Clinical Pharmacokinetics

, Volume 35, Issue 4, pp 275–291 | Cite as

Ritonavir

Clinical Pharmacokinetics and Interactions with Other Anti-HIV Agents
  • Ann Hsu
  • G. Richard Granneman
  • Richard J. Bertz
Review Articles Drug Disposition

Abstract

Ritonavir is 1 of the 4 potent synthetic HIV protease inhibitors, approved by the US Food and Drug Administration (FDA) between 1995 and 1997, that have revolutionised HIV therapy. The extent of oral absorption is high and is not affected by food. Within the clinical concentration range, ritonavir is approximately 98 to 99% bound to plasma proteins, including albumin and α1-acid glycoprotein. Cerebrospinal fluid (CSF) drug concentrations are low in relation to total plasma concentration. However, parallel decreases in the viral burden have been observed in the plasma, CSF and other tissues.

Ritonavir is primarily metabolised by cytochrome P450 (CYP) 3A isozymes and, to a lesser extent, by CYP2D6. Four major oxidative metabolites have been identified in humans, but are unlikely to contribute to the antiviral effect. About 34% and 3.5% of a 600mg dose is excreted as unchanged drug in the faeces and urine, respectively. The clinically relevant t½β is about 3 to 5 hours. Because of autoinduction, plasma concentrations generally reach steady state 2 weeks after the start of administration. The pharmacokinetics of ritonavir are relatively linear after multiple doses, with apparent oral clearance averaging 7 to 9 L/h.

In vitro, ritonavir is a potent inhibitor of CYP3A. In vivo, ritonavir significantly increases the AUC of drugs primarily eliminated by CYP3 A metabolism (e.g. clarithromycin, ketoconazole, rifabutin, and other HIV protease inhibitors, including indinavir, saquinavir and nelfinavir) with effects ranging from an increase of 77% to 20-fold in humans. It also inhibits CYP2D6-mediated metabolism, but to a significantly lesser extent (145% increase in desipramine AUC). Since ritonavir is also an inducer of several metabolising enzymes [CYP1A4, glucuronosyl transferase (GT), and possibly CYP2C9 and CYP2C19], the magnitude of drug interactions is difficult to predict, particularly for drugs that are metabolised by multiple enzymes or have low intrinsic clearance by CYP3 A. For example, the AUC of CYP3A substrate methadone was slightly decreased and alprazolam was unaffected. Ritonavir is minimally affected by other CYP3A inhibitors, including ketoconazole. Rifampicin (rifampin), a potent CYP3A inducer, decreased the AUC of ritonavir by only 35%.

The degree and duration of suppression of HIV replication is significantly correlated with the plasma concentrations. Thus, the large increase in the plasma concentrations of other protease inhibitors when coadministered with ritonavir forms the basis of rational dual protease inhibitor regimens, providing patients with 2 potent drugs at significantly reduced doses and less frequent dosage intervals. Combination treatment of ritonavir with saquinavir and indinavir results in potent ans sustained clinical activity. Other important factors with combination regimens include reduced interpatient variability for high clearance agents, and elimination of the food effect on the bioavailibility of indinavir.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Kempf DJ, Norbeck DW, Codacovi L, et al. Structure-based C2symmetric inhibitors of HIV protease. J Med Chem 1990; 33: 2687–9.PubMedCrossRefGoogle Scholar
  2. 2.
    Kohl NE, Emini EA, Schleif WA, et al. Active human immunodeficiency virus protease is required for viral infectivity. Proc Natl Acad Sci U S A 1988; 85: 4686–90.PubMedCrossRefGoogle Scholar
  3. 3.
    Carpenter CJ, Fischl MA, Hammer SM, et al. Antiretroviral therapy for HIV infection in 1997: updated recommendations of the International AIDS Society-USA panel. JAMA 1997; 277: 1962–9.PubMedCrossRefGoogle Scholar
  4. 4.
    Kempf DJ, Rode RA, Xu Y, et al. The duration of viral suppression during protease inhibitor therapy for HIV-1 infection is predicted by plasma HIV-1 RNA at the nadir. AIDS 1998; 12 (5):F9–F14.PubMedCrossRefGoogle Scholar
  5. 5.
    Montaner J, Demasi R, Hill A, et al. Validation of HIV-1 RNA and CD4 count as surrogate markers in the CAESAR trial [abstract 207]. Sixth European Conference on Clinical Aspects and Treatment of HIV-Infection; 1997 Oct 11–15; Hamburg, Germany.Google Scholar
  6. 6.
    Ruiz NM, Manion DJ, Labriola DF, et al. Demographic and laboratory predictors of virologic treatment failures in patients achieving viral load reductions to below quantifiable levels (BQL) by Amplicor assay receiving indinavir +/- DMP 266 (efavirenz) [abstract 908]. Sixth European Conference on Clinical Aspects and Treatment of HIV-Infection; 1997 Oct 11–15; Hamburg, Germany.Google Scholar
  7. 7.
    Ho DD, Neumann AU, Perelson AS, et al. Rapid turnover of plasma virions and CD-4 lymphocytes in HIV-1 infection. Nature 1995; 373: 123–6.PubMedCrossRefGoogle Scholar
  8. 8.
    Perelson AS, Neumann AU, Markowitz M, et al. HIV-1 dynamics in vivo: vision clearance rate, infected cell lifespan, and viral generations. Science 1995; 271: 1582–6.CrossRefGoogle Scholar
  9. 9.
    Mulder J, McKinney N, Christpherson C, et al. Rapid and simple PCR assay for quantitation of human immunodeficiency virus type 1 RNA in plasma: application to acute retroviral infection. J Clin Microbiol 1994; 32: 292–300.PubMedGoogle Scholar
  10. 10.
    Pachl C, Todd JA, Kern DG, et al. Rapid and precise quantification of HIV-1 RNA in plasma using a branched DNA signal amplification assay. J Acquir Immune Defic Syndr Hum Retrovirol 1995; 8: 446–54.PubMedCrossRefGoogle Scholar
  11. 11.
    CAESAR Coordinating Committee. Randomized trial of addition of lamivudine or lamivudine plus loviride to zidovudinecontaining regimens for patients with HIV-1 infection: the CAESAR trial. Lancet 1997; 349: 1413–21.CrossRefGoogle Scholar
  12. 12.
    Hammer SM, Katzenstein DA, Hughes MD, et al. A trial comparing nucleoside monotherapy with combination therapy in HIV-infected adults with CD4 cell counts from 200 to 500 per cubic millimeter. N Engl J Med 1996; 335: 1081–90.PubMedCrossRefGoogle Scholar
  13. 13.
    Delta Coordinating Committee. Delta: a randomized doubleblind trial comparing combinations of zidovudine plus didanosine or zalcitabine with zidovudine alone in HIV-infected individuals. Lancet 1996; 348: 283–91.CrossRefGoogle Scholar
  14. 14.
    Lalezari J, Haubrich R, Burger H, et al. Improved survival and decreased progression of HIV in patients treated with saquinavir (invirase, SQV) plus Hivid (zalcitabine, ddC) [abstract LB.B.6033]. XI International Conference on AIDS; 1996 Jul 7–12; Vancouver.Google Scholar
  15. 15.
    Cameron DW, Heath-Chiozzi M, Kravcik S, et al. Prolongation of life and prevention of AIDS complications in advanced HIV immunodeficiency with RTV, update [abstract Mo.B.411]. XI International Conference on AIDS; 1996 Jul 7–12; Vancouver.Google Scholar
  16. 16.
    Danner SA, Carr A, Leonard JM, et al. Safety, pharmacokinetics, and preliminary efficacy of RTV, an inhibitor of HIV-1 protease. N Engl J Med 1995; 333: 1528–33.PubMedCrossRefGoogle Scholar
  17. 17.
    Markowitz M, Saag M, Powderly W, et al. Apreliminary study of ritonavir, an inhibitor of HIV-1 protease, to treat HIV-1 infection. N Engl J Med 1995; 333: 1534–9.PubMedGoogle Scholar
  18. 18.
    Lalezari J, Haubrich R, Burger H, et al. Improved survival and decreased progression of HIV in patients treated with saquinavir (invirase, SQV) plus hivid (zalcitabine, ddC) [abstract LB.B.6033]. XI International Conference on AIDS; 1996 Jul 7–12; Vancouver.Google Scholar
  19. 19.
    Cameron DW, Japour A, Mellors J, et al. Antiretroviral safety and durability of ritonavir (RIT)-saquinavir (SQV) in protease inhibitor-naive patients in year two of follow-up [abstract 388]. 5th Conference on Retroviruses and Opportunistic Infections; 1998 Feb 1–5; Chicago.Google Scholar
  20. 20.
    Shapiro JM, Winters MA, Stewart F, et al. The effect of high dose saquinavir on viral load and CD4+ T-cell counts in HIV infected patients. Ann Intern Med 1996; 124 (12): 1039–50.Google Scholar
  21. 21.
    Acosta EP, Henry K, Weiler D, et al. Indinavir pharmacokinetics and relationships between exposures and antiviral effect [abstract A-15]. 37th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1997 Sep 28–Oct 1; Toronto.Google Scholar
  22. 22.
    Drusano GL, Sadler BM, Millard J, et al. Pharmacodynamics of 141W94 as determined by short term change in HIV RNA: Influence of viral isolate baseline EC50 [abstract A-16]. 37th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1997 Sep 28–Oct 1; Toronto.Google Scholar
  23. 23.
    Burger DM, Koopmans PP, Brinkman K, et al. Therapeutic drug monitoring of the HIV-Protease inhibitor Indinavir [abstract A-19]. 37th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1997 Sep 28–Oct 1; Toronto.Google Scholar
  24. 24.
    Kempf DL, Marsh KC, Kumar G, et al. Pharmacokinetic enhancement of inhibitors of the human immunodeficiency virus by coadministration with ritonavir. Antimicrob Agents Chemother 1997; 41 (3): 654–60.PubMedGoogle Scholar
  25. 25.
    Merry C, Barry MG, Mulcahy F, et al. Saquinavir pharmacokinetics alone and in combination with ritonavir in HIV-infected patients. AIDS 1997 Mar; 11 (4): F29–33.PubMedCrossRefGoogle Scholar
  26. 26.
    Hsu A, Granneman GR, Japour A, et al. Evaluation of potential ritonavir and indinavir combination BID regimens [abstract A-57]. 37th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1997 Sep 28–Oct 1; Toronto.Google Scholar
  27. 27.
    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. 4th Conference on Retroviruses and Opportunistic Infections; 1997 Jan 22–26; Washington, DC.Google Scholar
  28. 28.
    Crixivan™ package insert. Merck and Co., Inc., 1996.Google Scholar
  29. 29.
    Viracept® package insert. Agouron Pharmaceuticals, Inc., 1997.Google Scholar
  30. 30.
    Invirase™ package insert. Roche Laboratories, Inc.,1996.Google Scholar
  31. 31.
    Kempf DJ, Marsh KC, Denissen JF, et al. ABT-538 is a potent inhibitor of human immunodeficiency virus protease and has high oral bioavailability in humans. Proc Natl Acad Sci US A 1995; 92: 2484–8.CrossRefGoogle Scholar
  32. 32.
    Norvir™ package insert. Abbott Laboratories, 1998.Google Scholar
  33. 33.
    Fortovase™ package insert. Roche Laboratories, Inc. 1998.Google Scholar
  34. 34.
    Denissen JF, Grabowski BA, Johnson MK, et al. Metabolism and disposition of the HIV-1 protease inhibitor ritonavir (ABT-538) in rats, dogs, and humans. Drug Metab Dispos 1996; 25 (4): 489–501.Google Scholar
  35. 35.
    Kumar GN, Rodrigues AD, Buko AM, et al. Cytochrome P450- mediated metabolism of the HIV-1 protease inhibitor ritonavir (ABT-538) in human liver microsomes. J Pharmacol Exp Ther 1996; 277 (1): 423–31.PubMedGoogle Scholar
  36. 36.
    Hsu A, Granneman GR, Witt G, et al. Multiple-dose pharmacokinetics of ritonavir in human immunodeficiency virus-infected subjects. Antimicrob Agents Chemother 1997; 41 (5): 898–905.PubMedGoogle Scholar
  37. 37.
    Flexner C, Hsu A, Kerr B, et al. Steady-state pharmacokinetic interactions between ritonavir (RTV), nelfinavir (NFV), and the nelfinavir active metabolite M8 (AG1402). Submitted. 12th World Congress on AIDS; 1998 Jun 28–Jul 3; Geneva.Google Scholar
  38. 38.
    Ouellet D, Hsu A, Qian J, et al. Effect of ritonavir on the pharmacokinetics of ethinyl estradiol in healthy female volunteers. Br J Clin Pharmacol. 1998; 46 (2): 111–6.PubMedCrossRefGoogle Scholar
  39. 39.
    Hsu A, Granneman GR, Witt G, et al. Assessment of multiple doses of ritonavir on the pharmacokinetics of theophylline [abstract Mo.B. 1200]. XI International Conference on AIDS; 1996 Jul 7–12; Vancouver.Google Scholar
  40. 40.
    Cato III A, Qian J, Hsu A, et al. Pharmacokinetics of ritonavir and zidovudine in human immunodeficiency virus-infected patients. Antimircob Agents Chemother 1998; 42 (7): 1788–93.Google Scholar
  41. 41.
    Zhang MH, Pithavala YK, Lee CA, et al. Apparent genetic polymorphism in nelfinavir metabolism: evaluation of clinical relevance. 12th International Symposium on Microsomes and Drug Oxidation; 1998 Jul 20–24; Montpellier, France.Google Scholar
  42. 42.
    Kumar GN, Grabowski B, Lee R, et al. Hepatic drug-metabolizing activities in rats after 14 days of oral administration of the human immunodeficiency virus-type 1 protease inhibitor ritonavir (ABT-538). Drug Metab Dispos 1996; 24 (5): 615–7.PubMedGoogle Scholar
  43. 43.
    Woolley J, Studenberg S, Boehlert C, et al. Cytochrome P-450 isozyme induction, inhibition, and metabolism studies with the HIV protease inhibitor 141W94 [abstract A-60]. 37th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1997 Sep 28–Oct 1; Toronto.Google Scholar
  44. 44.
    Inaba T, Fischer N, Riddick DS, et al. HIV protease inhibitors, saquinavir, indinavir and ritonavir: inhibition of CYP3A4-mediated metabolism of testosterone and benzoxazino-rifamycin, KRM-1648, in human liver microsomes. Toxicol Lett 1997; 93: 215–9.PubMedCrossRefGoogle Scholar
  45. 45.
    Chiba M, Hensleigh M, Nishime JA, et al. Role of cytochrome P450 3A4 in human metabolism of MK-639, a potent human immunodeficiency virus protease inhibitor. Drug Metab Disp 1996; 24 (3): 307–14.Google Scholar
  46. 46.
    Wu EY, Sandoval TM, Lee CA, et al. In vitro metabolism studies with the HIV-1 protease inhibitor, viracept (AG-1343). ISSX proceedings, 10: 326. 7th North American ISSX Meeting; 1996 Oct 20–24; San Diego.Google Scholar
  47. 47.
    Livington DJ, Pazhanisamy S, Porter DJ, et al. Weak binding of VX-478 to human plasma proteins and implications for antihuman immunodeficiency virus therapy. J Infect Dis 1995; 172 (5): 1238–45.PubMedCrossRefGoogle Scholar
  48. 48.
    Polk RE, Israel DS, Patron R, et al. Pharmacokinetic (PK) interaction between 141W94 and rifabutin (RFB) and rifampin (RFP) after multiple-dose administration [abstract 340]. 5th Conference on Retroviruses and Opportunistic Infections; 1998 Feb 1–5; Chicago.Google Scholar
  49. 49.
    McDowell JA, Sadler BM, Millard J, et al. Evaluation of potential pharmacokinetic (PK) drug interaction between 141W94 and 1592U89 in HIV+ patients [abstract A-62]. 37th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1997 Sep 28–Oct 1; Toronto.Google Scholar
  50. 50.
    Adkin JC, Faulds D. Amprenavir. Drugs 1998; 55 (6): 837–42.CrossRefGoogle Scholar
  51. 51.
    Kumar GN, Dykstra J, Jayanti V, et al. Potent inhibition of the in vitro human liver microsomal metabolism of the HIV-1 protease inhibitor ABT-378 by ritonavir: potential for a positive durg interaction [abstract 211]. 4th Conference on Retroviruses and Opportunistic Infections; 1997 Jan 22–26; Washington, DC.Google Scholar
  52. 52.
    Lai R, Hsu A, Chen P, et al. Single dose pharmacokinetics of ABT-378 in combination with ritonavir [abstract I-194]. 37th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1997 Sep 28–Oct 1; Toronto.Google Scholar
  53. 53.
    Lai R, Hsu A, Granneman R, et al. Multiple dose safety, tolerability and pharmacokinetics of ABT-378 in combination with ritonavir [abstract 647]. 5th Conference on Retroviruses and Opportunistic Infections; 1998 Feb 1–5; Chicago.Google Scholar
  54. 54.
    Baldwin JR, Borin MT, Wang Y, et al. Effect of food and antacid on bioavailability of the protease inhibitor PNU-140690 in healthy volunteers [abstract 649]. 5th Conference on Retroviruses and Opportunistic Infections; 1998 Feb 1–5; Chicago.Google Scholar
  55. 55.
    Borin MT, Carlson GF, Wang Y, et al. Single-Dose safety, tolerance, and pharmacokinetics of PNU-140690, a new HIV protease inhibitor, in healthy volunteers [abstractl-195]. 37th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1997 Sep 28–Oct 1; Toronto.Google Scholar
  56. 56.
    Borin MT, Wang Y, Schneck DW, et al. Multiple-dose safety, tolerance, and pharmacokinetics of the protease inhibitor PNU-140690 in healthy volunteers [abstract 648]. 5th Conference on Retroviruses and Opportunistic Infections; 1998 Feb 1–5; Chicago.Google Scholar
  57. 57.
    Cato III A, Bertz RJ, Cao G, et al. Evaluation of the role of CYP3 A inhibition in food and formulation effects on ritonavir absorption. 7th North America ISSX Annual Meetings; 1996 Oct 20–24; San Diego.Google Scholar
  58. 58.
    Bertz RJ, Shi H, Cavanaugh JH, et al. Effect of three vehicles, Advera®, Ensure®, and chocolate milk, on the bioavailability of an oral liquid formulation of ritonavir [abstract A-5]. 36th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1996 Sep 15–18; New Orleans.Google Scholar
  59. 59.
    Yeh KC, Deutsch PJ, Haddix H, et al. Single-dose pharmacokinetics of indinavir and the effect of food. Antimicrob Agents Chemother 1998; 42 (2): 332–8.PubMedGoogle Scholar
  60. 60.
    Abbott Laboratories, 1996–1998 (Data on file).Google Scholar
  61. 61.
    Farthing C, Japour A, Cohen C, et al. Cerebrospinal fluid (CSF) and plasma HIV RNA suppression with ritonavir (RIT)-saquinavir (SQV) in protease inhibitor naive patients [abstract LB-3]. 37th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1997 Sep 28–Oct 1; Toronto.Google Scholar
  62. 62.
    Cavert W, Notermans DW, Staskus K, et al. Kinetics of response in lymphoid tissues to antiretroviral therapy of HIV-1 infection. Science 1997; 276 (1): 960–4.PubMedCrossRefGoogle Scholar
  63. 63.
    Shimada T, Yamazaki H, Mimura M, et al. Inter-individual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. J Pharmacol Exp Ther 1994; 270: 414–23.PubMedGoogle Scholar
  64. 64.
    Bertz RJ, Cao G, Cavanaugh JH, et al. Effect of ritonavir on the pharmacokinetics of desipramine [abstract Mo.B. 1201]. XI International Conference on AIDS; 1996 Jul 7–12; Vancouver.Google Scholar
  65. 65.
    Hsu A, Granneman RG. Kinetics of ABT-538, a protease inhibitor, in humans after single oral rising doses [abstract PPDM 8272]. Pharm Res 1994; 11: S400.Google Scholar
  66. 66.
    Hsu A, Granneman GR, Cao G-L, et al. Pharmacokinetic interactions between ritonavir and indinavir in healthy volunteers. Antimicrob Agents Chemother. In press.Google Scholar
  67. 67.
    Hicks C, Lehman L, Eron, et al. Safety and efficacy of ritonavir administered at two potentially maximum tolerated doses [abstract Mo.B. 415]. XI International Conference on AIDS; 1996 Jul 7–12; Vancouver.Google Scholar
  68. 68.
    Lai AA, Levy RH, Cutler RE. Time-course of interaction between carbamazepine and clonazepam in normal man. Clin Pharmacol Ther 1979; 24: 316–23.Google Scholar
  69. 69.
    Deeks SG, Smith M, Holodniy M, et al. HIV-1 protease inhibitors. Areview for clinicians. JAMA 1997; 277 (2): 145–53.PubMedCrossRefGoogle Scholar
  70. 70.
    Müller BU, Zuckerman J, Nelson RP, et al. A phase I/II study of protease inhibitor ritonavir in children with human immunodeficiency virus infection. J Pediatr 1998 Mar; 101 (3R1): 335–43.Google Scholar
  71. 71.
    Yogev R, Stanley K, Nachman SA, et al. Virologic efficacy of ZDV +3TC versus d4T + RTV versus ZDV + 3TC +RTV in stable antiretroviral experienced HIV-Infected children. 37th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1997 Sep 28–Oct 1; Toronto.Google Scholar
  72. 72.
    Hsu A, Cameron DW, Valdes J, et al. Ritonavir pharmacokinetics in HIV-infected patients with underlying hepatic disease 1998 [abstract 359]. 5th Conference on Retroviruses and Opportunistic Infections; 1998 Feb 1–5; Chicago.Google Scholar
  73. 73.
    Ouellet D, Hsu A, Quian J, et al. Assessment of the effect of fluoxetine on the pharmacokinetics of ritonavir. Antimicrob Agents Chemother. In press.Google Scholar
  74. 74.
    Bertilsson L, Lou Y-Q, Du Y-L, et al. Pronounced differences between native Chinese and Swedish populations in the polymorphic hydroxylations of debrisoquin and S-mephenytoin. Clin Pharmacol Ther 1992; 51: 388–97.PubMedCrossRefGoogle Scholar
  75. 75.
    Molla A, Granneman GR, Sun E, et al. Recent developments in HIV protease inhibitor therapy. Antiviral Res 1998. In press.Google Scholar
  76. 76.
    Molla A, Chernyavskiy T, Vasavanonda S, et al. Synergistic anti-HIV activity of ritonavir and other protease inhibitors in the presence of human serum. 12th World Congress on AIDS; 1998 Jun 28–Jul 3; Geneva.Google Scholar
  77. 77.
    Hsu A, Granneman GR, Molla A, et al. Ritonavir-containing dual protease inhibitor regimens may have synergistic antiviral effects in patients—based on in vitro model. 12th World Congress on AIDS; 1998 Jun 28–Jul 3; Geneva.Google Scholar
  78. 78.
    Lazdins JK A, Mestan J, Goutte G, et al. In vitro effect of alacid glycoprotein on the anti-human immunodeficiency virus (HIV) activity of the protease inhibitor CGP 61755: a comparative study with other relevant HIV protease inhibitors. J Infect Dis 1997; 175: 1063–70.PubMedCrossRefGoogle Scholar
  79. 79.
    Molla A, Korneyeva M, Cao Q, et al. Ordered accumulation of mutations in HIV protease confers resistance to ritonavir. Nature Med 1996; 2 (7): 760–6.PubMedCrossRefGoogle Scholar
  80. 80.
    Cato A, Cavanaugh JH, Shi H, et al. The effect of multiple doses of ritonavir on the pharmacokinetics of rifabutin. Clin Pharmacol Ther 1998; 63: 414–21.PubMedCrossRefGoogle Scholar
  81. 81.
    Ouellet D, Hsu A, Granneman GR, et al. Pharmacokinetic interaction between ritonavir and clarithromycin. Clin Pharmacol Ther. In press.Google Scholar
  82. 82.
    Bertz R, Wong C, Carothers L, et al. Evaluation of the pharmacokinetics of multiple dose ritonavir and ketoconazole in combination. Clin Pharmacol Ther 1998; 63: 230.Google Scholar
  83. 83.
    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.PubMedCrossRefGoogle Scholar
  84. 84.
    Frye R, Bertz RJ, Granneman GR, et al. Effect of ritonavir on the pharmacokinetics and pharmacodynamics of alprazolam [abstract A-59]. 37th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1997 Sep 28–Oct 1; Toronto.Google Scholar
  85. 85.
    Hsu A, Granneman GR, Carothers L, et al. Ritonavir does not increase methadone exposure in healthy volunteers [abstract 342]. 5th Conference on Retroviruses and Opportunistic Infections; 1998 Feb 1–5; Chicago.Google Scholar
  86. 86.
    Sun E, Heath-Chiozzi M, Cameron DW, et al. Concurrent ritonavir and rifabutin increases risk of rifabutin-associated adverse events [abstract Mo.B. 171]. XI International Conference on AIDS; 1996 Jul 7–12; Vancouver.Google Scholar
  87. 87.
    von Moltke LL, Greenblatt DJ, Cotreau-Bibbo MM, et al. Inhibitors of alprazolam metabolism in vitro: effect of serotonin-reuptake inhibitor antidepressants, ketoconazole and quinidine. Br J Clin Pharmacol 1994; 38: 23–31.CrossRefGoogle Scholar
  88. 88.
    Iribarne C, Berthou F, Baird S, et al. Involvment of cytochrome P450 3A4 enzyme in the N-demethylation of methadone in human liver microsomes. Chem Res Toxicol 1996; 9: 365–73.PubMedCrossRefGoogle Scholar
  89. 89.
    Iribarne C, Dreano Y, Bardou LG, et al. Interaction of methadone with substrates of human hepatic cytochrome P450 3A4. Toxicol 1997; 117: 13–23.CrossRefGoogle Scholar
  90. 90.
    Guibert A, Furla V, Martino J, Taburet AM. In vitro effect of HIV protease inhibitors on methadone metabolism [abstract A-58]. 37th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1997 Sep 28–Oct 1; Toronto.Google Scholar
  91. 91.
    Fleishaker JC, Hülst LK. A pharmacokinetic and pharmacodynamic evaluation of the combined administration of alprazolam and fluvoxamine. Eur J Clin Pharmacol 1994; 46: 35–9.PubMedCrossRefGoogle Scholar
  92. 92.
    Hossain M, Wright E, Baweja R, et al. Nonlinear mixed effects modeling of single dose and multiple dose data for an immediate release (IR) and a controlled release (CR) dosage form of alprazolam. Pharm Res 1997; 14: 309–15.PubMedCrossRefGoogle Scholar
  93. 93.
    Cobb M, Desai J, Brown LS, et al. The effect of fluconazole on the clinical pharmacokinetics of methadone [abstract Mo.B.1196]. XI International Conference on AIDS; 1996 Jul 7–12; Vancouver.Google Scholar
  94. 94.
    Bertz RJ, Granneman GR. Use of in vitro and in vivo data to estimate the likelihood of metabolic pharmacokinetic interactions. Clin Pharmacokinet 1997; 32 (3): 210–58.PubMedCrossRefGoogle Scholar
  95. 95.
    Ludden LK, Ludden T, Collins JM, et al. Effect of albumin on the estimation, in vitro, of phenytoin V max and Km values: implications for clinical correlation. J Pharmacol Exp Ther 1997; 282 (1): 391–6.PubMedGoogle Scholar
  96. 96.
    Bertz RJ, Cao G, Cavanaugh JH, et al. Effect of ritonavir on the pharmacokinetics of trimethoprim/sulfamethoxazole [abstract Mo.B.1197]. XI International Conference on AIDS; 1996 Jul 7–12; Vancouver.Google Scholar
  97. 97.
    Levy RH. Cytochrome P450 isozymes and antiepileptic drug interactions. Epilepsia 1995; 36: S8–13.PubMedCrossRefGoogle Scholar
  98. 98.
    Fiske WD, Benedek IH, Kornhauser DM, et al. Pharmacokinetics of efavirenz (EFV) and ritonavir (RIT) after multiple oral doses in healthy volunteers. Submitted. 12th World Congress on AIDS; 1998 Jun 28–Jul 3; Geneva.Google Scholar
  99. 99.
    Cato III A, Cao G, Hsu A, et al. Evaluation of the effect of fluconazole on the pharmacokinetics of ritonavir. Drug Metab Dispos 1997; 25 (9): 1104–6.PubMedGoogle Scholar
  100. 100.
    Baciewicz AM, Self TH. Rifampin drug interactions. Arch Intern Med 1984; 144: 1667–71.PubMedCrossRefGoogle Scholar
  101. 101.
    Bjornsson T, Chiou R, Deutsch P, et al. Pharmacokinetics of indinavir. Pharm Res 1996; 13 (9): S485.Google Scholar
  102. 102.
    Hsu A, Granneman GR, Sun E, et al. Assessment of single- and multiple-dose interactions between ritonavir and saquinavir [abstract LB.B 6041]. XI International Conference on AIDS; 1996 Jul 7–12: Vancouver.Google Scholar
  103. 103.
    Hsu A, Granneman GR, Heath-Chiozzi M, et al. Indinavir can be given with regular meals when taken with ritonavir. 12th World Congress on AIDS; 1998 Jun 28–Jul 3; Geneva.Google Scholar
  104. 104.
    Zhang K, Wu E, Patick A, et al. Plasma metabolites of nelfinavir, a potent HIV protease inhibitor, in HIV positive patients: quantitation by LC-MS/MS and antiviral activities. 11: 128. 6th European ISSX Meeting; 1997 Jun 30–Jul 3; Gothenburg, Sweden.Google Scholar
  105. 105.
    Cato A, Qian J, Carothers, L, et al. Pharmacokinetic interactions between ritonavir and didanosine when administered concurrently to HIV-infected patients. J Acquir Immune Defic Syndr Hum Retrovirol 1998; 18: 466–72.PubMedCrossRefGoogle Scholar
  106. 106.
    Rescriptor™ package insert. Pharmacia & Upjohn, 1998.Google Scholar
  107. 107.
    Morse GD, Shelton MJ, Hewitt RG, et al. Ritonavir (RIT) pharmacokinetics (PK) during combination therapy with delavird-ine (DLV) [abstract 343]. 5th Conference on Retroviruses and Opportunistic Infections; 1998 Feb 1–5; Chicago.Google Scholar
  108. 108.
    Shelton MJ, Hewitt RG, Adams JM, et al. Delavirdine (DLV) mesylate pharmacokinetics (PK) during combination therapy with ritonavir (RIT) [abstract A-63]. 37th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1997 Sep 28–Oct 1; Toronto.Google Scholar
  109. 109.
    Viramune™ Package Insert. Raxane Laboratories, 1998.Google Scholar
  110. 110.
    Murphy R, Gagnier P, Lamson M, et al. Effect of nevirapine (NVP) on pharmacokinetics (PK) of indinavir (IDV) and ritonavir (RTV) in HIV-1 patients [abstract 374]. 4th Conference on Retroviruses and Opportunistic Infections; 1997 Jan 22–26: Washington, DC.Google Scholar
  111. 111.
    Fiske WD, Benedek IH, White SJ, et al. Pharmacokinetic interaction between DMP 266 and nelfinavir mesylate (NFV) in healthy volunteers [abstractl-174]. 37th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1997 Sep 28–Oct 1; Toronto.Google Scholar
  112. 112.
    Cox SR, Schneck DW, Herman BD, et al. Delavirdine (DLV) and nelfinavir (NFV): a pharmacokinetic (PK) drug-drug interaction study in healthy adult volunteers [abstract 345]. 5th Conference on Retroviruses and Opportunistic Infections; 1998 Feb 1–5; Chicago.Google Scholar
  113. 113.
    Workman C, Musson R, Dyer W, et al. Novel double protease combinations-combining indinavir (IDV) with ritonavir (RTV): results from first study. 12th World Congress on AIDS; 1998 Jun 28–Jul 3; Geneva.Google Scholar
  114. 114.
    Chong KT, Pagano PJ. In vitro combination of PNU140690, a human immunodeficiency virus type 1 protease inhibitor, with ritonavir against ritonavir-sensitive and -resistant clinical isolates. Antimicrob Agents Chemother 1997; 41: 2367–73.PubMedGoogle Scholar
  115. 115.
    Dudley MN. Clinical pharmacokinetics of nucleoside antiviral agents. J Infect Dis 1995; 171 Suppl. 2: S99–112.PubMedCrossRefGoogle Scholar
  116. 116.
    Knupp CA, Graziano FM, Dixon RM, et al. Pharmacokinetic interaction study of didanos?ine and ranitidine in patients seropositive for human immunodeficiency virus. Antimicrob Agents Chemother 1992; 36: 2075–9.PubMedCrossRefGoogle Scholar
  117. 117.
    Cox SR, Ferry JJ, Batts DH, et al. Delavirdine (D) and marketed protease inhibitors (PIs): pharmacokinetic (PK) interaction studies in healthy volunteers [abstract 372]. 4th Conference on Retroviruses and Opportunistic Infections; 1997 Jan 22–26; Washington, DC.Google Scholar
  118. 118.
    Erickson DA, Riske PS, Hattox SE, et al. Nevirapine hydroxylation, an in vitro probe for the simultaneous determination of CYP3 A and CYP2B6 activity in human liver microsomes [abstract 98]. 8th North American ISSX Meeting; 1997 Oct 26–30; Hilton Head, South Carolina.Google Scholar
  119. 119.
    Havlir D, Cheeseman SH, McLaughlin M, et al. High-Dose nevirapine: safety, pharmacokinetics, and antiviral effect in patients iwth human immunodeficiency virus infection. J Infect Dis 1995; 171: 537–45.PubMedCrossRefGoogle Scholar
  120. 120.
    Merry C, Barry MG, Mulcahy FM, et al. The pharmacokinetics of nelfinavir alone and in combination with nevirapine [abstract 351]. 5th Conference on Retroviruses and Opportunistic Infections; 1998 Feb 1–5: Chicago.Google Scholar
  121. 121.
    Skowron G, Leoung G, Dusek A, et al. Stavudine (d4T), nelfinavir (NFV) and nevirapine (NVP): preliminary safety, activity and pharmacokinetic (PK) interactions [abstract 350]. 5th Conference on Retroviruses and Opportunistic Infections; 1998 Feb 1–5: Chicago.Google Scholar
  122. 122.
    Christ DD, Fiske WD, Grubb MF, et al. The novel non-nucleoside reverse transcriptase inhibitor DMP 266 produces autoinduction of metabolism in rats and rhesus monkeys [abstract 299]. 8th North American ISSX Meeting; 1997 Oct 26–30: Hilton Head, South Carolina.Google Scholar
  123. 123.
    Grubb M, Rao GP, Christ DD. effects of non-nucleoside reverse transcriptase inhibitor DMP 266 on AZT glucuronidation in vitro [abstract 188]. 8th North American ISSX Meeting; 1997 Oct 26–30: Hilton Head, South Carolina.Google Scholar
  124. 124.
    Fiske WD, Mayers D, Wagner K, et al. pharmacokinetics of DMP 266 and indinavir multiple oral doses in HIV-1 infected individuals [abstract 568]. 4th Conference on Retro-viruses and Opportunistic Infections; 1997 Jan 22–26: Washington, DC.Google Scholar
  125. 125.
    Piscitelli S, Vogel S, Sadler B, et al. Effect of efavirenz (DMP 266) on the pharmacokinetics of 141W94 in HIV-infected patients [abstract 346]. 5th Conference on Retroviruses and Opportunistic Infections; 1998 Feb 1–5: Chicago.Google Scholar
  126. 126.
    Wacher VJ, Wu C-Y, Benet LZ. Overlapping substrate specificities and tissue distribution of cytochrome P450 3A and p-glycoprotein: implications for drug delivery and activity in cancer chemotherapy. Mol Carcinog 1995; 13: 129–34.PubMedCrossRefGoogle Scholar
  127. 127.
    Washington CB, Duran GE, Sikic BI, et al. Saquinavir is a high affinity substrate for the multidrug transporter, P-glycoprotein. Clin Pharmacol Ther 1997; 61 (2): 193.Google Scholar
  128. 128.
    Hoff T, Brandt T, Demmer A, et al. Interaction of HIV protease inhibitors with MDR1: competitive binding and resistance modulation [abstract I-111]. 37th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1997 Sep 28–Oct 1: Toronto.Google Scholar
  129. 129.
    Kim RB, Fromm MF, Wandel C, et al. The drug transporter P-glycoprotein limits oral absorption and brain entry of HIV-1 protease inhibitors. J Clin Invest 1998; 101 (2): 289–94.PubMedCrossRefGoogle Scholar

Copyright information

© Adis International Limited 1998

Authors and Affiliations

  • Ann Hsu
    • 1
  • G. Richard Granneman
    • 1
  • Richard J. Bertz
    • 1
  1. 1.D-4PK, AP13A, Abbott LaboratoriesAbbott ParkUSA

Personalised recommendations