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Antimicrob Agents Chemother. 1997 Mar; 41(3): 654–660.
doi: 10.1128/aac.41.3.654
PMCID: PMC163767
PMID: 9056009

Pharmacokinetic enhancement of inhibitors of the human immunodeficiency virus protease by coadministration with ritonavir.

D J Kempf, K C Marsh, G Kumar, A D Rodrigues, J F Denissen, E McDonald, M J Kukulka, A Hsu, G R Granneman, P A Baroldi, E Sun, D Pizzuti, J J Plattner, D W Norbeck, and J M Leonard
Author information Copyright and License information PMC Disclaimer

Abstract

Coadministration with the human immunodeficiency virus (HIV) protease inhibitor ritonavir was investigated as a method for enhancing the levels of other peptidomimetic HIV protease inhibitors in plasma. In rat and human liver microsomes, ritonavir potently inhibited the cytochrome P450 (CYP)-mediated metabolism of saquinavir, indinavir, nelfinavir, and VX-478. The structural features of ritonavir responsible for CYP binding and inhibition were examined. Coadministration of other protease inhibitors with ritonavir in rats and dogs produced elevated and sustained plasma drug levels 8 to 12 h after a single dose. Drug exposure in rats was elevated by 8- to 46-fold. A > 50-fold enhancement of the concentrations of saquinavir in plasma was observed in humans following a single codose of ritonavir (600 mg) and saquinavir (200 mg). These results indicate that ritonavir can favorably alter the pharmacokinetic profiles of other protease inhibitors. Combination regimens of ritonavir and other protease inhibitors may thus play a role in the treatment of HIV infection. Because of potentially substantial drug level increases, however, such combinations require further investigation to establish safe regimens for clinical use.

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Selected References

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  • Coffin JM. HIV population dynamics in vivo: implications for genetic variation, pathogenesis, and therapy. Science. 1995 Jan 27;267(5197):483–489. [PubMed] [Google Scholar]
  • Condra JH, Schleif WA, Blahy OM, Gabryelski LJ, Graham DJ, Quintero JC, Rhodes A, Robbins HL, Roth E, Shivaprakash M, et al. In vivo emergence of HIV-1 variants resistant to multiple protease inhibitors. Nature. 1995 Apr 6;374(6522):569–571. [PubMed] [Google Scholar]
  • Danner SA, Carr A, Leonard JM, Lehman LM, Gudiol F, Gonzales J, Raventos A, Rubio R, Bouza E, Pintado V, et al. A short-term study of the safety, pharmacokinetics, and efficacy of ritonavir, an inhibitor of HIV-1 protease. European-Australian Collaborative Ritonavir Study Group. N Engl J Med. 1995 Dec 7;333(23):1528–1533. [PubMed] [Google Scholar]
  • Dorsey BD, Levin RB, McDaniel SL, Vacca JP, Guare JP, Darke PL, Zugay JA, Emini EA, Schleif WA, Quintero JC, et al. L-735,524: the design of a potent and orally bioavailable HIV protease inhibitor. J Med Chem. 1994 Oct 14;37(21):3443–3451. [PubMed] [Google Scholar]
  • Greenberg RN. Overview of patient compliance with medication dosing: a literature review. Clin Ther. 1984;6(5):592–599. [PubMed] [Google Scholar]
  • Ho DD, Neumann AU, Perelson AS, Chen W, Leonard JM, Markowitz M. Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature. 1995 Jan 12;373(6510):123–126. [PubMed] [Google Scholar]
  • Kempf DJ, Marsh KC, Denissen JF, McDonald E, Vasavanonda S, Flentge CA, Green BE, Fino L, Park CH, Kong XP, et al. ABT-538 is a potent inhibitor of human immunodeficiency virus protease and has high oral bioavailability in humans. Proc Natl Acad Sci U S A. 1995 Mar 28;92(7):2484–2488. [PMC free article] [PubMed] [Google Scholar]
  • Kempf DJ, Marsh KC, Fino LC, Bryant P, Craig-Kennard A, Sham HL, Zhao C, Vasavanonda S, Kohlbrenner WE, Wideburg NE, et al. Design of orally bioavailable, symmetry-based inhibitors of HIV protease. Bioorg Med Chem. 1994 Sep;2(9):847–858. [PubMed] [Google Scholar]
  • Kempf DJ, Marsh KC, Paul DA, Knigge MF, Norbeck DW, Kohlbrenner WE, Codacovi L, Vasavanonda S, Bryant P, Wang XC, et al. Antiviral and pharmacokinetic properties of C2 symmetric inhibitors of the human immunodeficiency virus type 1 protease. Antimicrob Agents Chemother. 1991 Nov;35(11):2209–2214. [PMC free article] [PubMed] [Google Scholar]
  • Keogh A, Spratt P, McCosker C, Macdonald P, Mundy J, Kaan A. Ketoconazole to reduce the need for cyclosporine after cardiac transplantation. N Engl J Med. 1995 Sep 7;333(10):628–633. [PubMed] [Google Scholar]
  • Kronbach T, Fischer V, Meyer UA. Cyclosporine metabolism in human liver: identification of a cytochrome P-450III gene family as the major cyclosporine-metabolizing enzyme explains interactions of cyclosporine with other drugs. Clin Pharmacol Ther. 1988 Jun;43(6):630–635. [PubMed] [Google Scholar]
  • Kumar GN, Rodrigues AD, Buko AM, Denissen JF. Cytochrome P450-mediated metabolism of the HIV-1 protease inhibitor ritonavir (ABT-538) in human liver microsomes. J Pharmacol Exp Ther. 1996 Apr;277(1):423–431. [PubMed] [Google Scholar]
  • Markowitz M, Saag M, Powderly WG, Hurley AM, Hsu A, Valdes JM, Henry D, Sattler F, La Marca A, Leonard JM, et al. A preliminary study of ritonavir, an inhibitor of HIV-1 protease, to treat HIV-1 infection. N Engl J Med. 1995 Dec 7;333(23):1534–1539. [PubMed] [Google Scholar]
  • Molla A, Korneyeva M, Gao Q, Vasavanonda S, Schipper PJ, Mo HM, Markowitz M, Chernyavskiy T, Niu P, Lyons N, et al. Ordered accumulation of mutations in HIV protease confers resistance to ritonavir. Nat Med. 1996 Jul;2(7):760–766. [PubMed] [Google Scholar]
  • Nedelcheva V, Gut I. P450 in the rat and man: methods of investigation, substrate specificities and relevance to cancer. Xenobiotica. 1994 Dec;24(12):1151–1175. [PubMed] [Google Scholar]
  • Perelson AS, Neumann AU, Markowitz M, Leonard JM, Ho DD. HIV-1 dynamics in vivo: virion clearance rate, infected cell life-span, and viral generation time. Science. 1996 Mar 15;271(5255):1582–1586. [PubMed] [Google Scholar]
  • Reedijk M, Boucher CA, van Bommel T, Ho DD, Tzeng TB, Sereni D, Veyssier P, Jurriaans S, Granneman R, Hsu A, et al. Safety, pharmacokinetics, and antiviral activity of A77003, a C2 symmetry-based human immunodeficiency virus protease inhibitor. Antimicrob Agents Chemother. 1995 Jul;39(7):1559–1564. [PMC free article] [PubMed] [Google Scholar]
  • Roberts NA, Martin JA, Kinchington D, Broadhurst AV, Craig JC, Duncan IB, Galpin SA, Handa BK, Kay J, Kröhn A, et al. Rational design of peptide-based HIV proteinase inhibitors. Science. 1990 Apr 20;248(4953):358–361. [PubMed] [Google Scholar]
  • Rodrigues AD, Lewis DF, Ioannides C, Parke DV. Spectral and kinetic studies of the interaction of imidazole anti-fungal agents with microsomal cytochromes P-450. Xenobiotica. 1987 Nov;17(11):1315–1327. [PubMed] [Google Scholar]
  • Rodrigues AD, Mulford DJ, Lee RD, Surber BW, Kukulka MJ, Ferrero JL, Thomas SB, Shet MS, Estabrook RW. In vitro metabolism of terfenadine by a purified recombinant fusion protein containing cytochrome P4503A4 and NADPH-P450 reductase. Comparison to human liver microsomes and precision-cut liver tissue slices. Drug Metab Dispos. 1995 Jul;23(7):765–775. [PubMed] [Google Scholar]
  • Schapiro JM, Winters MA, Stewart F, Efron B, Norris J, Kozal MJ, Merigan TC. The effect of high-dose saquinavir on viral load and CD4+ T-cell counts in HIV-infected patients. Ann Intern Med. 1996 Jun 15;124(12):1039–1050. [PubMed] [Google Scholar]
  • Stein DS, Fish DG, Bilello JA, Preston SL, Martineau GL, Drusano GL. A 24-week open-label phase I/II evaluation of the HIV protease inhibitor MK-639 (indinavir). AIDS. 1996 May;10(5):485–492. [PubMed] [Google Scholar]
  • Vacca JP, Dorsey BD, Schleif WA, Levin RB, McDaniel SL, Darke PL, Zugay J, Quintero JC, Blahy OM, Roth E, et al. L-735,524: an orally bioavailable human immunodeficiency virus type 1 protease inhibitor. Proc Natl Acad Sci U S A. 1994 Apr 26;91(9):4096–4100. [PMC free article] [PubMed] [Google Scholar]
  • Vincent SH, Karanam BV, Painter SK, Chiu SH. In vitro metabolism of FK-506 in rat, rabbit, and human liver microsomes: identification of a major metabolite and of cytochrome P450 3A as the major enzymes responsible for its metabolism. Arch Biochem Biophys. 1992 May 1;294(2):454–460. [PubMed] [Google Scholar]
  • Wei X, Ghosh SK, Taylor ME, Johnson VA, Emini EA, Deutsch P, Lifson JD, Bonhoeffer S, Nowak MA, Hahn BH, et al. Viral dynamics in human immunodeficiency virus type 1 infection. Nature. 1995 Jan 12;373(6510):117–122. [PubMed] [Google Scholar]
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