Drugs

, Volume 52, Issue 1, pp 93–112 | Cite as

Saquinavir

A Review of its Pharmacology and Clinical Potential in the Management of HIV Infection
  • Stuart Noble
  • Diana Faulds
Drug Evaluation

Abstract

Synopsis

Saquinavir is a peptide derivative which inhibits the HIV protease enzyme, preventing post-translational processing of viral polyproteins. It was the first agent of its class to become available for the treatment of HIV infection.

Well controlled studies have assessed the effects of saquinavir, when used alone or in combination with reverse transcriptase inhibitors, in patients with advanced HIV infection. Analysis of CD4+ cell counts and measures of viral load in the ACTG 229 study suggest that triple therapy with saquinavir, zidovudine and zalcitabine is more effective than double therapy with saquinavir plus zidovudine or zidovudine plus zalcitabine in patients who have previously received long term treatment with zidovudine. Similar assessments from a small study in previously untreated patients suggest that double therapy with saquinavir plus zidovudine is more effective than monotherapy with either agent. Combination therapy with saquinavir and zalcitabine significantly reduced the time to the first AIDS-defining event or death, and the time to death, compared with zalcitabine alone, according to data from a large, long term study (NV 14256) in patients with advanced HIV infection who had previously received zidovudine.

Saquinavir is generally well tolerated, either as monotherapy or in combination with reverse transcriptase inhibitors; no change in tolerability profile was reported when saquinavir was added to treatment with nucleoside analogues. In vitro and clinical studies have documented the emergence of saquinavir-resistant HIV strains. Although the possible impact of resistance on the clinical efficacy of saquinavir has yet to be fully characterised, genotypic and phenotypic resistance appear to develop slowly during treatment with saquinavir, and the drug does not appear to have a significant effect on the incidence of mutations associated with cross-resistance to other protease inhibitors.

Thus, laboratory and clinical results suggest that saquinavir in combination with reverse transcriptase inhibitors is effective in the treatment of advanced HIV infection. Initial data on the effects of saquinavir on disease progression and mortality are promising, and the apparent absence of mutations conferring cross-resistance to other protease inhibitors is a potentially valuable clinical feature. Additional data on disease progression, mortality and viral resistance, together with information on relative efficacy (in comparison with other protease inhibitors), will need to be assessed before the clinical value of saquinavir can be fully determined. Nevertheless, saquinavir represents a valuable new pharmacological option for the treatment of HIV infection and is likely to be a useful component of combined therapy with reverse transcriptase inhibitors and/or other protease inhibitors.

Pharmacodynamic Properties

Saquinavir is an HIV protease inhibitor which is a transition-state mimetic of the phenylalanine-proline (Phe-Pro) peptide bond. It competitively inhibits HIV-1 and HIV-2 protease-mediated cleavage of the HIV gag and pol polyproteins. Proteolytic processing at Phe-Pro is rare in mammalian systems and saquinavir is therefore unlikely to inhibit mammalian proteases.

In vitro studies have shown that saquinavir inhibits processing of HIV poly-proteins, thus preventing the formation of mature viral particles and reducing subsequent viral replication as assessed by p24 antigen levels, culturable viral titre, polymerase chain reaction analysis of proviral DNA, syncytium formation and cell death. The concentration of saquinavir required to produce 50% inhibition of HIV-1 ranged from about 2 to 7 nmol/L (≈1.5 to 5.4 μg/L) in most studies. Combination of saquinavir with nucleoside analogue inhibitors of HIV reverse transcriptase and/or other anti-HIV compounds produced synergistic inhibition of HIV replication.

Two common mutations conferring resistance to saquinavir have been identified in vitro and in vivo. One or both of these mutations were identified in 45% of patients receiving saquinavir as monotherapy and in 31% of those receiving the drug as part of combination therapy (mean treatment duration ≈1 year). In general, viral resistance appears to develop slowly during saquinavir treatment. Analysis of HIV protease sequences from clinical HIV isolates suggests that saquinavir as monotherapy or in combination regimens has little or no effect on the incidence of mutations associated with resistance to other protease inhibitors. Such mutations occurred infrequently (2 to 9%) and/or at a frequency similar to or lower than that seen at baseline (sequences from patients treated for up to 147 weeks).

Pharmacokinetic Properties

Peak plasma concentrations (Cmax) of saquinavir are reached about 3 to 4 hours after single- or multiple-dose oral administration of capsules with food in healthy volunteers. The bioavailability of a single dose of saquinavir under these conditions is 4%, 18 times greater than the value obtained when the drug is administered in the fasting state. Mean Cmax values ranged from 35.5 to 127.0 μg/L after single-dose administration of saquinavir 600mg with food in healthy volunteers; multiple administration of the same dose produced a mean Cmax of 90.4 μg/L. A Cmax of 242.3 μg/L was reached 2 hours after administration in patients receiving saquinavir 600mg 3 times daily under steady-state conditions.

Saquinavir is metabolised by the cytochrome P4503A4 isozyme to a number of inactive derivatives. The terminal elimination half-life of saquinavir after intravenous administration was 13.2 hours. 88% of a 600mg oral dose was detected in the faeces, with 1 % found in the urine. The relative bioavailability of saquinavir was increased when it was coadministered with ketoconazole or ranitidine and decreased when it was given with rifampicin (rifampin) or rifabutin.

Clinical Potential

The ACTG 229 study compared the efficacy of triple therapy with saquinavir 600mg, zidovudine 200mg and zalcitabine 0.75mg 3 times daily with that of 2 double therapy combinations in 297 zidovudine-experienced patients with advanced HIV infection who were treated for 24 weeks or more [median duration of prior zidovudine treatment was 27 months; median CD4+ cell count was 156 (range 25 to 394) cells/μl at baseline]. Triple therapy produced a larger and more sustained increase in CD4+ cell counts than treatment with saquinavir plus zidovudine or zidovudine plus zalcitabine. Similarly, measurement of HIV-1 titres in peripheral blood mononuclear cells (PBMCs) and plasma HIV-1 RNA titres indicated that triple therapy was significantly more effective than either of the double therapies. Although the mean CD4+ cell count after 48 weeks was below that seen at baseline in patients receiving triple therapy, viral suppression was still evident (39% decrease in mean PBMC HIV-1 titre compared with baseline).

Saquinavir 600mg plus zidovudine 200mg 3 times daily produced a greater increase in CD4+ cell counts and a larger reduction in plasma HIV-1 RNA titres than monotherapy with either saquinavir 600mg or zidovudine 200mg 3 times daily in a small group of previously untreated patients (n = 71; study V13330).

Final disease progression/mortality data are available from the NV 14256 study, which assessed the effects of saquinavir and zalcitabine, either alone or in combination, in 940 evaluable patients with advanced HIV infection who had previously received zidovudine for at least 16 weeks. The median initial treatment duration was 56 weeks for combination therapy (n = 308), 48 weeks for zalcitab-ine monotherapy (n = 314) and 56 weeks for saquinavir monotherapy (n = 318). Median follow-up in all groups was 73 to 74 weeks. When compared with zalcitabine monotherapy, treatment with saquinavir plus zalcitabine significantly increased the time to first AIDS-defining event or death (p = 0.0002, risk ratio 0.47), and the time to death (p = 0.002, risk ratio 0.28), according to an intent-to-treat log-rank analysis of event rates. The number of first AIDS-defining events or deaths was reduced by about 46%, and the number of deaths by about 68%, for combination therapy compared with zalcitabine monotherapy. There were no significant differences between the 2 monotherapies (statistical analysis not provided for combination therapy vs saquinavir).

Tolerability

Saquinavir was generally well tolerated when given as monotherapy or as part of combination antiretroviral regimens. Gastrointestinal disturbances were the most common adverse events in 159 patients who received saquinavir monotherapy as part of a double-blind study (median duration 42 weeks); diarrhoea was the most common single event, occurring with moderate or greater severity in 3.8% of patients. Fatigue, diarrhoea and nausea were the most common clinical adverse events considered possibly related to treatment in patients receiving saquinavir plus zidovudine plus zalcitabine as part of study ACTG 229 (17, 5 and 9% incidence, respectively, for moderate events; 2, 1 and 0%, respectively, for severe events). The addition of saquinavir to zidovudine and/or zalcitabine did not produce any significant change in clinical or laboratory-assessed tolerability profiles.

Dosage and Administration

Saquinavir is currently recommended, in combination with nucleoside analogues, for the treatment of advanced HIV infection in selected patients. The drug should be administered within 2 hours of a full meal at a dosage of 600mg 3 times daily.

Keywords

Human Immunodeficiency Virus Human Immunodeficiency Virus Type Human Immunodeficiency Virus Infection Zidovudine Saquinavir 

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Copyright information

© Adis International Limited 1996

Authors and Affiliations

  • Stuart Noble
    • 1
  • Diana Faulds
    • 1
  1. 1.Adis International LimitedMairangi Bay, Auckland 10New Zealand

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