Abstract
All the currently available protease inhibitors are metabolised by the cyto-chrome P450 (CYP) enzyme system. All are inhibitors of CYP3A4, ranging from weak inhibition for saquinavir to very potent inhibition for ritonavir. Thus, they are predicted to have numerous drug interactions, although few such interactions have actually been documented either in pharmacokinetic studies or in clinical reports. This article reviews the published literature with an emphasis on the magnitude of interactions and on practical recommendations for management.
Many of the drugs commonly taken by patients with HIV have a strong potential to interact with the protease inhibitors. In particular, the non-nucleoside reverse transcriptase inhibitors are also metabolised by C YP and have been shown to interact with protease inhibitors. Delaviridine is an inhibitor of CYP3A4, but nevirapine and efavirenz are inducers of CYP3A4. The protease inhibitors also interact with each other, and these interactions are being explored for their potential therapeutic benefits. Other commonly used drugs are also known to affect protease inhibitor metabolism, including inhibitors such as clarithromycin and the azole antifungals and inducers such as the rifamycins. Drugs that are known to be significantly affected by the protease inhibitors include ethinylestradiol and terfenadine; many other drugs have lesser or potential interactions.
Although little specific data is available on the drug interactions of protease inhibitors, this lack of data should not be interpreted as a lack of interaction. Retrospective chart reviews have demonstrated that potentially severe drug interactions are frequently overlooked. Much more clinical data is needed, but pharmacists and physicians must always be vigilant for drug interactions, both those that are already documented and those that are predictable from pharmaco-kinetic profiles, in patients receiving protease inhibitors.
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References
Barry M, Gibbons S, Back D, et al. Protease inhibitors in patients with HIV disease. Clin Pharmacokinet 1997; 32: 194–209
Lewis JS, Terriff CM, Coulston DR, et al. Protease inhibitors: a therapeutic breakthrough for the treatment of patients with human immunodeficiency virus. Clin Ther 1997; 19: 187–214
Eagling VA, Back DJ, Barry MG. Differential inhibition of cyto-chrome P450 isoforms by the protease inhibitors, ritonavir, saquinavir, and indinavir. Br J Clin Pharmacol 1997; 44: 190–4
von Moltke LL, Greenblatt DJ, Grassi JM, et al. Protease inhibitors as inhibitors of human cytochromes P450: high risk associated with ritonavir. J Clin Pharmacol 1998; 38: 106–11
Deeks SG, Smith M, Holodniy M, et al. HIV-1 protease inhibitors: a review for clinicians. JAMA 1997; 277: 145–53
Heylen R, Miller R. Adverse effects and drug interactions of medications commonly used in the treatment of adult HIV positive patients. Genitourin Med 1997; 73(Pt 2): 5–11
Kakuda TN, Struble KA, Piscitelli SC. Protease inhibitors for the treatment of human immunodeficiency virus infection. Am J Health Syst Pharm 1998; 55: 233–54
Moyle G, Gazzard B. Current knowledge and future prospects for the use of HIV protease inhibitors. Drugs 1996; 51:701–12
McDonald CK, Kuritzkes DR. Human immunodeficiency virus type 1 protease inhibitors. Arch Intern Med 1997; 157: 951–9
Oliphant CM, Bonnema SM. New advances in the pharmacological treatment of human immunodeficiency virus (HIV) infection: focus on protease inhibitors. J Pharm Practice 1997; 10: 20–51
Flexner C. HIV-protease inhibitors. N Engl J Med 1998; 338: 1281–92
Tseng AL, Foisy MM. Management of drug interactions in patients with HIV. Ann Pharmacother 1997; 31: 1040–58
Piscitelli SC, Flexner C, Minor JR, et al. Drug interactions in patients infected with human immunodeficiency virus. Clin Infect Dis 1996; 23: 685–93
Hsu A, Granneman GR, Bertz RJ. Ritonavir: clinical pharma-cokinetics and interactions with other anti-HIV agents. Clin Pharmacokinet 1998; 35: 275–91
Fortovase® package insert. New Jersey: Roche Laboratories Inc., 1997
Viracept® package insert. California: Agouron Pharmaceuticals Inc., 1997
Dieleman J, Gyssens IC, van der Ende MEM, et al. Urologic complaints in relation to indinavir plasma levels in HIV-infected patients [abstract no. 12372]. 12th World AIDS Conference: 1998 Jun 28-July 3; Geneva
Crixivan® package insert. Pennsylvania: Merck and Company Inc., 1997
Iribarne C, Berthou F, Carlhant D, et al. Inhibition of methadone and buprenorphine N-dealkylations by three HIV-1 protease inhibitors. Drug Metab Dispos 1998; 26: 257–60
Centers for Disease Control and Prevention. Prevention and treatment of tuberculosis among patients with human immunodeficiency virus: principles of therapy and revised recommendations. MMWR Morb Mortal Wkly Rep 1998; 47: 1–58
Invirase® package insert. New Jersey: Roche Laboratories Inc., 1998
Norvir® package insert. Illinois: Abbott Laboratories, 1997
Vanhove GF, Schapiro JM, Winters MA, et al. Patient compliance and drug failure in protease inhibitor monotherapy [letter]. JAMA 1996; 276: 1955–6
Acosta EP, Henry K, Weller D, et al. Indinavir pharmacokinet-ics and relationships between exposure and antiviral effect [abstract no. A-15]. 37th Interscience Conference on Antimicrobial Agents and Chemotherapy: 1997 Sept 28-Oct 1; Toronto (ON)
Burger DM, Koopmans PP, Brinkman K, et al. Therapeutic drug monitoring of the HIV-protease inhibitor indinavir [abstract no. A-19]. 37th Interscience Conference on Antimicrobial Agents and Chemotherapy: 1997 Sept 28-Oct 1; Toronto (ON)
Harris M, Durakovic C, Rae S, et al. Virologic response to indinavir/nevirapine/3TC correlates with indinavir trough concentrations [abstract no. I-173]. 37th Interscience Conference on Antimicrobial Agents and Chemotherapy: 1997 Sept 28-Oct 1; Toronto (ON)
Hoetelmans RMW, Reijers MHE, Weberling GF, et al. The rate of decline of HIV-1 RNA in plasma correlates with nelfinavir concentrations in plasma [abstract no. 42259]. 12th World AIDS Conference: 1998 Jun 28-July 3; Geneva
Hoetelmans RMW, Heeswijk RPG, Meenhorst PL, et al. Plasma concentrations of saquinavir (SQV) determine HIV-1 RNA response over a 48-week period [abstract no. 42261]. 12th World AIDS Conference: 1998 Jun 28-July 3; Geneva
Burger DM, Hoetelmans RMW, Mulder JW, et al. Low plasma levels of indinavir (IDV) are highly predictive of virological treatment failure in patients using IDV-containing triple therapy [abstract no. 42275]. 12th World AIDS Conference: 1998 Jun 28-July 3; Geneva
Buss N. Saquinavir soft gel capsule (Fortovase®): pharmacoki-netics and drug interactions [abstract]. 5th Conference on Retroviruses and Opportunistic Infections; 1998 Feb 1-5; Chicago (IL)
Maserati R, Villani P, Cocchi L, et al. Co-trimoxazole administered for Pneumocystis carinii pneumonia prophylaxis does not interfere with saquinavir pharmacokinetics [letter]. AIDS 1998; 12: 815–6
Brinkman K, Huysmans F, Burger DM. Pharmacokinetic interaction between saquinavir and cyclosporine [letter]. Ann Intern Med 1998; 129: 914–5
Cox SR, Ferry JJ, Batts DH, et al. Delaviridine (D) and marketed protease inhibitors (Pis): pharmacokinetic (PK) interaction studies in healthy volunteers [abstract no. 372]. 4th Conference on Retroviruses and Opportunistic Infections: 1996 Jan 28-Feb 1; Washington (DC)
Data on file. DuPont Research Laboratories, 1998
McCrea J, Buss N, Stone J, et al. Indinavir-saquinavir single dose pharmacokinetic study [abstract no. 608]. 4th Conference on Retroviruses and Opportunistic Infections: 1996 Jan 28-Feb 1; Washington (DC)
Merry C, Mulcahy F, Barry M, et al. Saquinavir interaction with midazolam: pharmacokinetic considerations when prescribing protease inhibitors for patients with HIV disease [letter]. AIDS 1997; 11: 268–9
Kravcik S, Sahai J, Kerr B, et al. Nelfinavir mesylate (NFV) increases saquinavir-soft gel capsule (SQV-SGC) exposure in HIV+ patients [abstract]. 4th Conference on Retroviruses and Opportunistic Infections: 1996 Jan 28-Feb 1; Washington (DC)
Merry C, Barry MG, Mulcahy FM, et al. Saquinavir pharmacokinetics alone and in combination with nelfinavir in HIV-infected patients. AIDS 1997; 11: F117–20
Gallicano K, Sahai J, Kravcik S, et al. Nelfinavir (NFV) increases plasma exposure of saquinavir in hard gel capsule (SQV-HGC) in HIV+ patients [abstract no. 353]. 5th Conference on Retroviruses and Opportunistic Infections: 1998 Feb 1-5; Chicago (IL)
Sahai J, Cameron W, Salgo M, et al. Drug interaction study between saquinavir (SQV) and nevirapine (NVP) [abstract no. 614]. 4th Conference on Retroviruses and Opportunistic Infections: 1996 Jan 28-Feb 1; Washington (DC)
Sahai J, Stewart F, Swick L, et al. Rifabutin (RBT) reduces saquinavir (SAQ) plasma levels in HIV-infected patients [abstract no. A27]. 36th Interscience Conference on Antimicrobial Agents and Chemotherapy: 1996 Sept 15-18; New Orleans
Hsu A, Granneman GR, Cao G, et al. Pharmacokinetic interactions between two human immunodeficiency virus protease inhibitors, ritonavir and saquinavir. Clin Pharmacol Ther 1998; 63: 453–64
Merry C, Barry MG, Mulcahy F, et al. Ritonavir pharmacokinetics alone and in combination with saquinavir in HIV-infected patients. AIDS 1998; 12: 325–7
Darlington MR. Hypoprothrombinemia during concomitant therapy with warfarin and saquinavir [letter]. Ann Phar-macother 1997; 31: 647
Rescriptor® package insert. Michigan: Pharmacia & Upjohn Company, 1997
Viramune® package insert. Ohio: Roxane Laboratories Inc., 1996
Frye R, Bertz R, Granneman GR, et al. Effect of ritonavir on the pharmacokinetics and pharmacodynamics of alprazolam [abstract A59]. 37th Interscience Conference on Antimicrobial Agents and Chemotherapy: 1997 Sept 28-Oct 1; Toronto (ON)
Ouellet D, Hsu A, Granneman GR, et al. Pharmacokinetic interaction between ritonavir and clarithromycin. Clin Pharmacol Ther 1998; 64: 355–62
Morse GD, Shelton MJ, Hewitt RG, et al. Ritonavir (RIT) pharmacokinetics (PK) during combination therapy with delaviridine (DLV) [abstract no. 343]. 5th Conference on Retroviruses and Opportunistic Infections: 1998 Feb 1-5; Chicago (IL)
Shelton MJ, Hewitt RG, Adams JM, et al. Delaviridine (DLV) mesylate pharmacokinetics (PK) during combination therapy with ritonavir (RIT) [abstract A63]. 37th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1997 Sept 28-Oct 1; Toronto (ON)
Bertz RJ, Cao G, Cavanaugh JH, et al. Effect of ritonavir on the pharmacokinetics of desipramine [abstract no. Mo.B.1201]. XI International Conference on AIDS: 1996 July 7-12; Vancouver
Cato A, Qian J, Carothers L, et al. Pharmacokinetic interaction between ritonavir and didanosine when administered concurrently to HIV-infected patients. J Acquir Immune Defic Synd 1998; 18: 466–72
Fiske W, Benedek IH, Joseph JL, et al. Pharmacokinetics of efavirenz (EFV) and ritonavir (RIT) after multiple oral doses in healthy volunteers [abstract no. 42269]. 12th World AIDS Conference: 1998 Jun 28-July 3; Geneva
Caballero-Granado FJ, Viciana P, Cordero E, et al. Ergotism related to concurrent administration of ergotamine tartrate and ritonavir in an AIDS patient [letter]. Antimicrob Agents Chemother 1997; 41: 1207
Ouellet D, Hsu A, Qian J, et al. Effect of ritonavir on the phar-macokinetics of ethinyl oestradiol in healthy female volunteers. Br J Clin Pharmacol 1998; 46: 111–6
Cato A, Cao G, Hsu A, et al. Evaluation of the effect of fluconazole on the pharmacokinetics of ritonavir. Drug Metab Dispos 1997; 25: 1104–6
Ouellet D, Hsu A, Qian J, et al. Effect of fluvoxamine on pharmacokinetics of ritonavir. Antimicrob Agents Chemother 1998; 42: 107–12
Hsu A, Granneman GR, Cao G, et al. Pharmacokinetic interaction between ritonavir and indinavir in healthy volunteers. Antimicrob Agents Chemother 1998; 42: 2784–91
Bertz, Wong C, Carothers L, et al. Evaluation of the pharmacokinetics of multiple dose ritonavir and ketoconazole in combination [abstract no. PIII-94]. Clin Pharmacol Ther 1998; 63: 230
Tseng A, Fletcher D. Interaction between ritonavir and levothyroxine [abstract no. 60571]. 12th World AIDS Conference; 1998 Jun 28-July 3; Geneva
Hsu A, Granneman GR, Carothers L, et al. Ritonavir does not increase methadone exposure in healthy volunteers [abstract no. 342]. 5th Conference on Retroviruses and Opportunistic Infections: 1998 Feb 1-5; Chicago (IL)
Kerr B, Lee C, Yuen G, et al. Overview of in. vitro and in vivo drug interaction studies of nelfinavir mesylate (NFV), a new HIV-1 protease inhibitor [abstract no. 373]. 4th Conference on Retroviruses and Opportunistic Infections; 1996 Jan 28-Feb 1; Washington (DC)
Cato A, Cavanaugh J, Shi H, et al. The effect of multiple doses of ritonavir on the pharmacokinetics of rifabutin. Clin Pharmacol Ther 1998; 63: 414–21
Sun E, Heath-Chiozzi M, Cameron DW, et al. Concurrent ritonavir and rifabutin increases risk of rifabutin-associated adverse events [abstract no. Mo.B. 171]. XI International Conference on AIDS; 1996 July 7-12; Vancouver (BC)
Bertz RJ, Cao G, Cavanaugh JH, et al. Effect of ritonavir on the pharmacokinetics of trimethoprim/sulfamethoxazole [abstract no. Mo.B.1197]. XI International Conference on AIDS; 1996 July 7-12; Vancouver (BC)
Hsu A, Granneman GR, Witt G, et al. Assessment of multiple doses of ritonavir on the pharmacokinetics of theophylline [abstract no. Mo.B.1200]. XI International Conference on AIDS; 1996 July 7-12; Vancouver (BC)
Gatti G, Alessandrtini A, Camera M, et al. Influence of indinavir and ritonavir on warfarin anticoagulation activity [letter]. AIDS 1998; 12: 825–6
Cato A, Qian J, Hsu A, et al. Multidose pharmacokinetics of ritonavir and zidovudine in human immunodeficiency virus-infected patients. Antimicrob Agents Chemother 1998; 42: 1788–93
Emmanuel A, Gillotin C, Farinotti R, et al. Atovaquone suspension and indinavir have minimal pharmacokinetic interactions [abstract no. 12384]. 12th World AIDS Conference; 1998 Jun 28-July 3; Geneva
Fiske WD, Mayers D, Wagner K, et al. Pharmacokinetics of DMP 266 and indinavir multiple oral doses in HIV-l infected individuals [abstract no. 568]. 4th Conference on Retroviruses and Opportunistic Infections: 1996 Jan 28-Feb 1; Washington (DC)
Ferry JJ, Herman BD, Carel BJ, et al. Pharmacokinetic drug-drug interaction study of delaviridine and indinavir in healthy volunteers. J Acquir Immune Defic Syndr 1998; 18: 252–9
DeWit S, Debier M, DeSmet M, et al. Effect of fluconazole on indinavir pharmacokinetics in human immunodeficiency virus-infected patients. Antimicrob Agents Chemother 1998; 42: 223–7
Rana KZ, Okereke CS, Melbourne KM, et al. Effect of GMCSF on the pharmacokinetics of indinavir in HIV-infected patients. 38th Interscience Conference on Antimicrobial Agents and Chemotherapy: 1998 Sept 27-27; San Diego (CA)
Piscitelli SC, Vogel S, Figg WD, et al. Alteration in indinavir clearance during interleukin-2 infusions in patients infected with the human immunodeficiency virus. Pharmacother 1998; 18: 1212–6
Squires K, Riddler S, Havlir D, et al. Co-administration of indinavir (IDV) 1000mg with escalating nelfinavir (NFV) does in a twice daily regimen: preliminary safety, pharmacokinetic (PK) and anti-viral activity [abstract no. 464]. 36th Annual Meeting of the Infectious Diseases Society of America. 1998 Nov 11-14, Denver (CO)
Murphy R, Gagnier P, Lamson M, et al. Effect of nevirapine (NVP) on pharmacokinetics (PK) of indinavir (IDV) and ritonavir (RTV) in HIV-l patients [abstract no. 374]. 4th Conference on Retroviruses and Opportunistic Infections: 1996 Jan 28-Feb 1; Washington (DC)
Cox SR, Schneck DW, Herman BD, et al. Delaviridine (DLV) and nelfinavir (NFV): a pharmacokinetic (PK) drug-drug interaction study in healthy adult volunteers [abstract no. 345]. 5th Conference on Retroviruses and Opportunistic Infections; 1998 Feb 1-5; Chicago (IL)
Fiske WD, Benedek IH, White SJ, et al. Pharmacokinetic interaction between efavirenz (EFV) and nelfinavir mesylate (NFV) in healthy volunteers [abstract no. 349]. 5th Conference on Retroviruses and Opportunistic Infections; 1998 Feb 1-5; Chicago (IL)
Merry C, Barry MG, Mulcahy FM, et al. The pharmacokinetics of combination therapy with nelfinavir plus nevirapine. AIDS 1998; 12: 1163–7
Skowron G, Leoung G, Dusek A, et al. Stavudine (d4T), nelfinavir (NFV) and nevirapine (NVP): preliminary safety, activity and pharmacokinetic (PK) interactions [abstract no. 350]. 5th Conference on Retroviruses and Opportunistic Infections: 1998 Feb 1-5; Chicago (IL)
Skowron G, Leoung G, Kerr B, et al. Lack of pharmacokinetic interaction between nelfinavir and nevirapine [editorial]. AIDS 1998; 12: 1243–4
Carpenter CCJ, Fischl MA, Hammer SM, et al. Antiretroviral therapy for HIV infection in 1997: updated recommendations of the International AIDS Society— USAPanel. JAMA 1997; 277: 1962–9
Centers for Disease Control and Prevention. Report of the NIH panel to define principles of therapy of HIV infection and guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. MMWR Morb Mortal Wkly Rep 1998; 47(RR-5): 1–82
Merrill D, Manion DJ, Chou TC, et al. Antagonism between human immunodeficiency virus type 1 protease inhibitors indinavir and saquinavir in. vitro. J Infect Dis 1997; 176: 265–8
Hsu A, Granneman R, Heath-Chiozzi M, et al. Indinavir can be taken with regular meals when administered with ritonavir [abstract no. 22361]. 12th World AIDS Conference: 1998 Jun 28-July 3; Geneva
Havlir DV, Riddler S, Squires K, et al. Co-administration of indinavir (IDV) and nelfinavir (NFV) in a twice daily regimen: preliminary safety, pharmacokinetic and anti-viral activity results [abstract no. 393]. 5th Conference on Retroviruses and Opportunistic Infections: 1998 Feb 1-5; Chicago (IL)
Sadler BM, Eron J, Wakeford J, et al. Pharmacokinetics of 141W94 and indinavir (IDV) after single-dose coadministra-tion in HIV-positive volunteers [abstract no. A56]. 4th Conference on Retroviruses and Opportunistic Infections: 1996 Jan 28-Feb 1; Washington (DC)
Kempf DJ, Marsh KC, Kumar G, et al. Pharmacokinetic enhancement of inhibitors of the human immunodeficiency virus protease by coadministration with ritonavir. Antimicrob Agents Chemother 1997; 41: 654–60
Sadler B, Gillotin C, Chittick GE, et al. Pharmacokinetic drug interactions with amprenavir [abstract no. 12389]. 12th World AIDS Conference: 1998 Jun 28-July 3; Geneva
Polk RE, Israel DS, Pastor A, et al. Effects of clarithromycin (CLR) on the pharmacokinetics of amprenavir (APV). 38th Interscience Conference on Antimicrobial Agents and Chemotherapy: 1998 Sept 24-28; San Diego (CA)
Kumar GN, Jayanti V, Johnson MK, et al. Increased bioavaila-bility and plasma levels of the HIV-1 protease inhibitor ABT-378 in rats due to inhibition of the in vivo metabolism by ritonavir [abstract no. 207]. 4th Conference on Retroviruses and Opportunistic Infections: 1996 Jan 28-Feb 1; Washington (DC)
Van Cleef GF, Fisher EJ, Polk RE. Drug interaction potential with inhibitors of HIV protease. Pharmacother 1997; 17: 774–8
Preston SL, Postelnick M, Purdy BD, et al. Drug interactions in HIV-positive patients initiated on protease inhibitor therapy. AIDS 1998; 12: 228–30
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Malaty, L.I., Kuper, J.J. Drug Interactions of HIV Protease Inhibitors. Drug-Safety 20, 147–169 (1999). https://doi.org/10.2165/00002018-199920020-00005
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DOI: https://doi.org/10.2165/00002018-199920020-00005