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Drug interactions with antiretrovirals

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Abstract

The recent development of new antiretroviral drugs, along with the evolution in clinical practice guidelines that include the recommendation of the use of three- to four-drug combination regimens for achieving optimal suppression of viral replication, has focused clinicians on the relevance of drug-drug interactions in the chronic care of HIV-infected individuals. However, the routine clinical management of drug interactions is complicated by our expanding knowledge of the physiologic mechanisms underlying pharmacokinetic interactions, particularly as they relate to drug transport and tissue distribution (eg, P-glycoprotein) and biotransformation (hepatic cytochrome p450 monooxygenase induction and inhibition). This review provides an updated summary of key drug interactions that have been reported since its initial publication.

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References and Recommended Reading

  1. Ambudkar SV, Dey S, Hrycyna CA, et al.: Biochemical, cellular, and pharmacological aspects of the multidrug transporter. Ann Rev Pharmacol Toxicol 1999, 39:361–398. A comprehensive review of the pharmacologic aspects of P-gp and its contribution to the cause and understanding of drug-drug interactions.

    Article  CAS  Google Scholar 

  2. Wacher VJ, Silverman JA, Zhang Y, et al.: Role of P-glycoprotein and cytochrome P450 3A in limiting oral absorption of peptides and peptidomimetics. J Pharm Sci 1998, 87:1322–1330. A summary of data describing P-gp inhibitors, cyclosporine, saquinavir, and a new cysteine PI (ie, K02) and their impact on the oral absorption of peptides and peptidomimetics.

    Article  PubMed  CAS  Google Scholar 

  3. Kim RB, Fromm MF, Wandel C, et al.: The drug transporter P-glycoprotein limits oral absorption and brain entry of protease inhibitors. J Clin Invest 1998, 101:289–294.

    Article  PubMed  CAS  Google Scholar 

  4. de MaatMM, Ekhart GC, Huitema AD, et al.: Drug interactions between antiretroviral drugs and comedicated agents. Clin Pharmacokinet 2003, 42:223–282. A comprehensive review of pharmacokinetics of antiretroviral agents and the pharmacokinetic and pharmacodynamic mechanisms of drug interactions with other coadministered medications.

    Article  PubMed  Google Scholar 

  5. Berger DS: Viread, Epivir and Ziagen combination: failure in naive patients with a once-daily regimen. Posit Aware 2003, 14:51–52.

    PubMed  Google Scholar 

  6. Feinberg J: Meeting notes from the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). Suboptimal response to once-daily abacavir + 3TC + tenofovir. AIDS Clin Care 2003, 15:94.

    Google Scholar 

  7. Kearney BP, Isaacson E, Sayre J, et al.: Didanosine and tenofovir DF drug-drug interaction: assessment of didanosine dose reduction [abstract]. Paper presented at the 10th Conference on Retroviruses and Opportunistic Infections. Boston, MA; February 10–14, 2003.

  8. Kaul S, Bassi K, Damle B, et al.: Pharmacokinetic evaluation of the combination of atazanavir (ATV), enteric coated didanosine (ddI-EC), and tenofovir disoproxil fumarate (TDF) for a once-daily antiretroviral regimen [abstract]. Paper presented at the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago, IL; September 14–17, 2003.

  9. Hsu A, Isaacson J, Brun S, et al.: Pharmacokinetic-pharmacodynamic analysis of lopinavir-ritonavir in combination with efavirenz and two nucleoside reverse transcriptase inhibitors in extensively pretreated human immunodeficiency virus-infected patients. Antimicrob Agents Chemother 2003, 47:350–359.

    Article  PubMed  CAS  Google Scholar 

  10. Hsu A, Granneman GR, Cao G, et al.: Pharmacokinetic interaction between ritonavir and indinavir in healthy volunteers. Antimicrob Agent Chemother 1998, 42:2784–2791.

    CAS  Google Scholar 

  11. Sham HL, Kempf DJ, Molla A, et al.: ABT-378, a highly potent inhibitor of the human immunodeficiency virus protease. Antimicrob Agent Chemother 1998, 42:3218–3224.

    CAS  Google Scholar 

  12. Sadler BM, Piliero PJ, Preston SL, et al.: Pharmacokinetics and safety of amprenavir and ritonavir following multipledose, coadministration to healthy volunteers. AIDS 2001, 15:1009–1018.

    Article  PubMed  CAS  Google Scholar 

  13. Basso S, Solas C, Quinson AM, et al.: Pharmacokinetic interaction between lopinavir/r and amprenavir in salvage therapy. J Acquir Immune Defic Syndr 2002, 31:115–117.

    PubMed  Google Scholar 

  14. Kashuba AD, Tierney C, Downey GF, et al.: Combining GW433908 with lopinavir/ritonavir in HIV-1 infected adults results in substantial reductions in amprenavir and lopinavir concentrations: pharmacokinetic results from adult ACTG protocol A5143 [abstract]. Paper presented at the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago, IL; September 14–17, 2003.

  15. Bertz RJ, Foit C, Ashbrenner E, et al.: Assessment of the steadystate pharmacokinetic interaction of lopinavir/ritonavir with either indinavir or saquinavir in healthy subjects. Paper presented at the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago, IL; September 14–17, 2003.

  16. Havlir DV, Riddler S, Squires K, et al.: Co-administration of indinavir and nelfinavir in human immunodeficiency virus type 1-infected adults: safety, pharmacokinetics, and antiretroviral activity. Antimicrob Agents Chemother 2002, 46:3877–3882.

    Article  PubMed  CAS  Google Scholar 

  17. DiCenzo R, Forrest A, Fischl MA, et al.: Pharmacokinetics of indinavir and nelfinavir in treatment-naïve, HIV-infected subjects. Antimicrob Agent Chemother 2004, in press.

  18. Haas DW, Zala C, Schrader S, et al.: Therapy with atazanavir plus saquinavir in patients failing highly active antiretroviral therapy: a randomized comparative pilot trial. AIDS 2003, 17:1339–1349.

    Article  PubMed  CAS  Google Scholar 

  19. Pfister M, Labbe L, Hammer SM, et al.: Population pharmacokinetics and pharmacodynamics of efavirenz, nelfinavir, and indinavir. Adult AIDS Clinical Trial Group Study 398. Antimicrob Agent Chemother 2003, 47:130–137.

    Article  CAS  Google Scholar 

  20. Piscitelli S, Bechtel C, Sadler B, et al.: The addition of a second protease inhibitor eliminates amprenavir-efavirenz drug interactions and increases plasma amprenavir concentrations [abstract]. Paper presented at the 7th Conference on Retroviruses and Opportunistic Infections. San Francisco, CA; January 31–February 3, 2000.

  21. Morse GD, Rosenkranz S, Para MF, et al.: 3-way pharmacokinetic interaction among amprenavir, efavirenz, and a second protease inhibitor [abstract]. Paper presented at the 11th Conference on Retroviruses and Opportunistic Infections. San Francisco, CA; February 8–11, 2004.

  22. Ribera E, Pou L, Lopez RM, et al.: Pharmacokinetic interaction between nevirapine and rifampicin in HIV-infected patients with tuberculosis. J Acquir Immune Defic Syndr 2001, 28:450–453.

    PubMed  CAS  Google Scholar 

  23. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. http://www.AIDSinfo.nih.gov. Accessed November 10, 2003.

  24. Reyataz (atazanavir) package insert. Princeton, NJ: Bristol-Myers Squibb Company; 2003.

  25. Perry CM, Noble S: Didanosine: an updated review of its use in HIV infection. Drugs 1999, 58:1099–1135.

    Article  PubMed  CAS  Google Scholar 

  26. Vfend (voriconazole) package insert. New York, NY: Pfizer Inc.; 2003.

  27. Rainey PM, Friedland G, McCance-Katz EF, et al.: Interaction of methadone with didanosine and stavudine. J Acquir Immune Defic Syndr 2000, 24:241–248.

    PubMed  CAS  Google Scholar 

  28. Clarke SM, Mulcahy FM, Tija J, et al.: Pharmacokinetic interactions of nevirapine and methadone and guidelines for use of nevirapine to treat injection drug users. Clin Infect Dis 2001, 33:1595–1597.

    Article  PubMed  CAS  Google Scholar 

  29. Clarke SM, Mulcahy FM, Tija J, et al.: The pharmacokinetics of methadone in HIV-positive patients receiving the non-nucleoside reverse transcriptase inhibitor efavirenz. Br J Clin Pharmacol 2001, 51:213–217.

    Article  PubMed  CAS  Google Scholar 

  30. Cantilena L, McCrea J, Blazes D, et al.: Lack of a pharmacokinetic interaction between indinavir and methadone. Am Soc Clin Pharmacol Ther 1999, 65:135.

    Article  Google Scholar 

  31. Gerber JG, Rosenkranz S, Segal Y, et al.: Effect of ritonavir/ saquinavir on stereoselective pharmacokinetics of methadone: results of AIDS Clinical Trials Group (ACTG) 401. J Acquir Immune Defic Syndr 2001, 27:153–160.

    PubMed  CAS  Google Scholar 

  32. McCance-Katz EF, Rainey PM, Friedland G, et al.: The protease inhibitor lopinavir-ritonavir may produce opiate withdrawal in methadone-maintained patients. Clin Infect Dis 2003, 37:476–482.

    Article  PubMed  CAS  Google Scholar 

  33. Clarke S, Mulcahy F, Bergin C, et al.: The pharmacokinetic interaction between methadone and nelfinavir. AIDS 2000, 14:S95.

    Google Scholar 

  34. Hsyu PH, Lillibridge JH, Miroldo L, et al.: Pharmacokinetic (PK) and pharmacodynamic (PD) interactions between nelfinavir and methadone [abstract]. Paper presented at the 7th Conference on Retroviruses and Opportunisitc Infections. San Francisco, CA; January 30–February 4, 2000.

  35. Smith PF, Booker BM, Difrancesco R, et al.: Effect of methadone or LAAM on the pharmacokinetics of nelfinavir and M8 [abstract]. Paper presented at the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago, IL; December 16–19, 2001.

  36. 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, 26:257–260.

    PubMed  CAS  Google Scholar 

  37. Lim ML, Min SS, Eron JJ, et al.: A two-way drug interaction between lopinavir/ritonavir and phenytoin [abstract]. Paper presented at the 10th Conference on Retroviruses and Opportunistic Infections. Boston, MA; February 10–14, 2003.

  38. Fichtenbaum CJ, Gerber JG, Rosenkranz SL, et al.: Pharmacokinetic interactions between protease inhibitors and statins in HIV seronegative volunteers: ACTG Study A5047. AIDS 2002, 16:569–577.

    Article  PubMed  CAS  Google Scholar 

  39. Gerber JG, Rosenkranz S, Fichtenbaum CJ, et al.: The effect of efavirenz (EFV) and nelfinavir (NFV) on the pharmacokinetics (PK) of pravastatin (P) [abstract]. Paper presented at the 2nd IAS Conference on HIV Pathogenesis and Treatment. Paris, France; July 13–16, 2003.

  40. Mildvan D, Yarrish R, Marshak A, et al.: Pharmacokinetic interaction between nevirapine and ethinyl estradiol/norethindrone when administered concurrently to HIV-infected women. J Acquir Immune Defic Syndr 2002, 29:471–477.

    PubMed  CAS  Google Scholar 

  41. Orme ML, Back DJ: Factors affecting the enterohepatic circulation of oral contraceptive steroids. Am J Obstet Gynecol 1990, 163:2146–2152.

    PubMed  CAS  Google Scholar 

  42. Viagra (sildenafil) package insert. New York, NY: Pfizer, Inc.; 2002.

  43. Cialis (tadalafil) package insert. Indianapolis, IN: Eli Lilly and Company; 2003.

  44. Greenblatt DJ, von Moltke LL, Daily JP, et al.: Extensive impairment of triazolam and alprazolam clearance by short-term low-dose ritonavir: the clinical dilemma of concurrent inhibition and induction. J Clin Psychopharmacol 1999, 19:293–296.

    Article  PubMed  CAS  Google Scholar 

  45. Olkkola KT, Palkama VJ, Neuvonen PJ: Ritonavir’s role in reducing fentanyl clearance and prolonging its half-life. Anesthesiology 1999, 91:681–685.

    Article  PubMed  CAS  Google Scholar 

  46. Risa KJ, Nepon L, Justis JC, et al.: Alternative therapy use in HIV-infected patients receiving highly active antiretroviral therapy. Int J STD AIDS 2002, 13:706–713.

    Article  PubMed  Google Scholar 

  47. Piscitelli SC, Burstein AH, Welden N, et al.: The effect of garlic supplements on the pharmacokinetics of saquinavir. Clin Infect Dis 2002, 34:234–238.

    Article  PubMed  Google Scholar 

  48. Piscitelli SC, Burstein AH, Chaitt D, et al.: Indinavir concentrations and St. John’s wort. Lancet 2000, 355:547–548.

    Article  PubMed  CAS  Google Scholar 

  49. Markowitz J, Donovan JL, DeVane CL, et al.: Effect of St. John’s wort on drug metabolism by induction of cytochrome P450 3A4 enzyme. JAMA 2003, 290:1500–1504.

    Article  PubMed  CAS  Google Scholar 

  50. Mitsunaga Y, Takanaga H, Matsuo H, et al.: Effect of bioflavonoids on vincristine transport across blood-brain barrier. Eur J Pharmacol 2000, 395:193–201.

    Article  PubMed  CAS  Google Scholar 

  51. DiCenzo R, Shelton M, Jordan K, et al.: Co-administration of milk thistle and indinavir in healthy subjects. Pharmacotherapy 2003, 23:866–870.

    Article  PubMed  CAS  Google Scholar 

  52. Piscitelli SC, Formentini E, Burstein AH, et al.: Effect of milk thistle on the pharmacokinetics of indinavir in healthy volunteers. Pharmacotherapy 2002, 22:551–556.

    Article  PubMed  CAS  Google Scholar 

  53. Haas D, Ribaudo H, Kim R, et al.: A common CYP2B6 variant is associated with efavirenz pharmacokinetics and central nervous system side effects: AACTG Study NWCS214. Paper presented at the 11th Conference on Retroviruses and Opportunistic Infections. San Francisco, CA; February 8–11, 2004.

  54. O’Mara E, Randall D, Passarell J, et al.: Pharmacodynamic assessment of atazanavir exposure, uridine diphosphateglucuronosyl transferase (UGT) 1A1 genotype and safety in healthy subjects. Paper presented at the 42nd Interscience Congress on Antimicrobial Agents and Chemotherapy. San Diego, CA; September 27–30, 2002.

  55. Fellay J, Marzolini C, Meaden ER, et al.: Response to antiretroviral treatment in HIV-1-infected individuals with allelic variants of the multidrug resistance transporter 1: a pharmacogenetics study. Lancet 2002, 359:30–36

    Article  PubMed  CAS  Google Scholar 

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Catanzaro, L.M., Slish, J.C., DiCenzo, R. et al. Drug interactions with antiretrovirals. Curr HIV/AIDS Rep 1, 89–96 (2004). https://doi.org/10.1007/s11904-004-0013-z

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