Summary
Antiviral drug interactions are a particular problem among immuno-compromised patients because these patients are often receiving multiple different drugs, i.e. antiretroviral drugs and drugs effective against herpesvirus. The combination of zidovudine and other antiretroviral drugs with different adverse event profiles, such as didanosine, zalcitabine and lamivudine, appears to be well tolerated and no relevant pharmacokinetic interactions have been detected. The adverse effects of didanosine and zalcitabine (i.e. peripheral neuropathy and pancreatitis) should be taken into account when administering these drugs with other drugs with the same tolerability profile.
Coadministration of zidovudine and ganciclovir should be avoided because of the high rate of haematological intolerance. In contrast, zidovudine and foscarnet have synergistic effect and no pharmacokinetic interaction has been detected. No major change in zidovudine pharmacokinetics was seen when the drug was combined with aciclovir, famciclovir or interferons. However, concomitant use of zidovudine and ribavirin is not advised.
Although no pharmacokinetic interaction was documented when didanosine was first administered with intravenous ganciclovir, recent studies have shown that concentrations of didanosine are increased by 50% or more when coadministered with intravenous or oral ganciclovir. The mechanism of this interaction has not been elucidated. Lack of pharmacokinetic interaction was demonstrated between foscarnet and didanosine or ganciclovir.
Clinical trials have shown that zidovudine can be administered safely with paracetamol (acetaminophen), nonsteroidal anti-inflammatory drugs, oxazepam or codeine. Inhibition of zidovudine glucuronidation has been demonstrated with fluconazole, atovaquone, valproic acid (valproate sodium), methadone, probenecid and inosine pranobex; however, the clinical consequences of this have not been fully investigated.
No interaction has been demonstrated with didanosine per se but care should be taken of interaction with the high pH buffer included in the tablet formulation. Drugs that need an acidic pH for absorption (ketoconazole, itraconazole but not fluconazole, dapsone, pyrimethamine) or those that can be chelated by the ions of the buffer (quinolones and tetracyclines) should be administered 2 hours before or 6 hours after didanosine.
Very few interaction studies have been undertaken with other antiviral drugs. Coadministration of zalcitabine with the antacid ‘Maalox’ results in a reduction of its absorption. Dapsone does not influence the disposition of zalcitabine. Cotrimoxazole (trimethoprim-sulfamethoxazole) causes an increase in lamivudine concentrations by 43%. Saquinavir, delavirdine and atevirdine appeared to be metabolised by cytochrome P450 and interactions with enzyme inducers or inhibitors could be anticipated.
Some studies showed that interferons can reduce drug metabolism but only a few studies have evaluated the pathways involved.
Further studies are required to better understand the clinical consequences of drug interactions with antiviral drugs. Drug-drug interactions should be considered in addition to individual drug clinical benefits and safety profiles.
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References
Fogelman I, Lim L, Bassett R, et al. Prevalence and patterns of use of concomitant medications among participants in three multicenter human immunodeficiency virus type I clinical trials. J Acquir Immune Defic Syndr 1994; 7: 1057–63
Darbyshire J. Perspectives in drug therapy of HIV infection. Drugs 1995; 49: 1–3
Coleman R. Overview of antiretroviral therapy. Pharmacotherapy 1994; 14 Suppl.: 3S–8S
Wills RJ. Clinical pharmacokinetics of interferons. Clin Pharmacokinet 1990; 19: 390–9
Morse GD, Shelton MJ, O’Donnell AM. Comparative pharmacokinetics of antiviral nucleoside analogues. Clin Pharmacokinet 1993; 24: 101–23
Campoli-Richards DM, Sorkin E, Heel RC. Inosine Pranobex: a preliminary review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy. Drugs 1986; 32: 383–424
Aoki FY, Sitar DS. Clinical pharmacokinetics of amantadine hydrochloride. Clin Pharmacokinet 1988; 14: 35–51
Mayers DL. Zidovudine and other antiretroviral agents including drug interactions and toxicities. Curr Opin Infect Dis 1993; 6: 210–7
Morris DJ. Adverse effects and drug interactions of clinical importance with antiviral drugs. Drug Saf 1994; 10: 281–91
Quinn DI, Day RO. Drug interactions of clinical importance: an updated guide. Drug Saf 1995; 12: 393–452
Wilde MI, Langtry HD. Zidovudine: an update of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy. Drugs 1993; 46: 515–78
Dudley MN. Clinical pharmacokinetics of nucleoside antiretroviral agents. J Infect Dis 1995; 7 Suppl.: S99–S112
Shelton MJ, O’Donnell AM, Morse GD. Didanosine. Ann Pharmacother 1992; 26: 660–700
Faulds D, Brogden RN. Didanosine: a review of its antiviral activity, pharmacokinetic properties and therapeutic potential in human immunodeficiency virus infection. Drugs 1992; 44: 94–116
Devinemi D, Gallo JM. Zalcitabine: clinical pharmacokinetics and efficacy. Clin Pharmacokinet 1995; 28: 351–60
Whittington R, Brogden RN. Zalcitabine, a review of its pharmacology and clinical potential in acquired immunodefiency syndrome (AIDS). Drugs 1992; 44: 656–83
Placidi L, Cretton E, Placidi M, et al. Reduction of 3′-azido-3′-deoxythymidine to 3′-amino-3′-deoxythymidine in human liver microsomes and its relationship to cytochrome P 450. Clin Pharmacol Ther 1993; 54: 168–76
Borin MT, Cox SR, Chambers JH, et al. Effect of rifampicin on delavirdine pharmacokinetics in HIV-positive patients [abstract no. A50]. 34th Interscience Conference on Antimicrobial Agents and Chemotherapy: 1994 Oct 4–7: Orlando
Borin MT, Cox SR, Driver MR, et al. Effect of rifabutin on delavirdine pharmacokinetics in HIV-positive patients [abstract no. A48]. 34th Interscience Conference on Antimicrobial Agents and Chemotherapy: 1994 Oct 4–7: Orlando
Farrar G, Mitchell AM, Hooper H, et al. Prediction of potential drug interactions of saquinavir (Ro 31 -8959) from in vitro data [abstract]. Br J Clin Pharmacol 1994; 38: 162P
Wagstaff AJ, Faulds D, Goa KL. Aciclovir: a reappraisal of its antiviral activity, pharmacokinetic properties and therapeutic efficacy. Drugs 1994; 47: 153–205
Markham A, Faulds D. Ganciclovir: an update of its therapeutic use in cytomegalovirus infection. Drugs 1994; 48: 455–84
Wagstaff AJ, Bryson HM. Foscarnet: a reappraisal of its antiviral activity, pharmacokinetic properties and therapeutic use in immunocompromised patients with viral infections. Drugs 1994; 48: 199–226
Daniels S. Schentag JJ. Drug interaction studies and safety of famciclovir in healthy volunteers: a review. Antiviral Chem Chemother 1993; 4 Suppl. 1: 57–64
Fowles SE, Pierce DM, Prince WT, et al. The tolerance to and pharmacokinetics of penciclovir, a novel antiherpes agent, administered by intravenous infusion to healthy volunteers. Eur J Clin Pharmacol 1992; 43: 513–6
Boike SC, Pue M, Audet PR, et al. Pharmacokinetics of famciclovir in subjects with chronic hepatic disease. J Clin Pharmacol 1994; 34: 1199–207
Weiler S, Blum R, Doucette M, et al. Pharmacokinetics of the acyclovir pro-drug valaciclovir after escalating single and multiple-dose administration to normal volunteers. Clin Pharmacol Ther 1993; 54: 595–605
Sim SM, Back DJ, Breckenridge AM. The effect of various drugs on the glucuronidation of zidovudine (azidothymidine, AZT) by human liver microsomes. Br J Clin Pharmacol 1991; 32: 17–21
Rajaonarison JF, Lacarelle B, Catalin J, et al. 3′-azido-3′-deoxythymidine drug interactions. Drug Metab Dispos 1992; 20: 578–84
Barry M, Howe L, Ormesher S, et al. Pharmacokinetics of zidovudine and dideoxyinosine alone and in combination in patients with the acquired immunodeficiency syndrome. Br J Clin Pharmacol 1994; 37: 421–6
Sahai J, Gallicano K, Seguin I, et al. Interaction between zidovudine and didanosine [abstract no. A60]. 34th Interscience Conference on Antimicrobial Agents and Chemotherapy: 1994 Oct 4–7: Orlando
Collier AC, Coombs RW, Fischl MA, et al. Combination therapy with zidovudine and didanosine compared with zidovudine alone in HIV-1 infection. Ann Intern Med 1993; 119: 786–93
Mueller BU, Pizzo PA, Farley M, et al. Pharmacokinetic evaluation of the combination of zidovudine and didanosine in children with human immunodeficiency virus infection. J Pediatr 1994; 125: 142–6
Qian M, Swagler AR, Mehta M, et al. Pharmacokinetic evaluation of drug interactions with anti-human immunotrophic virus (HIV) drugs. III. 2′, 3′-Dideoxycytidine (ddC) and zidovudine in monkeys. Pharm Res 1992; 9: 224–7
Meng TC, Fischl MA, Boota AM, et al. Combination therapy with zidovudine and dideoxycytidine in patients with advanced human immunodeficiency virus infection. Ann Intern Med 1992; 116: 13–20
Fischl MA, Stanley K, Collier AC, and the NIAID AIDS Clinical Trials Group. Combination and monotherapy with zidovudine and zalcitabine in patients with advanced HIV disease. Ann Intern Med 1995; 122: 24–32
Veal GJ, Wild MJ, Barry MG, et al. Effects of dideoxyinosine and dideoxycytidine on the intracellular phosphorylation of zidovudine in human mononuclear cells. Br J Clin Pharmacol 1994; 38: 323–8
Rana KZ, Horton CM, Yuen GJ, et al. Effect of lamivudine on zidovudine pharmacokinetics in asymptomatic HIV infected individuals [abstract no. A26]. 34th Interscience Conference on Antimicrobial Agents and Chemotherapy: 1994 Oct 4–7; Orlando
Horton CM, Yuen G, Mikolich DM, et al. Pharmacokinetics of oral lamivudine administered alone and with oral zidovudine in asymptomatic patients with human immuno-deficiency virus infection. Clin Pharmacol Ther 1994; 55: 198
Collier AC, Coombs RW, Timpone J, et al. Comparative study of Ro 31-8959 and zidovudine (ZDV) vs ZDV and zalcitabine (ddC) vs Ro 31-8959, ZDV and ddC [abstract no. 058B]. 10th International Conference on AIDS: 1994 Aug 7–12; Yokohama
Vella S. Update on a proteinase inhibitor. AIDS 1994; 8 (Suppl.): S25–S29
Johnson VA. Combination therapy: more effective control of HIV type 1? AIDS Res Hum Retroviruses 1994; 10: 907–12
LeLacheur SF, and Simon GL, et al. Exacerbation of dideoxycytidine induced neuropathy with dideoxyinosine. J Acquir Immune Defic Syndr 1991; 4: 538–9
Scifert RD, Stewart MB, Sramek JJ, et al. Pharmacokinetics of co-administered didanosine and stavudine in HIV-seropositive male patients. Br J Clin Pharmacol 1994; 38: 405–10
Morse GD, Fischl MA, Cox SR, et al. Effect of didanosine on the single dose pharmacokinetics of delavirdine in HIV-positive patients [abstract no. A52]. 34th Interscience Conference on Antimicrobial Agents and Chemotherapy: 1994 Oct 4–7; Orlando
Shelton MJ, Morse GD, Borin MT, et al. Didanosine reduces atevirdine absorption [abstract no. A56]. 34th Interscience Conference on Antimicrobial Agents and Chemotherapy: 1994 Oct 4–7; Orlando
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
Burger DM, Meenhorst PL, Koks CHW, et al. Drugs interactions with zidovudine. AIDS 1993; 7: 445–60
Burger DM, Meenhorst PL, Ten Napel CHH, et al. Pharmacokinetic variability of zidovudine in HIV-infected individuals: subgroup analysis and drug interactions. AIDS 1994; 8: 1683–9
Gaines K, Wong R, Jung D, et al. Pharmacokinetic interactions with oral ganciclovir: zidovudine, didanosine, probenecid [abstract no. 4B]. Xth International Conference on AIDS: 1994 Aug 7–12; Yokohama
Gowland PL, Kuster H, Nadai V, et al. Ganciclovir reduces the amount of intracellular zidovudine phosphorylation products [abstract no. 2218]. IXth International Conference on AIDS: 1993 Jun 6–11; Berlin
Jacobson MA, Van Der Horst C, Causey DM, et al. In vivo additive antiretroviral effect of combined zidovudine and foscarnet therapy for human immunodeficiency virus infection (ACTG protocol 053). J Infect Dis 1991; 63: 1219–22
Aweeka FT, Gambertogkio JG, Van Der Horst C, et al. Pharmacokinetics of concomitantly administered foscarnet and zidovudine for treatment of human immunodeficiency virus infection (AIDS clinical trials group protocol 053). Anti-microb Agents Chemother 1992; 36: 1773–8
Hollander H, Lifson AR, Maha M, et al. Phase I study of low-dose zidovudine and acyclovir in asymptomatic human immunodeficiency virus-seropositive individuals. Am J Med 1989; 87: 628–32
Stein DS, Graham NMH, Park LP, et al. The effect of the interaction of acyclovir with zidovudine on progression to AIDS and survival. Ann Intern Med 1994; 121: 100–8
Rousseau F, Scott S, Pratt S, et al. Safe coadministration of famciclovir and zidovudine [abstract no. A64]. 34th Interscience Conference on Antimicrobial Agents and Chemotherapy: 1994 Oct 4–7; Orlando
Nokta M, Loh JP, Douidar SM, et al. Metabolic interaction of recombinant interferon-β and zidovudine in AIDS patients. J Interferon Res 1991; 11: 159–64
Jacobson MA, Owen W, Campbell J, et al. Tolerability of combined ganciclovir and didanosine for the treatment of cytomegalovirus disease associated with AIDS. Clin Infect Dis 1993; 16: S69–S73
Hartman NR, Yarchoan R, Pluda JM, et al. Pharmacokinetics of 2′, 3′-dideoxyinosine in patients with severe human immunodeficiency infection: II. The effects of different oral formulations and the presence of other medications. Clin Pharmacol Ther 1991; 50: 278–85
Frascino RJ, Anderson RD, Gaines Griffy K, et al. Two multiple dose crossover studies of IV ganciclovir (GCV) and didanosine (ddI) in HIV infected persons [abstract no. A27]. 35th Interscience Conference on Antimicrobial Agents and Chemotherapy: 1995 Sep 17–20; San Francisco
Trapnell CB, Cimoch P, Gaines K, et al. Altered didanosine pharmacokinetics with concomitant oral ganciclovir. Clin Pharmacol Ther 1994; 55: 193
Aweeka FT, Mathur V, Dorsey R, et al. Pharmacokinetics of concomitant foscarnet and didanosine in patients with HIV disease. Clin Pharmacol Ther 1995; 57: 143
Aweeka FT, Gambertoglio JG, Van Der Host C, et al. Pharmacokinetics of foscarnet during alternating vs concomitant ganciclovir maintenance therapy for CMV retinitis. Clin Pharmacol Ther 1993; 53: 278
Gillum JG, Israel DS, Polk RE. Pharmacokinetic drug interactions with antimicrobial agents. Clin Pharmacokinet 1993; 25: 450–82
Narang PK, Sale M. Population based assessment of rifabutin effect on zidovudine disposition in AIDS patients. Clin Pharmacol Ther 1993; 53: 219
Sahai J, Gallicano K, Pakuts A, et al. Effect of fluconazole on zidovudine pharmacokinetics in patients infected with human immunodeficiency virus. J Infect Dis 1994; 169: 1103–7
Lee BL, Tauber MG, Sadler B, et al. Atovaquone inhibits the glucuronidation and increases the serum concentrations of zidovudine. Clin Pharmacol Ther 1996; 59: 14–21
Jatlow P, McCance EF, Rainey PM, et al. Methadone increases zidovudine exposure in HIV-infected injection drug users (ACTG 262) [abstract no. 405]. 3rd Conference on retro-viruses and opportunistic infections: 1996 Jun 28–Feb 1; Washington
De Simone C, Tzantzoglou S, Vullo V, et al. Inosine pranobex and zidovudine metabolism. Lancet 1989; II: 977
Knupp CA, Brater C, Relue J, et al. Pharmacokinetics of didanosine and ketoconazole after coadministration to patients seropositive for the human immunodeficiency virus. J Clin Pharmacol 1993; 33: 912–7
Moreno F, Hardin TC, Rinaldi MG, et al. Itraconazole-didanos-ine excipient interaction. JAMA 1993; 269: 1508
Hardin TC, Sharkey-Mathis PK, Rinaldi MG, et al. Evaluation of the pharmacokinetic interaction between Itraconazole and didanosine in HIV-infected subjects [abstract no. A29]. 35th Interscience Conference on Antimicrobial Agents and Chemotherapy: 1995 Sep 17–20; San Francisco
Blum RA, D’Andrea DT, Florentino BM, et al. Increased gastric pH and the bioavailability of fluconazole and ketoconazole. Ann Intern Med 1991; 114: 755–7
Sadovski DC. Drug interactions with antiacids: mechanisms and clinical significance. Drug Saf 1994; 11: 395–407
Opravil M, Joos B, Liithy R. Levels of dopsone and pyrimethamine in serum during once-weekly dosing for prophylaxis of pneumocystis carinii pneumonia and toxoplasmic encephalitis. Antimicrob Agents Chemother 1994; 38: 1197–9
Metroka CE, Me Mechan MF, Andrada R, et al. Failure of prophylaxis with dapsone in patients taking dideoxyinosine. N Engl J Med 1991; 325: 737
Horowitz HW, Jorde UP, Wormaser GP. Drug interactions in use of dapsone for Pneumocystis carinii prophylaxis. Lancet 1992; 339: 747
Huengsberg M, Castelino S, Sherrard J, et al. Does drug interaction cause failure of PCP prophylaxis with dapsone? Lancet 1993; 341: 48
Sahai J, Garber G, Gallicano K, et al. Effect of didanosine (ddI) on dapsone (DAP) absorption in HIV-infected patients [abstract no. A32]. 35th Interscience Conference on Antimicrobial Agents and Chemotherapy: 1995 Sep 17–20; San Francisco
Sahai J, Gallicano K, Oliveras L, et al. Cations in the didanosine tablet reduce ciprofloxacin bioavailability. Clin Pharmacol Ther 1993; 53: 292–7
Lomaestro BM, Bailie GR. Absorption interactions with fluoroquinolones. Drug Saf 1995; 12: 314–33
Knupp CA, Graziano FM, Dixon RM, et al. Pharmacokinetic interaction study of didanosine and ranitidine in patients seropositive for human immunodeficiency virus. Antimicrob Agents Chemother 1992; 36: 2075–9
Gallicano K, Sahai H, Zaror-Behrens G, et al. Effect of antacids in didanosine tablet on bioavailability of isoniazid. Antimicrob Agents Chemother 1994; 38: 849–97
Sahai J, Foss N, Li R, et al. Rifabutin and didanosine interaction in AIDS patients. Clin Pharmacol Ther 1993; 53: 197
Knupp CA, Milbrath RL and Barbhaiya RH. Effect of metoclo-pramide and loperamide on the pharmacokinetics of didanosine in HIV seropositive asymptomatic male and female patients. Eur J Clin Pharmacol 1993; 45(5): 409–13
Brivet FG, Naveau SH, Lemaigre GF, et al. Pancreatic lesions in HIV-infected patients. Baillieres Clin Endocrinol Metab 1994; 8: 589–877
Massarella JW, Holazo AA, Koss-Twardy S, et al. The effects of cimetidine and Maalox® on the pharmacokinetics of zalcitabine in HIV-positive patients. Pharm Res 1994; 11: 415
Lee BL, Tauber MG, Chambers HF, et al. Zalcitabine (ddC) and dapsone (DAP) pharmacokinetic interaction in HIV-infected patients. Clin Pharmacol Ther 1995; 57: 186
Lee BL, Tauber MG, Chambers HF, et al. The effect of trimethoprim (TMP) on the pharmacokinetics (PK) of zalcitabine (ddC) in HIV infected patients [abstract no. A28]. 35th Interscience Conference on Antimicrobial Agents and Chemotherapy: 1995 Sep 17–20; San Francisco
Murray M. P450 enzymes; inhibition mechanisms, genetic regulation and effects of liver disease. Clin Pharmacokinet 1992; 23: 132–46
Moore K, Raasch R, Yuen G, et al. Pharmacokinetics of lamivudine administered alone and with oral trimethoprim plus sulfamethoxazole in patients with human immunodeficiency virus infection. Clin Pharmacol Ther 1995; 57: 143
Kempf D, Marsh K, Denissen J, et al. Coadministration with ritonavir enhances the plasma levels of HIV protease inhibitors by inhibition of cytochrome P450 [abstract no. 143]. 3rd Conference on retroviruses and opportunistic infections: 1996 Jan 28–Feb 1; Washington
Israel BC, Blouin RA, McIntyre W, et al. Effect of interferon-α monotherapy on hepatic drug metabolism in cancer patients. Br J Clin Pharmacol 1993; 36: 229–35
Schiiller J, Czejka MJ, Banka S, et al. Continuous infusion of fluorouracil combined with interferon alfa 2B. Enhanced toxicity due to pharmacokinetic interaction. Ann Oncol 1994; 5: 48
Kellokumpu-Lehtinen P, Iisalo E, Nordman E. Hepatotoxicity of paracetamol in combination with interferon and vinblastine. Lancet 1989; I: 1143
Lee BL, Safrin S. Drug interactions and toxicities in patients with AIDS. Curr Opin Infect Dis 1992; 5: 231–40
Lee BL, Wong D, Benowitz NL, et al. Altered patterns of drug metabolism in patients with acquired immunodeficiency syndrome. Clin Pharmacol Ther 1993; 53: 529–35
Stretcher BN. Pharmacokinetic optimisation of antiretroviral therapy in patients with HIV infection. Clin Pharmacokinet 1995; 29: 46–65
Foulds G, Trapnell CB, Willavize SA, et al. Effect of concomitant azithromycin on the pharmacokinetics of zidovudine [abstract no. 2143]. 19th International Congress on Chemotherapy: 1995 Jul 16–21; Montreal
Cooper D. Antiretroviral Therapy 96. Third conference on retroviruses and opportunistic infections: 1996 Jan 28–Feb 1; Washington
Lange J. Combination antiretroviral therapy. Back to the future. Drugs 1995; 49: 32–7
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Taburet, AM., Singlas, E. Drug Interactions with Antiviral Drugs. Clin-Pharmacokinet 30, 385–401 (1996). https://doi.org/10.2165/00003088-199630050-00005
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DOI: https://doi.org/10.2165/00003088-199630050-00005