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Drugs

, Volume 60, Issue 2, pp 481–516 | Cite as

Saquinavir Soft-Gel Capsule

An Updated Review of its Use in the Management of HIV Infection
  • David P. Figgitt
  • Greg L. Plosker
Adis Drug Evaluation

Summary

Abstract

Saquinavir is a potent and highly selective HIV protease inhibitor. Initially formulated as a hard-gel capsule (HGC), saquinavir was the first protease inhibitor available commercially for the treatment of patients with HIV infection.

The limited oral bioavailability of saquinavir HGC has been improved significantly with the introduction of a soft-gel capsule (SGC) formulation. Saquinavir SGC displays greater than dose-proportional pharmacokinetics and mean area under the plasma concentration-time curve (AUC) values are 8- to 10-fold higher with saquinavir SGC 1200mg 3 times daily than with the HGC formulation 600mg 3 times daily, the recommended dosages of the 2 formulations. In combination with other protease inhibitors (particularly “low dose” ritonavir), the oral bioavailability of saquinavir (as either the HGC or SGC formulation) is markedly increased, allowing for reduced dosing frequency and/or dosage. The efficacy and tolerability of once- or twice-daily saquinavir SGC/“low dose” ritonavir combinations are currently being evaluated in patients with HIV infection.

Data (up to 48 weeks) from noncomparative and comparative clinical trials evaluating saquinavir SGC-containing combination regimens in adult patients with HIV infection, support and strengthen the clinical efficacy profile of the drug that was demonstrated in initial trials. In antiretroviral therapy-naive and -experienced patients, saquinavir SGC combined with ≥2 nucleoside reverse transcriptase inhibitors (NRTIs), or nelfinavir, or nelfinavir plus 2 NRTIs or non-nucleoside reverse transcriptase inhibitors (NNRTIs), markedly improved immunological nd virological surrogate markers (increased mean CD4+ cell counts and decreased mean plasma HIV RNA levels) of HIV infection. Saquinavir SGC demonstrated a trend to greater antiviral efficacy (measured by improvements in surrogate markers) than the HGC formulation (not statistically significant); a significantly greater proportion of patients treated with saquinavir SGC had plasma HIV RNA levels <400 copies/ml than patients receiving the HGC formulation. n the first direct comparison of 2 protease inhibitors, saquinavir SGC plus 2 NRTIs demonstrated similar antiviral efficacy to indinavir plus 2 NRTIs in patients with HIV infection (almost all of whom were antiretro viral therapy-naive); at 24 weeks, a significantly greater increase in CD4+ cell count from baseline was obtained in the saquinavir SGC group compared with the indinavir group, although this difference was not apparent at week 32. Triple therapy with saquinavir SGC plus 2 NRTIs was as effective as nelfinavir-containing tripletherapy, or quadruple therapy (saquinavir SGC plus 2 NRTIs plus nelfinavir) in markedly suppressing HIV RNA levels in antiretroviral therapy-experienced or -naive patients.

Saquinavir SGC is generally well tolerated. Gastrointestinal disturbances (generally nausea, diarrhoea, abdominal pain, vomiting and dyspepsia of moderate or greater intensity) are the most common adverse events associated with saquinavir SGC-containing therapy. In comparative trials, saquinavir SGC-containing therapy was as well tolerated as indinavir- and nelfinavir-containing therapy; although there were no statistical differences between treatment groups, the incidence of diarrhoea was lower in patients receiving saquinavir SGC compared with nelfinavir, saquinavir SGC plus nelfinavir (all combined with 2 NRTIs) or saquinavir SGC plus nelfinavir without additional therapy. Compared with the HGC formulation, saquinavir SGC appears to be associated with a higher overall incidence of adverse events.

Conclusions: Clinical trial data have shown that as part of triple or quadruple combination therapy, saquinavir SGC is an effective and generally well tolerated protease inhibitor in antiretroviral therapy-naive or -experienced patients with HIV infection. All treatment guidelines include protease inhibitor-containing regimens as a first-line option, although tolerability, resistance, drug interactions and patient compliance/adherence issues remain a concern. There is little doubt that protease inhibitors such as saquinavir SGC currently play a significant role as part of antiretroviral combination therapy. Given the evidence gained to date, saquinavir SGC represents an important component of antiretroviral treatment strategies in the management of patients with HIV infection; in combination with ldlow dose” ritonavir, once-daily saquinavir SGC has the potential to form the cornerstone of dual protease inhibitor therapy.

Overview of Pharmacodynamic Properties

Saquinavir is a potent and highly selective inhibitor of human HIV protease. It acts by binding to the HIV protease active site and inhibiting post-translational viral processing. In vitro, saquinavir has been shown to be the most potent member of its class, inhibiting replication of wild-type HIV by 50 and 90% at concentrations of 3.5 and 50 nmol/L, respectively. Saquinavir has demonstrated additive or synergistic in vitro antiviral activity with a large number of other antiretroviral agents, without host cell cytotoxicity. Substitution of HIV protease amino acids is the primary determinant of resistance to protease inhibitors. The 2 amino acid substitutions commonly observed in vitro and in vivo with saquinavir resistance occur at codons 48 (Gly → Val) [G48V] and 90 (Leu → Met) [L90M], with the G48V mutation being unique to saquinavir. In clinical isolates obtained from atients receiving the soft-gel capsule (SGC) formulation of saquinavir, L90M occurs more frequently than G48V or L90M/G48V double mutants. Cross resistance can develop across the entire class of protease inhibitors. Indeed, in patients treated with saquinavir hard-gel capsule (HGC) for a median of 112 weeks, there was evidence of reduced viral sensitivity to indinavir when patients were subsequently switched to indinavir or saquinavir SGC.

Overview of Pharmacokinetic Properties

In adult patients with HIV infection treated with saquinavir SGC 400 to 1200mg 3 times daily, maximum plasma concentrations (Cmax) ranged from 216 to 2476 µg/L after 1 week and 301 to 2181 µg/L after 3 weeks (a greater than dose-proportional increase in exposure with increasing dose). At weeks 1 and 3, saquinavir HGC 600mg 3 times daily achieved Cmax values of 189 and 198 µg/L, respectively. The area under the plasma concentration-time curve (AUC) was 8- to 10-fold higher in patients treated with saquinavir SGC 1200mg 3 times daily than in those receiving saquinavir HGC 600mg 3 times daily. After multiple doses of saquinavir SGC 1200mg 3 times daily, steady-state AUC values approximately 80% higher than those achieved after a single 1200mg dose were observed in healthy volunteers; Cmax and AUC values in patients with HIV infection were about twice those reported in healthy volunteers after 1 week of saquinavir SGC 1200mg 3 times daily (there is no clear explanation for this discrepancy). Food enhances the absorption of saquinavir SGC.

After a single intravenous dose of saquinavir 12mg, the mean steady-state volume of distribution was 700L. As for most other protease inhibitors, saquinavir SGC is highly bound to plasma proteins (about 97%). Following administration of saquinavir SGC, the drug is metabolised by the cytochrome P450 (CYP) 3A4 isoenzyme to a range of inactive mono- and di-hydroxylated compounds. The major route of saquinavir elimination is biliary, indicating that the impact of renal impairment should be minimal.

Saquinavir has less potential for drug interactions than other protease inhibitors based on their in vitro affinity for CYP3A4. Coadministration of saquinavir SGC with any of the currently available protease inhibitors (ritonavir, nelfinavir, indinavir and amprenavir; all CYP3A4 inhibitors) results in an interactive increase in saquinavir bioavailability; this interaction can be exploited clinically with, for example, the combined administration of saquinavir SGC and “low dose” ritonavir. Indeed, based on favourable pharmacokinetic interactions, a number of clinical trials evaluating once- or twice-daily saquinavir SGC/“low dose” ritonavir combinations (e.g. once-daily saquinavir SGC 1600mg/ritonavir 100mg) are planned or ongoing in patients with HIV infection. Coadministration of saquinavir SGC with drugs that induce CYP3A4 (e.g. rifabutin, rifampicin) causes an interactive decrease in saquinavir bioavailability. On the basis of observed or potential interactions, drugs that should not be coadministered with saquinavir SGC include rifampicin (although coadministration of saquinavir/ritonavir may enable concomitant therapy with rifampicin), midazolam, triazolam, cisapride and ergot derivatives.

Therapeutic Efficacy

The clinical efficacy of saquinavir SGC has been evaluated in a dose-ranging trial (as monotherapy) and, combined with other antiretroviral agents, in a number of noncomparative and comparative trials in antiretro viral therapy-naive or -experienced patients with HIV infection. As clinical end-point data are not available for trials of saquinavir SGC, all available efficacy data relate to surrogate markers (increases in CD4+ cells counts and reductions in plasma HIV RNA levels).

In the dose-ranging trial NV 15107 (protease inhibitor-naive, antiretro viral therapy-experienced patients), the greatest reductions in plasma HIV RNA levels were observed in patients treated with saquinavir SGC 1200mg 3 times daily for 8 weeks compared with those receiving 400 or 800mg 3 times daily or the HGC formulation 600mg 3 times daily (mean reduction from baseline of 0.92 vs 0.41, 0.57 or 0.31 log10 copies/ml, respectively).

In the largest trial (NV 15182) of saquinavir SGC 1200mg 3 times daily in combination with 2 nucleoside reverse transcriptase inhibitors (NRTIs) in antiretroviral therapy-experienced patients with HIV infection (n = 442), mean plasma HIV RNA levels were reduced by 0.9 log10 copies/ml and mean CD4+ counts increased by 80 cells/µl compared with baseline values at week 24.

At 24 weeks, saquinavir SGC as part of triple therapy (with zalcitabine and stavudine; MIKADO trial) markedly reduced plasma HIV RNA levels (median reduction from baseline of 3.05 log10 copies/ml) and significantly improved CD4+ counts (mean increase from baseline of 81 cells/µl; p <0.001 vs baseline) in antiretroviral therapy-naive patients (n = 35) with HIV infection.

Twice-daily saquinavir SGC 1000mg combined with nelfinavir 1250mg twice daily and NRTIs or non-nucleoside reverse transcriptase inhibitors (NNRTIs), has demonstrated efficacy in 2 noncomparative trials in heavily pretreated patients with advanced HIV infection.

Preliminary data also indicate that saquinavir SGC in combination with 2 NRTIs, or combined with nelfinavir plus 1 or 2 NRTIs, has antiviral efficacy in children with HIV infection.

In the first randomised clinical comparison of 2 protease inhibitors in patients with HIV infection [Comparative trial in HIV-infected persons Evaluating Efficacy and Safety of saquinavir-Enhanced oral formulation and indinavir as part of triple therapy (CHEESE study)], saquinavir SGC 1200mg 3 times daily in combination with zidovudine and lamivudine demonstrated similar antiviral efficacy to indinavir 800mg 3 times daily in combination with zidovudine and lamivudine in 70 antiretroviral therapy-naive (except for 3 patients who had received zidovudine for <1 year) patients. At week 24, mean reductions in plasma HIV RNA levels and the percentages of patients with HIV RNA levels below 400 or 50 copies/ml were similar in both treatment groups. However, CD4+ counts increased from baseline by a mean of 162 cells/µl in saquinavir SGC-treated patients compared with 89 cells/µl in indinavir-treated patients (p = 0.01); this difference was not apparent at week 32.

In antiretroviral therapy-experienced and -naive patients (n = 157) with HIV infection [Study of Protease Inhibitor Combinations in Europe (SPICE trial)], saquinavir SGC 1200mg 3 times daily in combination with 2 NRTIs (triple therapy) demonstrated similar clinical efficacy to nelfinavir 750mg 3 times daily plus 2 NRTIs or saquinavir SGC 800mg 3 times daily combined with nelfinavir 750mg 3 times daily plus 2 NRTIs (quadruple therapy) after 48 weeks. Quadruple therapy produced greater virological suppression than triple therapy in antiretroviral therapy-experienced patients, according to an ITT subanalysis of patients stratified by previous treatment. The durability of the virological response obtained with quadruple therapy was significantly greater than that achieved in the other 3 treatment arms (p = 0.006).

Saquinavir SGC 1200mg 3 times daily (n = 90) demonstrated better antiviral efficacy than the HGC formulation 600mg 3 times daily (n = 81), both given in combination with 2 NRTIs in antiretroviral therapy-naive patients with HIV infection (NV 15355). After 16 weeks of treatment, 80% of patients in the SGC treatment group had plasma HIV RNA levels <400 copies/ml compared with 43% of patients who received the HGC formulation (p = 0.001).

Preliminary data (TIDBID trial) indicate that twice-daily administration of saquinavir SGC 1600mg plus 2 NRTIs or 1200mg plus nelfinavir 1250mg twice daily plus 1 NRTI is as efficacious as saquinavir SGC 1200mg 3 times daily plus 2 NRTIs in antiretroviral therapy-experienced and -naive patients with HIV infection.

In patients experiencing virological failure with other protease inhibitors, saquinavir SGC has demonstrated efficacy as part of triple (2 protease inhibitors plus delavirdine or adefovir dipivoxil) or quadruple (2 protease inhibitors plus delavirdine and adefovir dipivoxil or 2 protease inhibitors plus abacavir plus nevirapine or 1 NRTI) salvage therapy.

Tolerability

In more than 500 antiretroviral therapy-experienced or -naive patients, saquinavir SGC as either mono therapy or in combination with other antiretroviral agents, has been shown to be generally well tolerated. Gastrointestinal disorders including diarrhoea, nausea, abdominal discomfort, dyspepsia, flatulence, vomiting and abdominal pain are the most common adverse events associated with saquinavir SGC; these events usually occur with moderate or greater intensity.

In comparative trials, saquinavir SGC-containing regimens were as well tolerated as indinavir- and nelfinavir-containing regimens. Although there were no statistical differences between treatment groups, the incidence of diarrhoea was lower in patients receiving saquinavir SGC 1200mg 3 times daily plus 2 NRTIs compared with nelfinavir 750mg 3 times daily plus 2 NRTIs, saquinavir SGC 800mg plus nelfinavir 750mg (both 3 times daily) plus 2 NRTIs or saquinavir SGC 800mg plus nelfinavir 750mg (both 3 times daily). Compared with saquinavir HGC 600mg 3 times daily (n = 81), saquinavir SGC 1200mg 3 times daily (n = 90) appears to be associated with a higher overall incidence of adverse events (58 vs 70%). Preliminary data indicate that twice-daily administration of saquinavir SGC (1600mg plus 2 NRTIs or 1200mg plus nelfinavir 1250mg twice daily plus 1 NRTI) is as well tolerated as saquinavir SGC 1200mg 3 times daily plus 2 NRTIs.

Dosage and Administration

In adult patients with HIV infection, the recommended dosage of saquinavir SGC is 1200mg 3 times daily, given with, or within 2 hours of, a meal. Saquinavir SGC dosage should be reduced when the drug is coadministered with ritonavir or nelfinavir, although no formal dosage recommendations exist. The potential exists for once-daily administration of saquinavir SGC and ritonavir, and clinical trials of this dosage regimen have been initiated. Storage of saquinavir SGC requires refrigeration until use and, after reaching room temperature, it should be used within 3 months.

Biochemical and laboratory abnormalities should be monitored in patients before and during saquinavir SGC administration. As saquinavir SGC is metabolised principally by the liver and the pharmacokinetic parameters of the drug have not been established in patients with hepatic impairment, saquinavir SGC should be administered with caution in this patient group. On the basis of observed or potential interactions, several drugs should not be coadministered with saquinavir SGC (see Overview of Pharmacokinetic Properties summary).

Keywords

Adis International Limited Ritonavir Triple Therapy Indinavir Saquinavir 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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  1. 1.Adis International LimitedMairangi Bay, Auckland 10New Zealand

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