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Saquinavir

Clinical Pharmacology and Efficacy

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  • Drug Disposition
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Abstract

Saquinavir is an HIV protease inhibitor with no, or limited, effect on the activity of other structurally related human aspartic proteinases. As with other HIV protease inhibitors, saquinavir inhibits the cleavage of the gag-pol protein substrate leading to the release of structurally defective and functionally inactive viral particles. It is active on both HIV-1 and HIV-2, and also has activity on chronically infected cells and HIV strains resistant to reverse transcriptase inhibitors. Synergy of action has been observed with other antiretroviral drugs.

Saquinavir is characterised by a low bioavailability which is further reduced in the fasting state. Metabolism is mainly hepatic through cytochrome P450 (CYP) 3A4, but intestinal metabolism through the same system has also been reported.

To achieve higher drug plasma concentrations and increase the antiviral effect, a new formulation of saquinavir with a higher bioavailability has recently been introduced. Higher plasma drug concentrations may also be obtained by combining the drug with CYP blockers, such as ritonavir or ketoconazole. Because of its metabolic interference with the CYP system, saquinavir cannot be coadministered with astemizole, terfenadine or cisapride. Rifampicin (rifampin) is also contraindicated because coadministration can lead to decreases in saquinavir concentrations. Interactions have also been reported with other drugs metabolised through the same system, including non-nucleoside reverse transcriptase inhibitors and HIV protease inhibitors.

Resistance has been observed after both in vitro and in vivo drug exposure, with a relatively specific mutation profile compared with other protease inhibitors. Saquinavir is generally well tolerated, with mild gastrointestinal symptoms representing the most commonly observed adverse effects.

Although characterised by low bioavailability, in phase III trials saquinavir has been shown to have clinical efficacy in terms of survival and progression rate. As with the other protease inhibitors, saquinavir should be used in combination with other antiretroviral drugs. Current therapeutic guidelines, however, recommend the selection of an initial treatment regimen with other protease inhibitors with higher in vivo activity in terms of RNA and CD4 response.

The results of ongoing studies will clarify to what extent a new saquinavir formulation, recently introduced, is superior to the previous one in terms of antiviral activity and to provide comparisons with other protease inhibitors.

Further studies are also needed to define the best place of saquinavir within treatment strategies based on protease inhibitors, particularly in respect to the optimal sequence for its use with other protease inhibitors, and the dynamics of cross-resistance and its role within regimens based on the combination of protease inhibitors.

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References

  1. Kohl NE, Emini EA, Schleif WA, et al. Active Human Immunodeficiency Virus protease is required for viral infectivity. Proc Natl Acad Sci USA. 1988; 85: 4686–90.

    Article  PubMed  CAS  Google Scholar 

  2. Kramer RA, Schaber MD, Skalka AM, et al. HTLV-III gag protein is processed in yeast cells by the virus pol protease. Science. 1986; 231: 1580–4.

    Article  PubMed  CAS  Google Scholar 

  3. Redshaw S. Inhibitors of HIV proteinase. Expert Opin Invest Drugs. 1994; 3: 273–86.

    Article  CAS  Google Scholar 

  4. Pettit SC, Michael SF, Swanstrom R. The specificity of HIV protease. Perspect Drug Discov Des. 1993; 1: 69–73.

    Article  CAS  Google Scholar 

  5. Roberts NA, Martin JA, Kinchington D, et al. Rational design of peptide-based HIV proteinase inhibitors. Science. 1990; 248: 858–61.

    Google Scholar 

  6. Nagy K, Young M, Baboonian C, et al. Antiviral activity of Human Immunodeficiency virus type 1 in a single cycle of infection: evidence for a role of protease in the early phase. J Virol. 1994; 68: 757–65.

    PubMed  CAS  Google Scholar 

  7. Bugelski PJ, Kirsh R, Hart TK. HIV protease inhibitors: effects on viral maturation and physiologic function in macrophages. J Leukoc Biol. 1994; 56: 374–380.

    PubMed  CAS  Google Scholar 

  8. Noble S, Faulds D. Saquinavir: a review of its pharmacology and clinical potential in the management of HIV infection. Drugs. 1996; 52: 93–112.

    Article  PubMed  CAS  Google Scholar 

  9. Craig JC, Greif C, Mills JS, et al. Anti-HIV activity of a specific inhibitor of HIV proteinase Ro31-8959 on virus maturation in a chronically infected promonocytic cell line. Antivir Chem Chemother. 1991; 2: 188–96.

    Google Scholar 

  10. Perno C-F, Aquaro S, Rosenwirth B, et al. In vitro activity of inhibitors of late stages of the replication og HIV in chronically infected macrophages. J Leukoc Biol. 1994; 56: 381–6.

    PubMed  CAS  Google Scholar 

  11. Richman DD. Resistance of clinical isolates of human immunodeficiency virus to antiretroviral agents. Antimicrob Agents Chemother. 1993; 37: 1207–3.

    Article  PubMed  CAS  Google Scholar 

  12. Merrill DP, Manion DJ, Chou T-C, et al. Antagonism between human immunodeficiency virus type 1 protease inhibitors indinavir and saquinavir in vitro. J Inf Dis. 1997; 176: 265–8.

    Article  CAS  Google Scholar 

  13. Hoffmann-La Roche. Ro 31-8959 Saquinavir Invirase™. Investigational Drug Brochure, 1996 (data on file).

  14. Williams PEO, Sampson AP, Green CP, et al. Disposition and bioavailability of the HIV proteinase inhibitor, Ro 31-8959, after single doses in healthy volunteers. Br J Clin Pharmacol 1992 Aug; 34: 155P–6P.

    Google Scholar 

  15. Muirhead GJ, Shaw T, Williams PEO, et al. Pharmacokinetics of the HIV proteinase inhibitor, Ro 31-8959, after single and multiple oral doses in healthy volunteers. Br J Clin Pharmacol 1992 Aug; 34: 170P–1P.

    Google Scholar 

  16. Shaw TM, Muirhead TJ, Parish N, et al. Tolerability and pharmacokinetics of single oral doses of Ro 1-8959, an HIV proteinase inhibitor. Br J Clin Pharmacol 1992 Aug; 34: 166P–7P.

    Google Scholar 

  17. Fitzsimmons ME, Collins JM. Selective biotransformation of the human immunodeficiency virus protease inhibitor saquinavir by human small-intestinal cytochrome P4503A4. Drug Metab Dispos. 1997; 25(2): 256–66.

    PubMed  CAS  Google Scholar 

  18. Merry C, Barry GM, Mulcahy F, et al. Saquinavir pharmacokinetics alone and in combination with ritonavir in HIV-infected patients. AIDS. 1997; 11: F29–F33.

    Article  PubMed  CAS  Google Scholar 

  19. Schapiro JM, Winters MA, Stewart F, et al. The effect of high dose saquinavir on viral load and CD4+ cell counts in HIV− infected patients. Ann Intern Med. 1996; 124: 1039–50.

    PubMed  CAS  Google Scholar 

  20. Vella S, Lazzarin A, Carosi G, et al. A randomized controlled trial of a protease inhibitor (saquinavir) in combination with zidovudine in previously untreated patients with advanced HIV infection. Antiviral Ther. 1996; 1: 129–40.

    CAS  Google Scholar 

  21. Kravcik S, Sahai J, Kerr B, et al. Nelfinavir mesylate increases saquinavir-soft gel capsule exposure in HIV+ patients [abstract 371]. 4th Conference on Retroviruses and Opportunistic Infections; 1997 Jan 22–26; Washington, DC.

    Google Scholar 

  22. Rutschmann OT, Kaiser L, Perrin L, et al. Adding saquinavir to stavudine in patients with advanced HIV infection. AIDS. 1997; 11: 548.

    PubMed  CAS  Google Scholar 

  23. Conway B, on behalf of the NV15355 study team. The activity and safety of two formulations of saquinavir combined with two nucleosides in treatment-naive patients [abstract 923]. 6th European Conference on Clinical Aspects and Treatment of HIV Infection; 1997 Oct 11–15; Hamburg.

    Google Scholar 

  24. Sahai J. Risks and synergies from drug interactions. AIDS. 1996; 10 Suppl. 1: S21–5.

    PubMed  CAS  Google Scholar 

  25. Merry C, Mulcahy F, Barry M, et al. Saquinavir interaction with midazolam: pharmacokinetic considerations when prescribing protease inhibitors for patients with HIV disease. AIDS. 1997; 11(2): 268–9.

    PubMed  CAS  Google Scholar 

  26. Cox SR, Ferry JJ, Batts DH, et al. Delavirdine and marketed protease inhibitors: pharmacokinetic interaction studies in healthy volunteers [abstract 372]. 4th Conference on Retroviruses and Opportunistic Infections; 1997 Jan 22–26; Washington.

    Google Scholar 

  27. Sahai J, Cameron W, Salgo M, et al. Drug interecation study between saquinavir and nevirapine [abstract 614]. 4th Conference on Retroviruses and Opportunistic Infections; 1997 Jan 22–26; Washington.

    Google Scholar 

  28. 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 Retroviruses and Opportunistic Infections; 1997 Jan 22–26; Washington.

    Google Scholar 

  29. Cox SR, Batts DH, Stewart F, et al. Evaluation of the pharmacokinetic interaction between saquinavir and delavirdine in healthy volunteers [abstract 372]. 4th Conference on Retroviruses and Opportunistic Infections; 1997 Jan 22–26; Washington.

    Google Scholar 

  30. Norbeck D, Kumar G, Marsh K, et al. Ritonavir and saquinavir: potential for tw-dimensional synergy between HIV protease inhibitors [abstract LB-7]. 35th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1995 Sep 17–20; San Francisco.

    Google Scholar 

  31. Mccrea J, Buss N, Stone J, et al. Indinavir-saquinavir single dose pharmacokinetic study [abstract 608]. 4th Conference on Retroviruses and Opportunistic Infections; 1997d Jan 22–26; Washington, DC.

    Google Scholar 

  32. Hirschel BJ, Rutschmann O, Fathi M, et al. Treatment of advanced HIV infection with ritonavir plus saquinavir [abstract]. XI International Conference on AIDS; 1996 Jul 7–12; Vancouver.

    Google Scholar 

  33. Barbour II, Clayton O. Efficacy and safety of quadruple combination therapy in treatment experienced HIV/AIDS patients [abstract 245]. 4th Conference on Retroviruses and Opportunistic Infections; 1997 Jan 22–26; Washington.

    Google Scholar 

  34. Berger DS, Bucher G, Delaney K, et al. Further reduction in plasma HIV load in patients with advanced AIDS when a second protease inhibitor was added to a triple drug combination therapy [abstract]. 4th Conference on Retroviruses and Opportunistic Infections; 1997 Jan 22–26; Washington.

    Google Scholar 

  35. Angel JB, Parato K, Kumar A, et al. Rapid improvement in cell mediated immune function with initiation of ritonavir plus saquinavir in HIV immune deficiency [abstract 33]. 4th Conference on Retroviruses and Opportunistic Infections; 1997 Jan 22–26; Washington.

    Google Scholar 

  36. Cameron W, Sun E, Markowitz M, Farthing C, et al. Combination use of ritonavir and saquinavir in HIV-infected patients: preliminary safety and acivity data [abstract Mo.B. 411]. XIth International Conference on AIDS; 1996 Jul 7–12; Vancouver.

    Google Scholar 

  37. Hirschel B, Lorenzi P, Yerly S, et al. Escape of viremia and rapid development of protease mutations in advanced HIV infection treated with saquinavir plus ritonavir [abstract 594]. 4th Conference on Retroviruses and Opportunistic Infections; 1997 Jan 22–26; Washington.

    Google Scholar 

  38. Paulous S, Clavel F. Sequential selection by protease inhibitors: effects of ritonavir resistance on further selection for HIV resistance by saquinavir [abstract 598]. 4th Conference on Retroviruses and Opportunistic Infections; 1997 Jan 22–26; Washington, DC.

    Google Scholar 

  39. Lee CA, Liang B-H, Wu EY, et al. Prediction of nelfinavir mesylate (Viracept) clinical drug interactons based on in vitro human P450 metabolism studies [abstract]. 4th Conference on Retroviruses and Opportunistic Infections; 1997 Jan 22–26; Washington, DC.

    Google Scholar 

  40. Vella S. Clinical implications of resistance to antiretroviral drugs. AIDS Clin Care. 1997; 9(6): 47–52.

    Google Scholar 

  41. Boucher C. Rational approaches to resistance: using saquinavir. AIDS. 1996; 10 Suppl. 1: S15–9.

    PubMed  CAS  Google Scholar 

  42. Roberts NA. Drug resistance patterns of saquinavir and other HIV proteinase inhibitors. AIDS 1995, 9 Suppl. 2: S27–32.

    CAS  Google Scholar 

  43. Condra JH, Schlief WA, Blahy OM, et al. In vivo emergence of HIV-1 variants resistant to multiple protease inhibitors [letter]. Nature. 1995; 374: 569–71.

    Article  PubMed  CAS  Google Scholar 

  44. Jacobsen H, Hanggi M, Ott M, et al. In vivo resistance to a Human Immunodeficiency Virus type 1 proteinase inhibitor: mutations, kinetics, and frequencies. J Infect Dis. 1996; 173: 1379–87.

    Article  PubMed  CAS  Google Scholar 

  45. Vella S, Galluzzo C, Giannini G, et al. Saquinavir/zidovudine combination in patients with advanced HIV infection and no prior antiretroviral therapy: CD4+ lymphocyte/plasma RNA changes, and emergence of HIV strains with reduced phenotypic sensitivity. Antiviral Res. 1996; 29: 91–3.

    Article  PubMed  CAS  Google Scholar 

  46. Valette M, Gerard Y, Ajana F, et al. Kaplan-Meier analysis of interruption probability of protease inhibitor, saquinavir, indinavir or ritonavir in 177 patients receiving a combination of protease inhibitors and reverse transcriptase inhibitors [abstract 197]. 4th Conference on Retroviruses and Opportunistic Infections; 1997 Jan 22–26; Washington, DC.

    Google Scholar 

  47. Hoffmann-La Roche. Ro-31.8959. Saquinavir invirase™ Investigational Drug Brochure, W-144’962. 1996 (Data on file).

  48. Collier A, Coombs RW, Schoenfeld DA, et al. Treatment of Human immunodeficiency virus infection with saquinavir, zidovudine and zalcitabine. N Engl J Med. 1996; 334: 1011–7.

    Article  PubMed  CAS  Google Scholar 

  49. Lalezari J, Haubrich R, Burger HU, et al. Improved survival and decreased progression of HIV in patients treated with saquinavir plus zalcitabine [abstract LB.B. 6033]. XI International Conference on AIDS; 1996 Jul 7–12; Vancouver.

    Google Scholar 

  50. Stellbrink HJ, for the INvirase International Phase III Trial (SV14604) Group. Clinical and survival benefits of saquinavir (SQV) in combination with zalcitabine (ddC) and zidovudine (ZDV) in untreated/minimally treated HIV-infected patients [abstract no. 923]. 6th European Conference on Clinical Aspects and Treatment of HIV Infection. 1997 Oct 11–15; Hamburg.

    Google Scholar 

  51. Kitchen VS, Skinner C, Ariyoshi K, et al. Safety and activity of saquinavir in HIV infection. Lancet. 1995; 345: 952–5.

    Article  PubMed  CAS  Google Scholar 

  52. Carpenter CJ, Fischl MA, Hammer SM, et al. Antiretroviral therapy for HIV infection in 1997. Updated recommndations of the International AIDS Society — USA Panel. JAMA. 1997; 277: 1962–9.

    CAS  Google Scholar 

  53. Clinical update: impact of HIV protease inhibitors on the treatment of HIV-infected tuberculosis patients with rifampin. MMWR Morbid Mortal Wkly Rep 1996 Oct 25; 45: 921–5.

  54. Horsburgh CR. Advances in the prevention and treatment of Mycobacterium avium disease. N Engl J Med. 1996; 335: 428–30.

    Article  PubMed  Google Scholar 

  55. Angel JB, Parato K, Kumar A, et al. Rapid and sustained improvement in immune function during potent anti-HIV therapy with ritonavir plus saquinavir [abstract I-75]. 37th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1997 Sep 28–Oct 1; Toronto.

    Google Scholar 

  56. Montaner JSG, Rhone S, Yip, B, et al. The antiviral effect of ritonavir and saquinavir in combination among HIV-infected adults: results from a community-based study [abstract 437]. 6th European Conference on Clinical Aspects and Treatment of HIV Infection; 1997 Oct 11–15; Hamburg.

    Google Scholar 

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  1. Laboratory of Virology, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy

    Stefano Vella & Marco Floridia

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  2. Marco Floridia
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Vella, S., Floridia, M. Saquinavir. Clin Pharmacokinet 34, 189–201 (1998). https://doi.org/10.2165/00003088-199834030-00002

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