunteers: ACTG Study A5047. AIDS 2002; 16: 569-77. http://www.amedeo.com/lit.php?id=11873000 33. Carr RA, Andre AK, Bertz RJ, et al. Concomitant administration of ABT-378/ritonavir results in a clinically important pharmacokinetic interaction with atorvastatin but not pravastatin. Abstract 1644, 40th ICAAC 2000, Toronto. 34. Doser N, Kubli S, Telenti A et al. Efficacy and safety of fluvastatin in hyperlipidemic protease inhibitor-treated HIV-infected patients. AIDS 2002; 16: 1982-3. http://www.amedeo.com/lit.php?id=12351967 35. Dube MP, Sprecher D, Henry WK, et al. Preliminary guidelines for the evaluation and management of dyslipidemia in HIV-infected adults receiving antiretroviral therapy. Recommendations of the adult ACTG Cardiovascular Disease Focus Group. Clin Infec Dis 2000; 31: 1216-24. http://www.amedeo.com/lit.php?id=11073755 36. Antoniou T, Lin-in Tseng. Interactions between recreational drugs and antiretroviral agents. Annals Pharmacother 2002; 36: 1598-613. http://www.amedeo.com/lit.php?id=12243611 37. Centers for Disease Control and Prevention (CDC). Notice to Readers: Updated guidelines for the use of rifamycins for the treatment of tuberculosis among HIV-infected patients taking protease inhibitors or nonnucleoside reverse transcriptase inhibitors. MMWR; 2004; 53: 37. http://www.amedeo.com/lit.php?id=11795500 38. Lam M, Ignoffo R, Meibohm B: Ein Leitfaden für klinisch-relevante Arzneimittel-Interaktionen in der Onkologie, Institute for Applied Healthcare Science. 39. Ghofrani HA, Olschewski H, Seeger W et al. Sildenafil for treatment of severe pulmonary hypertension and commencing right-heart failure. Pneumologie. 2002; 56: 665-72. http://www.amedeo.com/lit.php?id=12442206 40. DICenzo R, Petersen D, Cruttenden K, et al. Effect of Valproic Acid Coadministration on Plasma Efavirenz and Lopinavir Concentrations in Human Immunodeficiency Virus-Infected Adults. Antimicrobial Agents and Chemotherapy 2004; 48: 4328-31. http://www.amedeo.com/lit.php?id=15504860 41. Breilh D, Rouzes A, Djabarouti S et al. Pharmacokinetic drug interaction of lopinavir/ritonavir in combination with tenofovir in experienced HIV+patients. Abstract A-445, 44th ICAAC 2004, Washington. 42. Kearney BP, Mittan A, Sayre J, et al. Pharmacokinetic drug interaction and long term safety profile of tenofovir DF and lopinaivr/ritonavir. Abstract A-1617, 43rd ICAAC 2003, Chicago. http://www.natap.org/2003/ICAAC/day5_2.htm 43. Jain AB, Venkataramanan R, Eghtesad B, et al. Effect of coadministered lopinavir and ritonavir (Kaletra) on tacrolimus blood concentration in liver transplantation patients. Liver Transpl 2003, 9:954-60. http://amedeo.com/lit.php?id=12942457 44. Bertz RJ, Chiu YL, Naylor C et al. Lack of Effect of gastric acid reducing agents on lopinavir/ritonavir plasma concentrations in HIV-infected patients. Abstract 201, 7th Int Congr Drug Ther HIV Inf 2004, Glasgow. 45. Negredo E, Moltó J, Burger D et al. Lopinavir/ritonavir plus nevirapine as a nucleoside-sparing approach in antiretroviral-experienced patients (NEKA study). JAIDS 2005; 38: 47-52. http://www.amedeo.com/lit.php?id=15608524 46. Vezina HE, Tschampa JM, Jennings C et al. Steady-state pharmacokinetic of lopinavir/ritonavir coadministered with atazanavir in HIV-infected subjects. Abstract 48. 7th Int Worksh Clin Pharmacol HIV Ther 2005, Lissabon. 47. Van der Lee MJ, Dawood L, ter Hofstede H, et al. The effect of lopinavir / ritonavir on the pharmacokinetic of lamotrigine in healthy subjects. Abstract 12, 6th Int Worksh Clin Pharmacol HIV Ther 2005, Quebec. 48. Faivre L, T. H., Vincent I, Abbara C, et al (2005). Potent drug interactions between tacrolismus and lopinavir / ritonavir therapy in HIV-infected liver transplant recipients. Abstract 26, 6th Int Worksh Clin Pharmacol HIV Ther 2005, Quebec. 49. Leith J, Walmsley S, Katlama C, et al. Pharmacokinetics and safety of tipranavir/ritonavir alone or in combination with saquinavir, amprenavir, or lopinavir: interim analysis of BI1182.51. Abstract 34 , 5th Int Worksh Clin Pharmacol HIV-Ther 2004, Rome. 50. Klein C, ZHU T, Chiu YL et al. Effect of efavirenz on lopinavir/ritonavir pharmacokinetics from a new tablet formulation. Abstract 4.3/2, 10th EACS 2005, Dublin. 51. Pham P, Parson T, Flexner C et al. Beneficial Pharmacokinetic Interaction between Atazanavir and Lopinavir/r. Abstract 585.13th CROI 2006, Denver. 52. US product information on Prezista®. Nelfinavir (NFV, Viracept) Approved dose: 1250 mg BID. Metabolism: nelfinavir (NFV) is primarily metabolized by CYP2C19 more than CYP3A4 and CYP2D6. NFV is an inhibitor of CYP3A4. It is metabolized to an active metabolite M8 (approx. 30 % of parent compound), with equal potency to NLF. M8 is metabolized by CYP3A4 [1,2]. Drugs Interactions Comments NRTIs ddI [1,2] ddI: fasting, NFV: with a light meal Take ddI 2h apart. TDF [3] No clinically significant interaction NNRTIs EFV [2,4,5] NFV 750 TID + EFV 600 QD: NFV ? 20 %, M8 ? 40 % NFV 1250 BID + EFV 600 QD: NFV ? 38 % (Cmin 65 % ?) No clinically significant interaction, possibly monitor for NLF by TDM. NVP [6] NFV 750 TID + NVP 200 BID no dose adjustment. PIs ATV [8,28] NFV 1250 BID + ATV 400 QD: Cmin NFV: 57,4 % , M8: 124 % , No effect on AUC, Cmax, Tmax APV [9] NFV 750 + APV 800 TID: APV: (Cmin 2.9-fold ?), NFV ? 15 % TDM. IDV [10] NFV 1250 + IDV 1200 BID no dose adjustment. LPV/r [1,7] NFV 1000 + LPV/r 400/100 BID: LPV/r ? 27 % (Cmin 33 % ?) Tablets: LPV/r 400/100 BID in ART-naive patients, LPV/r 600/150 BID in pre- treated patients [1]. TDM. SQV [11-13,14] NFV 1250 + SQV/r 1000/100 BID M8 ? 2.7-fold no dose adjustment. TPV/r No data Avoid combination. TMC/r No data. Avoid combination. Antiarrhythmics Amiodarone, bepridil, flecainide, lidocaine, propafenone [2] Theoretically: antiarrhythmic drugs ? Avoid combination or monitor for toxic effects. Antibiotics Azi-, Clari-, Ery-thromycin [1,15] NFV 750 TID + azithromycin 1200 QD: NFV ? 28 %, M8 ? 23 % Azithromycin ? >100 % Caution: azithromycin side- effects.No dose adjustment with Clari-, ery-thromycin. Antidepressants Nefazodone Theoretically: NFV ? Avoid combination. Th. alternative: SSRIs. St. John's Wort [2] Theoretically: NFV ? Avoid combination. Antiepileptics Carbamazepine, phenytoin, primidone [2,18] NFV + Phenytoin: NFV: adequate plasma concentration, phenyotin ? Caution: TDM of antiepileptics and NFV. Antifungal drugs Caspofungin [1,19] Caspofungin: approved dose 50 mg, theoretically increase dose up to 70 mg/QD Azole: no dose adjustment is necessary. Antihistamines Astemizole, Lorata-dine (> 20 mg), terfenadine [2,16,17] Theoretically: antihistamines ? Increased risk of QT-prolongation Avoid combination: terfenadine. Th. alternative: cetirizine, fexofenadine. Antihypertensives Calcium channel blockers [20] Theoretically: calcium channel blockers ? Theoretically: dose reduction of ccbs. Bosentan [20,26] Theoretically: NFV ? Avoid combination or TDM. Antimalarials Mefloquine [18] No clinically significant interaction Antipsychotic drugs several drugs [16] Theoretically: NFV and antipsychotic drugs ? Avoid combination with pimozide. Monitor for side-effects. Prefer: atypical neuroleptics (less anticholinergic). Antituberculosis drugs Rifabutin [23] NFV 750 TID + Rifabutin 300 QD: NFV ? 32 % Rifabutin ? 207 % Rifabutin: 150 mg/QD. 1. NFV: 1000 TID. 2. NFV: 1250 BID. Rifampicin [2,23] NFV ? 82 % Avoid combination. Hypnotics Barbexaclone, phenobarbital Theoretically: NFV ? Avoid combination or TDM. Benzodiazepines, zolpidem [2] Benzodiazepines ?, prolonged sedation Avoid combination: midazolam, triazolam. Immunosuppressants Cylosporine, siroli-mus, tacrolimus [20,27] Theoretically: immunosuppressants ? NFV + Tacrolimus: tacrolimus dose needed 16-fold lower [27] Dose adjustment of immunosuppressants with TDM. Lipid-lowering drugs Atorvastatin, lovastatin, simvastatin [21,2] NFV 1250 BID + Atorvastatin 10 or simvastatin 20 QD: Atorvastatin ? 74 % Simvastatin ? 506 % Avoid combination: simvastatin. Low dose atorvastatin. T. alternative: pravastatin, fluvastatin. PDE5 inhibitors (PPHs) Sildenafil, tadalafil, vardenafil [18,24,25] Theoretically: PPHs ? Sildenafil 25 mg every 48h. Oral contraceptives [2] NFV 750 TID + 0.4 norethisterone + 35 µg estradiol: ethinyl estradiol ? 47 %, norethisterone ? 18 % Use additional contraceptive methods. Substitution Methadone [2,22] NFV 1250 BID + methadone: methadone ? 47 %; in this study, no opiate withdrawal [22] But monitor for opiate withdrawal. References 1. Tseng A. www.tthhivclinic.com, General Hospital, Toronto, 2004. 2. Viracept, Hoffmann-La Roche. 3. Kruse G, Esser S, Stocker H, et al.Tenofovir does not impair the pharmacokinetic of Nelfinavir in HIV-infected patients. Abstract A446, 44th ICCAC 2004, Washington. 4. Lee CA, Liang BH, Wu EY, et al. Prediction of nelfinavir mesylate (Viracept) clinical drug interactions based on in vitro human P450 metabolism studies. 4th CROI 1997, Washington. 5. Smith PF, Robbins G, Shafer R, et al. Effect of efavirenz on the pharmacokinetics of nelfinavir and M8 in naïve, HIV-infected subjects receiving long-term HAART therapy. Abstract 148, 10th CROI 2003, Boston. 6. Vilaro J, Mascaro J, Colomer J, et al. The pharmacokinetics of combination therapy with nelfinavir plus nevirapine in HIV-positive patients. Abstract A497, 41st ICAAC 2001, Chicago. 7. Klein C, Bertz R, Ashbrenner E, et al. Assessment of the multiple dose pharmacokinetic interaction of lopinavit/ritonavir with nelfinavir. Abstract 536, 10th CROI 2003, Boston. 8. Robinson BS, Riccardi KA, Gong YF, et al. BMS- 232632, a highly potent human immunodeficieny virus protease inhibitor that can be used in in combination with other available antirtroviral agents. Antimicrob Agents Chemother 2000; 44: 2093-9. http://www.amedeo.com/lit.php?id=10898681. 9. Sadler BM, Gillotin C, Lou Y, et al. Pharmacokinetic study of human immunodeficiency virus protease inhibitors used in combination with amprenavir. Antimicrob Agents Chemother 2001; 45: 3663-8. http://www.amedeo.com/lit.php?id=11709366 10. Riddler S, Havlir D, Sqires KE, et al. Coadministration of indinavir and nelfinavir in human immunodeficiency virus type 1-infected adults: safety, pharmacokinetics and antiretroviral activity. Antimicrob Agent Chemother 2002; 46: 3877-82. http://www.amedeo.com/lit.php?id=12435691 11. Buss N. Saquinavir soft gel capsule (Fortovase): Pharmacokinetics and drug interactions. Abstract 354, 5th CROI 1998, Chicago. 12. Merry C, Barry MG, Mulcahy FM, et al. Saquinavir pharmacokinetics alone and in combination with nelfinavir in HIV infected patients. Abstract 352, 5th CROI 1998, Chicago. 13. Gallicano K, Sanai J, Kravcik S, et al. Nelfinavir increases plasma exposure of saquinavir in hard gel capsule in HIV+ patients. Abstract 353, 5th CROI 1998, Chicago. 14. Stocker H, Kruse G, Arasteh K, et al. Pharmacokinetic interaction between saquinavir/r und nelfinavir in HIV-Infected patients. Abstract A-454, 44th ICAAC 2004, Washington. 15. Amsden GW, Foulds G. The pharmacokinetics of azithromycin and nelfinavir when coadministered in healthy volunteers. Abstract 1651, 40th ICAAC 2000, Toronto. 16. Pratt CM, Mason J, Russell T. Cardiovascular safety of fexofenadine HCL. Am J Cardiol 1999; 84: 278-9. http://www.amedeo.com/lit.php?id=10335761 17. Abernethy DR, Barbey JT. Loratadine and terfenadine interaction with nefazodone: Both antihistamines are associated with QT-prolongation. Clin Pharmacol Ther 2001; 69: 96-103. http://www.amedeo.com/lit.php?id=11240972 18. Schippers EF, Eugen PW, den Hartigh J, et al. No drug drug interaction between nelfinavir and indinavir mefloquine in HIV-1 infected patients. AIDS 2000; 14: 2794-5. http://www.amedeo.com/lit.php?id=11125902 19. Kerr B, Yuen G, Daniels R, et al. Strategic approach to nelfinavir mesylate (NFV) drug interactions involving CYP3A metabolism. 4th National CROI 1997, Washington. 20. Clinical Pharmacology, Gold Standard Multimedia, 2004. http://www.gsm.com 21. Hsyu PH,Smith MD, Lillibridge JH, et al. Pharmacokinetic interactions between nelfinavir and 3-hydroxy-3-methylglutarylcoenzyme A reductase inhibitors atorvastatin and simvastatin. Antimicrob Agents Chemother 2001; 45: 3445-50. http://www.amedeo.com/lit.php?id=11709322 22. Smith PF, Booker BM, Difrancesco R, et al. Effect of methadone or LAAM on the Pharmacokinetics of nelfinavir & M8. Abstract A-491, 41st ICAAC 2001, Chicago. 23. Centers for Disease Control and Prevention. Updated guidelines for the use of rifamycins for the treatment of tubercolosis among HIV-infected patients taking protease inhibitors or nonnucleoside reverse transcriptase inhibitors. MMWR Morbid Mortal Wkly Rep 2004; 53:37. http://www.amedeo.com/lit.php?id=11795500 24. Nandwani R, Gourlay Y. Possible Interaction between sildenafil and HIV combination therapy. Lancet 1999; 353: 840. http://www.amedeo.com/lit.php?id=10459981 25. Bratt G, Stahle L. Sildenafil does not alter nelfinavir pharmacokinetics. Therapeutic Drug Monitoring 2003; 25: 240-2. http://www.amedeo.com/lit.php?id=12657921 26. Ghofrani HA, Olschewski H, Seeger W, et al. Sildenafil for treatment of severe pulmonary hypertension and commencing right-heart failure. Pneumologie. 2002; 56: 665-72. http://www.amedeo.com/lit.php?id=12442206 27. Jain AK, Venkataramanan R, Shapiro R, et al. The interaction between antiretroviral agents and tacrolimus in liver and kidney transplant patients. Liver Transpl. 2002, 8:841-5. http://amedeo.com/lit.php?id=12200788 28. Kurowski M, Breske A, Kruse G, et al. Atazanavir (ATV) enhances through concentrations of nelfinavir (NFV) and its M8 metabolite in a treatment regimen without ritonavir (RTV). Abstract 90, 6th Int Worksh Clin Pharmacol HIV Ther 2005, Quebec. Nevirapine (NVP, Viramune) Approved dose: NVP 200 mg BID (lead-in period: 200 mg QD in the first 14 days) Metabolism: nevirapine (NVP) is primarily metabolized by CYP3A4 and is an inducer of CYP3A4 and 2B6 [1,2]. Drugs Interactions (IAs) Comments NRTIs No clinically significant IA [1] NNRTIs EFV [2,4,32] EFV 600 QD + NVP 400 QD [4]: EFV ? 22 % (Cmin 36 % ?) Unfavourable combination: less efficacy [32]. PIs ATV/r [2,30] Possibly: ATV ? no recommendation of dose adjustment of ATV. APV [6,7] APV/r 600/100 BID + NVP: APV ? 35 % (Cmin 20 % ?, Cmax 35 % ?) [6] TDM. APV/r 450/200 BID [7]. FPV [31] FPV/r 700/100 BID + NVP: No clinically significant interaction no dose adjustment was necessary. IDV and IDV/r [8,9,10] IDV/r 800/100 BID + NVP: IDV: Cmin 57 % ? RTV: Cmin 59 % ? but IDV > 100 ng/ml [8] 1. IDV: 1000 TID [9] 2. IDV/r: 800/100 BID [8] Probably pre-treated patients need an increased dose of IDV [8]. NVP QD decreases IDV/r more than NVP BID [10]. LPV/r [2,5,33,34] Capsules: 1. LPV/r 400/100 + NVP: pre-treated patients of clinical trial LPV/r ? 27 % (Cmin 51 % ?) 2. LPV/r 400/100 + NVP (VL < 80 c/ml, n=31): adequate levels of both drugs [33] Capsules: LPV/r: 533/133 BID [2]. Tablets: LPV/r 400/100 BID in naïve, LPV/r 600/150 BID in pre-treated patients [1]. TDM. NFV [11,12] NFV 750 TID + NVP: NFV ? 4 % (Cmax 14 % ?) In this study, no dose adjustment was necessary. Antiarrhythmics Amiodarone, bepridil, quinidine, flecainide, lidocaine, propafenone Theoretically: antiarrhythmics ? If necessary, increase dose of antiarrhythmic drugs. Antibiotics Clarithromycin, erythromycin [1,15] Clarithromycin 500 BID + NVP: Clarithromycin ? 35 %, active metabolite ? 58 %, NVP ? 26 % No dose adjustment. Monitor liver function tests. Alternative: azithromycin. Antidepressants Nefazodone Theoretically: NVP ? Avoid combination. St. John's Wort [2] Theoretically: NVP ? Avoid combination. Antiepileptics Carbamazepine, phenytoin Theoretically: NVP ? Avoid combination. Th. alternative: gabapentin, lamotrigine, valproic acid. Antifungal drugs Itra-, keto-, flu-, vori-conazole [2,16] Theoretically: NVP ?, Azole ? Ketoconazole 400 QD + NVP [16]: ketoconazole ? 63 % (Cmax 40 % ?), NVP ? 15-28 % Fluconazole + NVP [2]: NVP ?100% Voriconazole: no data TDM of NVP. Antihypertensives Calcium channel blockers such as amlodipine,nifedipine, verapamil Theoretically: calcium channel blockers ? If necessary, increase dose of calcium channel blockers. Bosentan [3,26] Theoretically: NVP ? Theoretical alternative: off label use of sildenafil for pulmonary hypertension. Antituberculosis drug Rifabutin [21,22] No dose adjustment. Rifampicin [22-25] NVP (Cmin 68 % ?) Avoid combination. Cytotoxic drugs Cyclophospamide [3] Theoretically: neurotoxic metabolite Avoid combination with 2 or more neurotoxic drugs. Drugs of abuse / recreational drugs Cocaine [18] Theoretically: norcocaine ? (liver toxicity) Avoid combination. Gastritis-/ Ulcer healing drugs Cimetidin Theoretically: NVP ? Th. alternative: famotidin, nizatidin, ranitidin. Hypnotics Barbexaclone, phenobarbital Theoretically: NVP ? Benzodiazepines, zolpidem Theoretically: benzodiazepines ? Th. alternative: lorazepam, oxazepam, temazepam. Immunosuppressants Cylosporine, sirolimus, tacrolimus Theoretically: immunosuppressants ? Dose adjustment of immunosuppressants with TDM. Lipid-lowering drugs Atorvastatin, lovastatin, simvastatin [1,15,16] Theoretically: statins ? Theoretical alternative: pravastatin. Oral contraceptives [17] Ethinyl estradiol 0.035 + norethindrone 1.0: estradiol ? 29 %, norethindrone ? 18 % Use additional contraceptive method. PDE5 inhibitors (PPHs) Sildenafil, tadalafil, vardenafil Theoretically: PPHs ? Caution: adapt dose indivi-dually for each patient. Substitution Methadone [2,19,20] Methadone ? after 4-10 days: opiate withdrawal Increase methadone dose in 10 mg steps. Others Dexamethasone Theoretically: NVP ? Warfarin [27] Warfarin ? ? Control INR. References 1. Tseng A. www.tthhivclinic.com, General Hospital, Toronto, 2006 2. Viramune, Boehringer Ingelheim. 3. Clinical Pharmacology, Gold Standard Multimedia, 2004. http://www.gsm.com 4. Veldkamp AI, Harris M, Montaner JSG, et al. The steady-state pharmacokinetics of efavirenz and nevirapine when used in combination in HIV type 1 infected persons. J Infect Dis 2001; 184: 37-42. http://www.amedeo.com/lit.php?id=11398107 5. Kaletra, Abbott. 6. Goujard C, Meynard JL, Choudet N, et al. Steady-state pharmacokinetics of amprenavir 600 mg BID and ritonavir 100 mg BID with or without NNRTI in HIV-1 infected patients. Abstract P268, 5th Int Congr Drug Ther HIV Inf 2000, Glasgow. http://www.aegis.com/conferences/hiv5/P268.html 7. Degen O, Kurowski M, van Lunzen J, et al. Amprenavir and ritonavir: intraindividual comparison of different doses and influence of concomitant NNRTI on steady-state pharmacokinetics in HIV-infected patients. Abstract 739, 8th CROI 2001, Chicago. http://www.retroconference.org/2001/abstracts/abstracts/abstracts/739.htm 8. Burger DM, Prins JM, van der Ende ME, et al. The effect of nevirapine on the pharmakokinetics of indinavir/ritonavir 800/100 mg BID. JAIDS 2004; 35: 97-8. http://www.amedeo.com/lit.php?id=14707800 9. Murphy R, Gagnier P, Lamson M, et al. Effect of nevirapine on pharmacokinetics of indinavir and ritonavir in HIV-1 patients. Abstract 374, 4th CROI 1997, Washington. 10. Crommentuyn KML, van Heeswijk RPG, Veldkamp AI, et al. Nevirapine once daily versus twice daily: implications for drug-drug interactions. Abstract 1.11, 2nd Int Worksh Clin Pharmacol HIV Ther 2001, Noordwijk. 11. Skowron G, Leoung G, Kerr B, et al. Lack of pharmacokinetic interaction between nelfinavir and Nevirapine. AIDS 1998; 12: 1243-4. http://www.amedeo.com/lit.php?id=9677174 12. Vilaro J, Mascaro J, Colomer J, et al. The pharmacokinetics of combination therapy with nelfinavir plus nevirapine in HIV-positive patients. Abstract A497, 41st ICAAC 2001, Chicago. 13. Sahai J, Cameron W, Salgo M, et al. Drug interaction study between saquinavir (SQV) and nevirapine (NVP). Abstract 376, 4th National CROI 1997, Washington. 14. Sabo J, MacGregor T, Lamson M, et al. Pharmacokinetics of tipranavir and nevirapine. Abstract 249, 10th Annual Canadian Conference on HIV/AIDS Research 2001, Toronto. 15. Robinson P, Gigliotti M, Lamson M, et al. Effect of the reverse transcriptase inhibitor nevirapine, on the steady-state pharmacokinetics of clarithromycin in HIV positive patients. Abstract 374, 6th CROI 1999, Chicago. 16. Lamson M, Robinson P, Gigliotti M, et al. The pharmacokinetic interactions of nevirapine and ketoconazol. Abstract 12218, 12th World AIDS Conference 1998, Geneva. 17. Mildvan D, Yarrish R, Marshak A, et al. Pharmacokinetic interaction between nevirapine and ethinyl estradiol/norethindrone when admnistered concurrently to HIV-infected women. Journal of the Acquired Immune Deficiency Syndrome 2002; 29: 471-7. http://www.amedeo.com/lit.php?id=11981363 18. Antoniou T, Lin-in Tseng. Interactions between Recreational Drugs and antiretroviral agents. Ann Pharmacother 2002; 36: 1598-613. http://www.amedeo.com/lit.php?id=12243611 19. Altice FL, Friedland GH, Cooney E. Nevirapine induced opiate withdrawal among injection drug users with HIV infection receiving methadon. AIDS 1999; 13: 957-62. http://www.amedeo.com/lit.php?id=10371177 20. Clarke S, Mulcahy F, Back D, et al. Managing methadone and non-nucleoside reverse transcriptase inhibitors: guidelines for clinical practise. Abstract 88, 7th CROI 2000, San Francisco. 21. Maldonaldo S, Lamson M, Gigliotti M, et al. Pharmacokinetic interaction between nevirapine and rifabutin. Abstract 341, 39th ICAAC 1999, San Francisco. 22. Centers for Disease Control and Prevention (CDC). Notice to Readers: Updated guidelines for the use of rifamycins for the treatment of tuberculosis among HIV-infected patients taking protease inhibitors or nonnucleoside reverse transcriptase inhibitors. MMWR; 2004; 53: 37. http://www.cdc.gov/mmwr/preview/mmwrhtml/mm4909a4.htm 23. Robinson P, Lamson M, Gigliotti M, et al. Pharmacokinetic interaction between nevirapine and rifampin. Abstract 60623, 12th World AIDS Conference 1998, Geneva. 24. Ribera E, Pou L, Lopez RM, et al. Pharmacokinetic interaction between nevirapine and rifampicin in HIV-infected patients with tuberculosis. JAIDS 2001; 28: 450-3. http://www.amedeo.com/lit.php?id=11744833 25. Oliva J, Moreno S, Sanz J, et al. Co-administration of rifampin and nevirapine in HIV-infected patients with tuberculosis [letter]. AIDS 2003; 17: 637-8. http://www.amedeo.com/lit.php?id=12598789 26. Ghofrani HA, Olschewski H, Seeger W, et al. Sildenafil for treatment of severe pulmonary hypertension and commencing right-heart failure. Pneumologie 2002; 56: 665-72. http://www.amedeo.com/lit.php?id=12442206 27. Dioniso D, Mininni S, Bartolozzi D, et al. Need for increased dose of warfarin in HIV patients taking nevirapine. AIDS 2001; 15: 277-8. http//www.amedeo.com/lit.php?id=11216940 28. Tripranavir Investigators Broschüre, Boehringer Ingelheim, 2004. 29. Barry M, Mulcahy F, Merry C, et al. Pharmacokinetics and potential interactions among antiretroviral agents used to treat patients with HIV infection. Clin Pharmacokinet. 1999; 36: 289-304. http://www.amedeo.com/lit.php?id=10320951 30. Alexander CS, Montaner JG, Langridge S, et al. Interaction between atazanavir/Ritonavir (ATV/r) and nevirapine (NVP) is observed in a clinical setting. Abstract P275, 7th Int Congr Drug Ther HIV Inf 2004, Glasgow. 31. DeJesus E, Piliero P, Summers K, et al. Evaluation of the pharmacokinetik drug interaction between fosamprenavir (FPV), FPV plus ritonavir (RTV) and nevirapine (NVP) in HIV-infected patients (APV10014). Abstract A-447, 44th ICAAC 2004, Washington. 32. van Leth F., Hassink E., Phanuphak P. et al. Results of the 2NN Study: A randomized comparative trial of first-line antiretroviral therapy with regimens containing either NVP alone, EFV alone or both drugs combined, together with stavudine and lamivudine. Abstract 176, 10th CROI 2003. 33. Bertz R, Foit C, Burt D, et al. Assessment of the effect of nevirapine on the pharmacokinetics of lopinavir/ritonavir after multiple dosing in HIV-infected adults. Abstract TUPEB4565, XIV Int AIDS Conf 2002, Barcelona. 34. Negredo E, Moltó J, Burger D et al. Lopinavir/ritonavir plus nevirapine as a nucleoside-sparing approach in antiretroviral-experienced patients (NEKA study). JAIDS 2005; 38: 47-52. http://www.amedeo.com/lit.php?id=15608524 Saquinavir (SQV, Invirase 500) Approved dose SQV: SQV/r: 1000/100 mg BID [3]. Metabolism: 90 % of SQV is metabolized by the isoenzyme CYP3A4. SQV is a weak inhibitor of CYP3A4. In vitro studies have shown that SQV is also a substrate of P-glycoprotein (P-gp) [1,2]. Drugs Interactions Comments NRTIs ddI [1] Take ddI 1h before or 2h after SQV. TDF [4,5] No clinically significant interactions NNRTIs EFV [6-9] SQV 1200 TID + EFV 600 QD: SQV ? 62 % [6] 1. SQV/r 400/400 BID [7]. 2. SQV/r 1200/100 QD [8]. 3. SQV/r 1000/100 BID[9]. PIs ATV [16-19] SQV 1600 QD + ATV/r 300/100 QD: SQV ? 60 %, RTV ? 41 % [16] SQV 1000 BID + ATV/r 300/100 QD: SQV, ATV, RTV ? [19] Synergistic effect. No dose adjustment necessary. APV [20] SQV/r 1000/100 + APV 600 BID: => adequate plasma concentration Insufficient data. => TDM. FPV/r [21] SQV 1000 + FPV/r 700/100 or 700/200 BID: no effect on FPV, but on 1. RTV 100: SQV ? 14 % 2. RTV 200: SQV ? 12 % SQV + FPV + RTV 100: TDM. SQV + FPV + RTV 200: safe. IDV [22-24] IDV 800 TID + single dose SQV: SQV ? 5-8-fold [22,24] Insufficient data. LPV/r [3,12-15] SQV 1000 + LPV/r 400/100 BID: adequate levels of SQV and LPV Synergistic effect. NFV [25-29] SQV/r 1000/100 + NFV 1250 BID: NFV-M8 ? 2.7-fold In this study no dose adjustment was necessary. TPV/r [48] TPV/r 500/200 + SQV 1000 BID: SQV? 70 %, (Cmin 81 % ?, Cmax 66 % ? ) Avoid combination. TMC/r [49] TMC/r 400/100 + SQV 1000 BID TMC ? 26 % Avoid combination. Antiarrhythmics Amiodarone, flecaini-de, lidocaine, propafenone [3] Theoretically: antiarrhythmics Avoid combination. Antibiotics Clarithromycin Erythromycin [2,3] SQV 1200 TID + clarithromycin 500 BID: SQV ? 177 % Clarithromycin ? 45 % SQV 1200 TID + Erythromycin 250 QD: SQV ? 99 % (Cmax 106 % ?) Unboosted SQV: no dose adjustment was necessary. Antidepressants Nefazodone [2] Theoretically: SQV ? Monitor for side-effects. Th. alternative: SSRIs. St. John's Wort [2] Theoretically: SQV ? Avoid combination or TDM. Antiepileptics Carbamazepine [3,30], phenytoin, primidone Theoretically: SQV ?, antiepileptics ? Theoretical alternative: gabapentin, lamotrigine, valproic acid [30]. Antifungal drugs Itraconazole, ketoconazole, voriconazole [2,33] Theoretically: SQV ? Invirase 600 TID + 200 ketoconazole QD: SQV ? 160 % No dose adjustment. Monitor for toxic effects. Antihistamines Astemizole, loratadine (> 20 mg), terfenadine [2,31,32] Risk of QT-prolongation ? (terfenadine ? 368 %) Avoid combination: terfenadine. Theoretical alternative: cetirizine, fexofenadine. Antihypertensives Calcium channel blockers [2] such as amlodipine, nifedipine, verapamil Theoretically: calcium channel blockers ? Theoretical dose reduction of calcium channel blockers. Bosentan [3,43] Theoretically: SQV ? Avoid combination or TDM. Antipsychotic drugs several drugs [2,40] Theoretically: SQV and antipsychotic drugs ? Avoid combination with pimozide. Monitor for side-effects. Prefer: atypical neuroleptics (less anticholinergic). Antituberculosis drugs Rifabutin [41] SQV 1200 TID + rifabutin QD: SQV ? 40 % SQV/r + rifabutin: 150 mg 3x/week. Rifampicin [2,41,47] SQV/r 1000/100 BID + rifampicin 600 QD: hepatotoxicity Avoid combination. Gastritis-/ Ulcer healing drugs Antacids, proton pump inhibitors (PPIs) No data Interactions unlikely. H2-blockers Cimetidine [3,35] SQV 1200 TID vs. SQV 1200 BID + cimetidine 400 BID: SQV ? 120 % (Cmax 179 % ?) Theoretical alternative: famotidine, nizatidine, ranitidine. Hypnotics Barbexaclone, phenobarbital Theoretically: SQV ? Avoid combination or TDM. Benzodiazepines, zolpidem [2,3,51] Prolonged sedation. SQV/r 1000/100 BID + midazolam: SQV ? 12.5-fold (Cmax 4.27-fold ?), half life prolongation: from 4.4h to 14.6h [ 51] Avoid combination: midazolam. Caution: alprazolam, triazolam. Theoretical alternative: lorazepam, oxazepam, temazepam [3]. Immunosuppressants Cylosporine, sirolimus tacrolimus [3,46] immunosuppressants ? Dose adjustment of immunosuppressants with TDM. Lipid-lowering drugs Atorvastatin, lovastatin, simvastatin [2,34] SQV/r 400/400 BID + 40 mg atorvastatin QD, pravastatin, simvastatin: atorvastatin ? 5.9-fold, pravastatin: ? 35 %, simvastatin ? 34.6-fold Avoid combination: simvastatin, lovastatin. Th. alternative: pravastatin, fluvastatin. PDE5 inhibitors (PPHs) Sildenafil, tadalafil, vardenafil [2,3,42] Theoretically: PPHs ? Fortovase 1200 TID + sildenafil 100: Sildenafil ? 210 % (Cmax 140 % ?) Sildenafil 25 mg every 48h. Other PPIs: start with a low dose. Substitution Methadone [36-39] SQV/r + R- and S-methadone: No significant changes of SQV. R-methadone ? 20 % Interactions unlikely. Others Dexamethasone Theoretically: SQV ? TDM. Ergot alkaloids [3] Theoretically: SQV ? Avoid combination. Theoretical alternative: triptans. Garlic capsules [44] ingredients: allicin SQV 1200 TID + allicin 300: SQV ? 51 % Avoid combination. Warfarin [3,45] Report of hypoprothrombinaemia: 20 % lower warfarin concentration with SQV If necessary, increase warfarin dose. References 1. Tseng A. http://www.tthhivclinic.com/, General Hospital, Toronto, 2004. 2. Fortovase, Hoffmann-La Roche. 3. Clinical Pharmacology, Gold Standard Multimedia, 2004. http://www.gsm.com 4. Ananworanich J, Siangphoe U, Mahanontharit A, et al. Saquinavir Cmin before and after switching NRTI to tenofovir in patients treated with once daily saquinavir-hard gel capsule/ritonavir 1600 mg/ 100 mg. Abstract 4.15, 5th Int Worksh Clin Pharmacol HIV Ther 2004, Rome. 5. Boffito M, DŽAvolio A, Di Perri G, et al. Repeated pharmacokinetics of tenofovir disoproxil fumarate (TDF) in HIV-infected-adults receiving saquinavir hard gel (SQV)/ritonavir (RTV) 1000/100 mg BID. Abstract 4.19, 5th Int Worksh Clin Pharmacol HIV Ther 2004, Rome. 6. Jorga K, Buss NE. Pharmacokinetic drug interaction with saquinavir soft gelatine capsule. Abstract 339, 39th ICAAC 1999, San Francisco. 7. van Heeswijk RP, Cooper C, Gallicano, et al. The pharmacokinetics of SQV/RTV 400/400 mg BID before, and after short- and long term co-administration of efavirenz 600 mg QD. Abstract 7.4, 3rd Int Worksh Clin Pharmacol HIV-Ther 2002, Washington. 8. Lopez-Cortes LF, Viciana P, Ruiz-Valderas R, et al. Pharmacokinetics, efficacy and safety of once-daily saquinavir-sgc plus low-dose ritonavir(1200/100 mg) in combination with efavirenz in HIV-pretreated patients. Abstract 441-w , 9th CROI 2002, Seatlle. 9. Boyd MA, Autar R, Burger D, et al. Saquinavir 1000 mg bid boosted with ritonavir 200 mg in the presence of efavirenz 600 mg results in adequate saquinavir minimum concentrations: HIV-NAT 012 pharmacokinetic study. Abstract 4.9, 5th Int Worksh Clin Pharmacol HIV Ther 2004, Rome. 10. Sahai J, Cameron W, Salgo M, et al. Drug interaction study between saquinavir (SQV) and nevirapine (NVP). 4th National CROI 1997, Washington. 11. Crommentuyn KML, van Heeswijk RPG, Veldkamp AI, et al. Nevirapine once daily versus twice daily: implications for drug-drug interactions. Abstract1.11, 2nd Int Worksh Clin Pharmacol HIV Ther 2001, Noordwijk. 12. La Porte CJ, Wasmuth JC, Schneider K, et al. Lopinavir/ritonavir plus saquinavir in salvage therapy: pharmacokinetics, tolerability and efficacy. AIDS 2003; 17: 1700-2. http://www.amedeo.com/lit.php?id=12853756 13. Ribera E, Diaz M, Pou L, et al. Steady-state pharmacokinetics of double boosting regimen of lopinavir, plus minidose Ritonavir, plus Saquinavir soft-gel in HIV-infected adults. Abstract TUPE4545, XIV Int AIDS Conf 2002, Barcelona. 14. Staszewski S, Dauer B, Von Hentig N, et al. The LopSaq study: 24 week analysis of the double protease inhibitor salvage regimen containing lopinavir plus saquinavir without any additional antiretroviral therapy. Abstract 583, 2nd IAS Conference on HIV Pathogenesis and Treatment 2003, Paris. 15. Stefan C, Von Hentig N, Kurowski, et al. Saquinavir drug exposure is not impaired by the boosted double protease inhibitor combination of lopinavir/Saquinavir. AIDS 2004; 18: 503-8. http://www.amedeo.com/lit.php?id=15090803 16. Boffito M, Kurowski M, Kruse G, et al. Atazanavir enhances saquinavir hard gel concentration in a ritonavir boosted once daily regimen. AIDS 2004; 18: 1292-7. http://www.amedeo.com/lit.php?id=15362661 17. Prelutsky D, Salvato P, Falcon R. Pharmacokinetics of saquinavir hard gel (invirase) when combined with atazanavir. Abstract 8.11, 4th Int Worksh Clin Pharmacol HIV Ther 2003, Cannes. http://216.198.241.125/hiv/upload_doc/2/4PK Falcon 8.11.PDF 18. DeJesus E, Grinsztejn B, Rodriguez C, et al. Efficacy and safety of atazanavir with ritonavir or saquinavir vs lopinavir/ritonavir in patients who have experienced virologic failure on multiple HAART Regimens: 48-Week results from BMS A1424-045. Abstract 54, 11th CROI 2004, San Francisco. http://www.retroconference.org/2004/cd/Abstract/547.htm 19. von Hentig N, Haberl A, Lutz T, et al. Pharmacokinetic interactions of atazanavir (ATV) and saquinavir (SQV) in a ritonavir (RTV) boosted protease inhibitor therapy regimen. Abstract P276, 7th Int Congr Drug Ther HIV Inf 2004, Glasgow. 20. Wolfe PR, Anderson PG, Gunawan S. Simultaneous administration of amprenavir and saquinavir does not appear to lower plasma levels of either agent when coadministered with low dose ritonavir. Abstract 7.11, 3rd Int Worksh Clin Pharmacol HIV Ther 2002, Washington. 21. Boffito M, Dickinson L, Hill A, et al. Steady state pharmacokinetics of saquinavir hard gel/fosamprenavir 1000/700 plus 100 mg und 200 mg of ritonavir twice daily in HIV+ patients. Abstract 608, 11th CROI 2004, San Francisco. 22. Mc Crea J, Buss N, Stone J, et al. Indinavir-saquinavir single dose pharmacokinetic study. 4th National CROI 1997, Washington. 23. Manion D, Merill DP, Hirsch MS. Combination drug regimens against multidrug resistant HIV-1 in vitro. 4th National CROI, 1997, Washington. 24. Buss N. Saquinavir soft gel capsule (Fortovase): Pharmacokinetics and drug interactions. Abstract 354, 5th CROI 1998, Chicago. 25. Merry C, Barry MG, Mulcahy FM, et al. Saquinavir pharmacokinetics alone and in combination with nelfinavir in HIV-infected patients. AIDS 1997; 11: 117-20. http://www.amedeo.com/lit.php?id=9084785 26. Gallicano K, Sanai J, Kravcik S, et al. Nelfinavir increases plasma exposure of saquinavir in hard gel capsule in HIV+ patients. Abstract 353, 5th CROI 1998, Chicago. 27. Kravcik S, Sahai J, Kerr B, et al. Nelfinavir mesylate (NFV) increases saquinavir soft gel capsule (SQV- SGC) exposure in HIV+ patients. 4th National CROI, 1997, Washington. 28. Squires K, Currier J, Clark R, et al. Final 48.week result of a phase 2, randomized study of the safety, efficacy and pharmacokinetics of BID vs. TID nelfinavir and saquinavir in combination with lamivudine and stavudine in HIV-positive women. Abstract 330, 8th CROI 2001, Chicago. 29. Stocker H, Kruse G, Arasteh K, et al. Pharmacokinetic interaction between saquinavir/r und nelfinavir in HIV-Infected patients. Abstract A-454, 44th ICAAC 2004, Washington. 30. Hugen PWH, Burger DM, Brinkmann K, et al. Carbamazepine-indinavir interaction causes antiretroviral failure. Ann Pharmacother 2000; 34: 465-70. http://www.amedeo.com/lit.php?id=10772431 31. Pratt CM, Mason J, Russell T. Cardiovascular safety of fexofenadine HCL. Am J Cardiol 1999; 84: 278-9. http://www.amedeo.com/lit.php?id=10335761 32. Abernethy DR, Barbey JT. Loratadine and terfenadine interaction with nefazodone: Both antihistamines are associated with QT-prolongation. Clin Pharmacol Ther 2001; 69: 96-103. http://www.amedeo.com/lit.php?id=11240972 33. Cardiello P, Samor T, Burger D, et al. Pharmacokinetics of lower doses of saquinavir soft gel caps (800 and 1200 mg BID) boosted with itracaconazol in HIV+ patients. Antivir Ther 2003; 8: 245-9. amedeo.com/lit.php?id=12924542 34. Fichtenbaum C, Gerber J, Rosenkranz S, et al. Pharmacokinetic interactions between protease inhibitors and selected HMG-CoA reductase inhibitors. Abstract LB6, 7th CROI 2000, San Francisco. 35. Boffito M, Trentini, Raiteri R, et al. Pharmacokinetics of saquinavir co-administered with cimetidine. J Antimicrob Chemother. 2002 ; 50:1081-4. http://www.amedeo.com/lit.php?id=12461038 36. Geletko SM, Erickson AD. Decreased methadone effect after ritonavir initiation. Ann Pharmacother 2000; 20: 93-4. http://www.amedeo.com/lit.php?id=10641980 37. Shelton M, Cloen D, Berenson C, et al. The effects of once daily saquinavir/mini-dose ritonavir on the pharmacokinetics of methadone isomers. J Clin Pharmacol 2004; 44: 293-304. http://www.amedeo.com/lit.php?id=14973306 38. Shelton MJ, Cloen D, Berenson C, et al. Pharmacokinetics of once daily saquinavir/ritonavir: effects on unbound methadone and alpha1-acid glycoprotein. Abstract A492, 41st ICAAC 2001, Chicago. 39. Gerber JG, Rosenkranz S, Segal Y . Effect of ritonavir/saquinavir on stereoselective pharmacokinetics of methadone: results of AIDS Clinical Trials Group (ACTG) 401. J Acquir Immune Defic Syndr. 2001; 27: 153-60. http://www.amedeo.com/lit.php?id=11404537 40. Tseng AL, Foisy MM. Significant Interactions wit New Antiretrovirals and Psychotropic Drugs, Ann Pharmacother 1999; 33: 461-73. http://www.amedeo.com/lit.php?id=10332538 41. Centers for Disease Control and Prevention (CDC). Notice to Readers: Updated guidelines for the use of rifamycins for the treatment of tuberculosis among HIV-infected patients taking protease inhibitors or nonnucleoside reverse transcriptase inhibitors. MMWR; 2004;53:37. http://www.amedeo.com/lit.php?id=11795500 42. Muirhead GJ, Wulff MB, Fielding A, et al. Pharmacokinetic interactions between sildefanil and saquinavir/ritonavir. Br J Clin Pharmacol 2000; 50: 99-107. http://www.amedeo.com/lit.php?id=9161669 43. Ghofrani HA, Olschewski H, Seeger W, et al. Sildenafil for treatment of severe pulmonary hypertension and commencing right-heart failure. Pneumologie. 2002; 56: 665-72. http://amedeo.com/lit.php?id=12442206 44. Piscitelli SC, Burstein AH, Welden N, et al. The effect of garlic supplements on the pharmacokinetics of saquinavir. Clin Infec Dis 2002; 34: 234-5. http://www.amedeo.com/lit.php?id=11740713 45. Darlington MR. Hypoprothombinemia during consomitant therapy with warfarin and saquinavir [letter]. Ann Pharmacother 1997; 31: 647. http://www.amedeo.com/lit.php?id=9161669 46. Brinkman K, Huysmans F, Burger DM. Pharmacokinetic interaction between saquinavir and cyclosporine. Ann Intern Med 1998, 129:915-916. 47. Roter Hand Brief Saquinavir, Hoffmann La-Roche. 48. Leith J, Walmsley S, Katlama C, et al. Pharmacokinetics and safety of tipranavir/ritonavir alone or in combination with saquinavir, amprenavir, or lopinavir: interim analysis of BI1182.51. Abstract 34, 5th Int Worksh Clin Pharmacol HIV-Ther 2004, Rome. 49. US product information on Prezista®. 50. Frohlich M, Burhenne J, Martin-Facklam M, et al. Oral contraception does not alter single dose saquinavir pharmacokinetics in women. Br J Clin Pharmacol 2004;57:244-52. http://www.amedeo.com/lit.php?id=14998420 51. Hofmann C et al. Effect of saquinavir/ritonavir on CYP-3A4 activityin healthy volunteers using midazolam as a probe. Abstract 47. 7th Int Worksh Clin Pharmacol HIV-Ther 2006, Lissabon. T-20 (Enfuvirtid, Fuzeon) No clinically significant interaction. Tenofovir (TDF, Viread; component of Truvada) Elimination: TDF is eliminated by a combination of glomerular filtration and active renal tubular secretion. Approved dose: TDF 300 mg QD Drugs Interactions Comments NRTIs ddI [1-5] ddI EC 250 QD + TDF 300 QD: ddI AUC equivalent to ddI 400 alone. Dose recommendation: patients = 60 kg: ddI 250 mg patients < 60 kg: ddI 200 mg Despite dose reduction of ddI, there is probably an increased risk of lactic acidosis and pancreatitis. Unfavourable combination. Virological failure [4]. Closely monitor for amylase, lipase and lactate. ddI and TDF can be taken with a meal. Other NRTIs [6-9] No clinically significant interaction NNRTIs EFV [9] No clinically significant interaction PIs ATV [11] ATV/r [10,12,13,27] ATV 400 QD + TDF 300 QD: ATV ? 25 % (Cmin 40 % ?) TDF ? 24 % [11] ATV/r 300/100 + TDF QD [10] ATV ? 25 % (Cmin 23 % ?, not significant) [12] ATV/r 300/100 QD: Administer with food. Boosted ATV-levels are 2-4-fold higher than unboosted ATV without TDF [13]. IDV [9] No clinically significant interaction LPV/r [14,15,23,28] Healthy volunteers: TDF 32 % (Cmax 15 % ) LPV/r: unchanged 18 heavily pre-treated patients: LPV: Cmin 34 % ?, RTV: Cmin 44 % ? In clinical studies, no increased appearance of renal side-effects. TDM of LPV/r. NFV [18] No clinically significant interaction SQV [16,17] No clinically significant interaction FPV [25,26] No clinically significant interaction TPV/r [15] TPV/r 500/100 or 750/200 BID + TDF 300 QD: TDF (depending on dose): TPF ? 11 % and 17 % respectively (Cmax 23-38 % ?) Avoid combination, clinical significance of this interaction is not firmed yet. DRV (TMC 114) /r [24] DRV/300/100 BID + TDF 300 QD: TDF 22 % No dose adjustement. Co-medication Methadone [20] No clinically significant interaction O. contraceptives [19] No clinically significant interaction Ribavirin [21] No clinically significant interaction Rifampicin [22] No clinically significant interaction Nephrotoxic drugs e.g. amphotericin B, aminoglycosides, cidofovir, foscarnet, pentamidine (i.v.), vancomycin [2] No data, but perhaps additive nephrotoxicity. Avoid combination. e.g. acyclovir, probe-necid, salicylate, tacrolimus, valaci-clovir, valganciclovir No data, but these drugs are renally eliminated as tenofovir Avoid combination in patients with risk of renal failure; or monitor for kidney function weekly. References 1. Tseng A. www.tthhivclinic.com, General Hospital, Toronto, 2006. 2. Viread, Gilead. 3. Clinical Pharmacology, Gold Standard Multimedia, 2004. http://www.gsm.com 4. Kearney BP, Damle B, Plummer A, et al.Tenofovir DF (TDF) and didanosine EC (ddl EC): investigation of pharmacokinetic (PK) drug-drug and drug-food interactions. Abstract LBPE9026, XIV Int AIDS Conf 2002, Barcelona. http://www.aegis.com/conferences/14WAC/LbPeB9026.html 5. Kearney BP, Isaacson E, Sayre J, et al. Didanosine and tenofovir DF drug-drug interaction: assessment of didanosine dose reduction. Abstract 533, 10th CROI 2003, Boston. http://www.retroconference.org/2003/abstract/abstract.aspx?abstractID=181 6. Blum MR, Begley J, Zong J, et al. Lack of a pharmacokinetic interaction between emtricitabine and tenofovir DF when coadministered to steady state healthy volunteers. Abstract A-1621, 43rd ICAAC 2003, Chicago. http://www.thebody.com/confs/icaac2003/pdfs/A-1621_poster.pdf 7. Kaul S, Bassi K, Damle B, et al. Stavudine extendend release formulation and tenofovir disoproxil fumarate: lack of a pharmacokinetic drug interaction. Abstract 602, 11th CROI San Francisco, 2004. http://www.retroconference.org/2004/cd/abstract/602.htm 8. Kearney BP, Isaacson E, Sayre J, et al. The pharmacokinetics of abacavir, a purine nucleotide analog, are not affected by tenofovir DF. AbstractA-1615, 43rd ICAAC 2003, Chicago. http://www.thebody.com/confs/icaac2003/pdfs/A-1615_poster.pdf 9. Kearney B, Flaherty J, Wolf J, et al. Lack of clinically relevant drug-drug interactions between tenofovir DF and efavirenz, indinavir, lamivudine and lopinavir/ritonavir in healthy subjects. Abstract P171, 8th European Conference on Clinical Aspects and Treatment of HIV Infection 2001, Athens. http://www.eacs.ws/conference/index/htm 10. Taburet A, Piketty C, Chazallon C, et al. interactions between atazanavir-ritonavir and tenofovir in heavily pretreated human immunodeficiency virus-infected patients. Antimicrob Agents Chemother 2004; 48:2091-6. http://www.amedeo.com/lit.php?id=15155205 11. Kaul S, Bassi K, Damle B, et al. Pharmacokinetic evaluation of the combination of atazanavir (ATV), enteric coated didanosine (ddl-EC), and tenofovir disoproxil fumarate (TDF) for a once-daily antiretroviral regimen. Abstract A-1616, 43rd ICAAC 2003, Chicago. http://www.natap.org/2003/ICAAC/day6_1.htm 12. Kruse G, Stocker H, Breske A et al. Trough levels of six different atazanavir regimes in HIV-infected patients. Abstract 6.6, 5th Int Worksh Clin Pharmacol HIV Ther 2004, Rome. 13. Truvada, Gilead Sciences, September 2004. 14. Kearney BP, Mittan A, Sayre J, et al. Pharmacokinetic drug interaction and long term safety profile of tenofovir DF and lopinaivr/ritonavir. Abstract A-1617, 43rd ICAAC 2003, Chicago. http://www.thebody.com/confs/icaac2003/pdfs/A.1617_poster.pdf 15. Roszko PJ, Curry K, Brazina B, et al. Standard doses of efavirenz (EFV), zidovudine (ZDV), tenofovir (TDF), and didanosine (ddl) may be given with tipranavir/ritonavir (TPV/r). Abstract 865, 2nd lAS Conference on HIV Pathogenesis and Treatment 2003, Paris. http://www.aegis.com/conferences/2ndIASHIVPT/865.html 16. Ananworanich J, Siangphoe U, Mahanontharit A, et al. Saquinavir Cmin before and after switching NRTI to tenofovir in patients treated with once daily saquinavir-hard gel capsule/ritonavir 1600 mg/ 100 mg. Abstract 4.15, 5th Int Worksh Clin Pharmacol HIV Ther 2004, Rome. http://www.amedeo.com/lit.php?id=15651763 17. Boffito M, DŽAvolio A, Di Perri G, et al. Repeated pharmacokinetics of tenofovir disoproxil fumarate (TDF) in HIV-infected-adults receiving Saquinavir hard gel (SQV)/Ritonavir (RTV) 1000/100 mg BID. Abstract 4.19, 5th Int Worksh Clin Pharmacol HIV Ther 2004, Rome. 18. Kruse G, EsserS, Stocker H, et al. Tenofovir does not impair the pharmacokinetics of nelfinavir in HIV-infected patients. Abstract A-446, 44th ICAAC 2004, Washington. 19. Kearney BP, Isaacson E, Sayre J, et al. Tenofovir DF and oral contraceptives: Lack of a pharmacokinetic drug interaction. Abstract A-1618, 43rd ICAAC 2003, Chicago. http://www.thebody.com/confs/icaac2003/pdfs/A-1618_poster.pdf 20. Smith P, Kearney B, Cloen D. Tenofovir DF does not affect the pharmacokinetics or pharmacodynamics of methadone. Abstract 869, 2nd IAS Conference on HIV Pathogenesis and Treatment 2003, Paris. http://www.aegis.com/conferences/2ndIASHIVPT/865.html 21. Kearney B, Benhamou Y, Flaherty J, et al. Lack of systemic or renal drug interactions of tenofovir DF with ribavirin or adefovir dipivoxil. Abstract 69, XV Int AIDS Conf 2004, Bangkok. 22. Droste JAH, Kearney BP, v Horssen P, et al. Lack of clinically relevant drug-drug interaction between tenofovir DF and rifampin in healthy volunteers. Abstract 4.11, 5th Int Worksh Clin Pharmacol HIV Ther 2004, Rome. 23. Kearney BP, Mittan A, Sayre J, et al. Pharmacokinetic drug interaction and long term safety profile of tenofovir DF and lopinaivr/ritonavir. Abstract A-1617, 43rd ICAAC 2003, Chicago. http://www.natap.org/2003/ICAAC/day5_2.htm 24. US Product information on Prezista. 25. Kurowski M, Walli R, Breske et al. Co-administration of tenofovir 300 mg QD with fosamprenavir / ritonavir 1400/100 mg QD or 1400/200 mg QD does not affect amprenavir pharmacokinetics. Abstract 10, 6th Int Worksh Clin Pharmacol HIV Ther 2005, Quebec. 26. Peytavin G, Rouault A, Agher R, et al. Plasma concentrations of amprenavir, ritonavir and tenofovir in HIV-infected patients treated with fosamprenavir / ritonavir (700 / 100 mg BID) and tenofovir (300 mg QD) containing regimen. Abstract 32, 6th Int Worksh Clin Pharmacol HIV Ther 2005, Quebec. 27. Agarwala S, Eley T, Villegas C, et al. Pharmacokinetic interaction between tenofovir and atazanavir co-administered with ritonavir in healthy subjects. Abstract 16, 6th Int Worksh Clin Pharmacol HIV Ther 2005, Quebec. 28. Breilh D, Rouzes A, Djabarouti S, et al. Pharmacokinetic drug interaction of lopinavir/ritonavir im combination with tenofovir in experienced HIV+ patients. Abstract A-445, 44th ICAAC 2004, Washington. Tipranavir (TPV/r, Aptivus) Approved dose: TPV/r: 500/200 mg BID taken with a meal [1,2]. Metabolism: TPV is metabolized by the isoenzme CYP3A4 and is also a substrate of P-glycoprotein. Further, TPV is an inducer of the isoenzyme CYP3A4, of the glucuronyltransferase, and of P-glycoprotein [1,2]. By means of boostering with RTV, TPV becomes to be an inhibitor of CYP3A4. Thus, interactions between TPV/r and drugs that are both metabolized by CYP3A4 and transported by P-glycoprotein are hardly predictable. Substance Interactions Comments NRTIs ABC [2,12] ABC ? 40 % Avoid combination, clinical significance of this interaction is not firmed yet. AZT [1,2,4,12] AZT ? 35 % (Cmax 46-61 % ?) [4] ddI [1,2,4,12] TPV: Cmax 32 % ?, Cmin 34 % ? [4] ddI 2 h before or after taking of TPV/r. TDF [1,2,4] TPV/r 500/100 or 750/200 BID + TDF 300 QD [4]: TDF (depending on dose): 11 % ? and 17 % ?, respectively (Cmax 23-38 % ?) Avoid combination, clinical significance of this interaction is not firmed yet. NNRTIs EFV [2,4,12] EFV ? 1-31 % [4] TPV ? (Cmax ?, Cmin ?) Limited data. No dose adjustment as yet. NVP [5] NVP ? 3-24 % Limited data. No dose adjustment as yet. PIs APV [6] TPV/r 500/200 + APV 600 BID: APV ? 44 % (Cmin 56 %? Cmax 39 % ?) Avoid combination. ATV [13] ATV 300 QD + TPV/r 500/100 BID: ATV ? 68 % (Cmin 81 % ?) Cmin TPV 75 % Avoid combination. IDV [2] Insufficient data Avoid combination. LPV/r [6] TPV 500 + LPV/r 400/100 BID: LPV ? 55 % (Cmin 52-70 % ? Cmax 47 % ?) Avoid combination. NFV [2] No data Avoid combination. SQV [2,6] TPV/r 500/200 + SQV 1000 BID: SQV ? 76 % (Cmin 81 % ?, Cmax 70 % ?) Avoid combination. Antiarrhythmics Amiodarone, flecainide, propafenone [2] Theoretically: antiarrhythmics ?, potential for severe, life-threatening arrhythmia Avoid combination. Antibiotics Clarithromycin [7] Clarithromycin: Cmin 68 % ?, active metabolite: 95 % ? TPV ? 66 % (Cmax 40 % ?) Caution with H. influenza infections, because here, the active metabolite is mainly effective. Antidepressants Desipramine [2] SSRIs: fluoxetine, paroxetine, sertraline [2] St. John's Wort Theoretically: desipramine ? Fluoxetine ?, paroxetine ?, sertraline ? Theoretically: TPV ? Close monitoring and, if necessary, dose reduction. SSRIs possess a high therapeutic range, but however, possibly dose adjustment. Avoid combination. Antihistamines Astemizole, terfenadine [2] Potential for severe, life-threatening cardiac arrhythmia Avoid combination. Antihypertensives Calcium channel blockers (ccb) Diltiazem, felodipine verapamil [2] Difficult to predict as ccbs are both substrates of CYP3A4 and P-glycoprotein;TPV/r inhibit CYP 3A4 and induce P-glycoprotein. Caution. Close monitoring. Antifungal drugs Fluconazole [8] Itraconazole [2] Ketoconazole [2] Voriconazole [2] TPV/r 500/200 BID + fluconazole 100 QD: TPV ? 56 % (Cmin ? 104 %) Theoretically: itraconazole ? Theoretically: ketoconazole ? Theoretically: voriconazole ?? Fluconazole dose of 200 mg should not be exceeded. Caution: dose > 200 mg are not recommended. Interactions with voriconazole hardly predictable. Antituberculosis drugs Rifabutin [10] Rifampicin [1] TPV/r 500/200 BID + rifabutin QD (single dose): rifabutin ? 3-fold, active metabolite 20-fold, TPV: Cmin 16 % ? No data. Theoretically: TPV ? TPV/r + rifabutin: 150 mg 3x/week. In occurrence of side-effects, possibly further dose reduction. Avoid combination. Ergotamines Theoretically: ergotamines ?. Possibly life-threatening ergotisms. Avoid combination. Theoretical alternative: triptans. Gastritis-/ Ulcer healing drugs Antacids [2,11] PPIs, H2-blockers TPV/r (single dose) + Maalox®: TPV ¯ 25-29 % No data Antacids: 2h before or after taking of TPV/r. Caution in combination of TPV/r and PPIs or H2-blockers. Hypnotics Benzodiazepines, (e.g.midazolam, triazolam) [2] Prolonged sedation Avoid combination. Alternative: lorazepam, oxazepam, temazepam. Possibly dose adjustment. Hypoglycaemia Glimepiride, glipizide, pioglitazone, repaglinide, rosiglitazone, tolbutamide [2] No data. Theoretically: level fluctuations as TPV as well as these substances are possibly metabolized by CYP2C8, CYP2C9 and CYP3A4. Closed monitoring for glucose levels. Avoid combination: pioglitazone weak inducer of CYP3A4. Alternative: rosiglitazone. Immunosuppessants Cyclosporine, sirolimus, tacrolimus No data. Theoretically: level fluctuations as interactions with CYP-3A4 and P-glycoprotein are possible. TDM.. Lipid-lowering drugs Atorvastatin [2,9] Lovastatin, simvastatin [2] TPV/r 500/200 BID + atorvastatin 10 QD: TPV ? 8 %, atorvastatin ? 936 % Myopathy, rhabdomyolysis risk ? Avoid combination or monitoring, start with the lowest possible dose. Avoid combination. Theoretical alternative: pravastatin, fluvastatin. Neuroleptics Pimozide, sertindole [2] Potential for severe, life-threatening cardiac arrhythmia. Avoid combination. Oral contraceptives Ethinyl estradiol [2] Ethinyl estradiol ? 50 % Use additional contraceptive method. PDE5 inhibitors Sildenafil, tadalafil, vardenafil [2] Theoretically: sildenafil ?, tadalafil ?, vardenafil ? Caution. Low initial dose. Sildenafil: 25 mg every 48h. Tadalafil: 10 mg every 72h. Vardenafil: 2.5 mg every 72h. Substitution Methadone [2] Methadone ? 50 % Monitor for withdrawal symptoms. Perhaps dose adjustment of methadone. Others [2] Disulfiram Metronidazole Theophylline Marcumar® No data. Theoretically: TPV capsules contain alcohol and can cause reactions similar to Disulfiram. Theophylline ? Not predictable. TDM of theophylline, possibly dose adjustment. Check for INR levels. References 1. Tseng A., General Hospital, Toronto, 2004, www.tthhivclinic.com. 2. Producy Information Aptivus®, Firma Boehringer Ingelheim. 3. Clinical Pharmacology, Gold Standard Multimedia, 2004, http://www.gsm.com. 4. Roszko PJ, Curry K, Brazina B, et al. Standard doses of efavirenz, zidovudine, tenofovir, and didanosine may be given with tipranavir/ritonavir. Abstract 865, 2nd IAS 2003, Paris. 5. Sabo J, MacGregor T, Lamson M, et al. Pharmacokinetics of tipranavir and nevirapine. Abstract 249, 10th Annual Canadian Conference on HIV/AIDS Research 2004, Toronto. 6. Leith J, Walmsley S, Katlama C, et al. Pharmacokinetics and safety of tipranavir/ritonavir alone or in combination with saquinavir, amprenavir, or lopinavir: interim analysis of BI1182.51. Abstract 34, 5th Int Worksh Clin Pharmacol HIV Ther 2004, Rome. 7. van Heeswijk RP, Sabo J, MacGregor TR, et al. The effect of tipranavir/ritonavir 500/200 mg BID on the pharmacokinetics of clarithromycin in healthy volunteers. Abstract A-457, 44th ICAAC 2004, Washington. 8. van Heeswijk RP, Sabo J, MacGregor TR, et al. The effect of tipranavir/ritonavir 500/200 mg BID on the pharmacokinetics of fluconazole in healthy volunteers. Abstract 20, 5th Int Worksh Clin Pharmacol HIV Ther 2004, Rome. 9. van Heeswijk RP, Sabo J, Cooper C, et al. The pharmacokinetic interactions between tipranavir/ritonavir 500/200 mg BID and atorvastatin, antacid, and CYP3A4 in healthy adult volunteers. Abstract 5.2, 5th Int Worksh Clin Pharmacol HIV Ther 2004, Rome. 10. van Heeswijk RP, Sabo J, MacGregor TR, et al. The pharmacokinetic interaction between single-dose rifabutin and steady-state tipranavir/ritonavir 500/200 mg BID in healthy volunteers. Abstract A-456, 44th ICAAC 2004, Washington. 11. Leen C. Pharmacokinetics of indinavir when co-administered with tipranavir/ritonavir. Abstract P299, 7th Int Congr Drug Ther HIV Inf 2004, Glasgow. 12. Goebel FD, Sabo JP, MacGregor TR et al. Pharmacokinetic Drug Interaction Screen of Three Doses of Tipranavir/Ritonavir (TPV/r) in HIV-Infected Patients on Stable Highly Active Antiretroviral Therapy (HAART), HIV DART. 2002, Naples. 13. Sabo JP, Elgadi M, Wruck J et al. The pharmacokinetic interaction between atazanavir/ritonavir and steady-state tipranavir/ritonavir in healthy volunteers. Abstract 41, 7th Int Worksh Clin Pharmacol HIV Ther 2005, Lissabon.

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