Saquinavir Soft-Gel Capsule Formulation
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Saquinavir is an HIV protease inhibitor which, formulated as a hard-gel capsule (HGC), was the first drug of its class to become available for the treatment of patients with HIV infection.
Despite the beneficial effects that saquinavir HGC-containing combination regimens have shown in the treatment of patients with HIV infection, the HGCformulation has limited oral bioavailability and has shown only modest antiviral activity in vivo. To overcome this limitation (with the aim of improving antiviral efficacy), a soft-gel capsule (SGC) formulation of the drug has been developed. At the recommended dosage of 1200mg 3 times daily, the SGC formulation of saquinavir achieves plasma concentrations >8 times higher than those in patients receiving saquinavir HGC 600mg 3 times daily.
Initial results of trials evaluating the therapeutic efficacy of saquinavir SGC-containing combination therapy in patients with moderate to advanced HIV infection are promising. In patients who were previously antiretroviral therapynaive or — experienced, short term (≤ 36 weeks) treatment with saquinavir SGC incombination with ≥ 2 nucleoside reverse transcriptase inhibitors (NRTIs), or nelfinavir, or 2 NRTIs plus nelfinavir led to marked improvements in virological and immunological markers of HIV disease. In comparative trials, saquinavir SGC showed improved antiviral activity compared with the HGC formulation in terms of reducing viral load. Furthermore, saquinavir SGC in combination with 2 NRTIs was as effective as indinavir plus 2 NRTIs in antiretroviral-naive or — experienced patients. Available data suggest that saquinavir SGC-containing combination therapy may be of greatest benefit in patients naive to previous antiretroviral therapy.
The SGC formulation of saquinavir appears to be generally well tolerated by adults with HIV infection. Gastrointestinal adverse events, notably diarrhoea, abdominal discomfort, nausea and dyspepsia, are the most common adverse events occurring during treatment with the drug.
Initial results of several trials that used surrogate markers to assess treatment efficacy indicate that the SGC formulation of saquinavir, administered in combination with other antiretroviral drugs, is an effective and well-tolerated treatment for patients with moderate or advanced HIV infection. Although further data are required before definitive conclusions can be drawn regarding the comparative efficacy and tolerability of the SGC and HGC formulations, it appears likely that the SGC formulation will replace the conventional formulation as a component of combination regimens for the treatment of patients with HIV infection.
Rationale for Developing a Soft-Gel Formulation
Because the hard-gel capsule (HGC) formulation of saquinavir HGC has low oral bioavailability, as a result of limited absorption and extensive first-pass metabolism, its therapeutic efficacy is less than optimal. To address this problem, saquinavir has been reformulated as a soft-gel capsule (SGC) which provides greater systemic exposure to the drug.
Overview of Pharmacodynamic Properties
Saquinavir is a selective inhibitor of HIV protease and a transition-state mimetic of the phenylalanine-proline (Phe-Pro) peptide cleavage site. Its antiviral activity is achieved by competitive inhibition of HIV protease-mediated cleavage of gag and gagpol polyproteins, thus preventing post-translational viral processing. At therapeutic concentrations, saquinavir does not appear to inhibit the activity of mammalian proteases.
In vitro, saquinavir shows activity against HIV-1, including zidovudine-resistant strains; concentrations required to produce 50% inhibition of various strains of HIV-1 ranged from 1 to 30 nmol/L (≈0.77 to 23.1 μg/L). Additive or synergistic in vitro antiviral activity occurs with saquinavir in combination with most nucleoside reverse transcriptase inhibitors (NRTIs) and/or other drugs with anti-HIV-1 activity.
HIV-1 resistance to saquinavir has been documented in vitro and in vivo. The key mutations conferring viral resistance to the drug are at codons 90 (Leu → Met) [L90M] and 48 (Gly → Val) [G48V]. In clinical isolates from patients treated with either the SGC or HGC formulation of saquinavir, the L90M mutation predominates. Although systemic exposure to saquinavir (and therefore selective pressure) is greater with the saquinavir SGC than with the HGC, available data suggest that the resistance profiles of the 2 formulations are the same or similar.
Although the mutations in HIV protease characterising resistance to saquinavir differ from those seen in patients receiving treatment with ritonavir, indinavir and nelfinavir, additional mutations may occur during long term treatment. These mutations may lead to resistance to other protease inhibitors.
Overview of Pharmacokinetic Properties
Mean maximum plasma concentration (Cmax) values of saquinavir ranged from 301.2 to 2181 μg/L in patients with HIV infection after doses of saquinavir SGC 400, 800 or 1200mg given 3 times daily. A lower saquinavir Cmax occurred in HIV-infected patients who received saquinavir HGC 600mg 3 times daily. The area under the plasma concentration-time curve (indicating the extent of systemic exposure to saquinavir) was >8 times higher in recipients of saquinavir SGC 1200mg 3 times a day (the recommended dosage) than after saquinavir HGC 600mg 3 times daily. Absorption of saquinavir from the SGC is enhanced by the presence of food.
Saquinavir has a large volume of distribution (about 700L) and is highly bound (about 97%) to plasma proteins. It is metabolised by the cytochrome P450 3A4 (CYP3A4) isoenzyme to mono- and di-hydroxylated metabolites, which have negligible antiviral activity.
Drugs that induce [e.g. rifampicin (rifampin), rifabutin, phenobarbital, phenytoin, carbamazepine] the CYP3A4 isoenzyme have the potential to cause an interactive decrease in the bioavailability of saquinavir. Conversely, administration of saquinavir with drugs that inhibit CYP3A4 (such as the protease inhibitors ritonavir, nelfinavir and indinavir) results in an interactive increase in the bioavailability of saquinavir.
The efficacy of saquinavir SGC has been investigated in several hundred adults with moderate or advanced HIV infection. Efficacy assessments were based on surrogate marker data (changes in plasma HIV RNA levels and in CD4+ cell counts); clinical end-point data are not yet available.
In a dose-ranging trial (NV 15107), the reduction in plasma HIV RNA levels was greater in HIV-infected patients who received saquinavir SGC 1200mg 3 times daily for 8 weeks than in recipients of saquinavir SGC 400 or 800mg 3 times daily or saquinavir HGC 600mg 3 times daily. The maximum median reduction in plasma HIV RNA in the saquinavir SGC 1200mg treatment group was 1.43 log10 copies/ml.
In trials of saquinavir SGC in combination with ≥2 NRTIs conducted in antiretroviral therapy-experienced adults with moderate to advanced HIV infection, plasma HIV RNA levels decreased by approximately 2.8 logio copies/ml after 16 or 36 weeks of treatment. HIV RNA levels became undetectable (limit of detection <400 copies/ml) in 43 to 80% of patients. Increases in CD4+ cell counts also occurred. Marked improvements in plasma HIV RNA levels and CD4+ cell counts were also evident in antiretroviral therapy-naive patients with HIV infection who received saquinavir SGC 1200mg 3 times daily in combination with zidovudine 300mg twice daily and lamivudine 150mg twice daily.
In addition, saquinavir SGC in combination with 2 NRTIs improved virological and immunological markers of HIV infection in a small number of antiretro viral therapy-experienced children with HIV infection.
Improvements in virological and immunological markers also occurred in antiretroviral therapy-experienced adults with HIV infection who received combination therapy with saquinavir SGC 1200mg 3 times daily plus nelfinavir 750mg 3 times daily.
In comparative trials, saquinavir SGC 1200mg 3 times daily in combination with 2 NRTIs was as effective as indinavir 800mg 3 times daily plus 2 NRTIs. Decreases in plasma HIV RNA levels were greater in patients who received saquinavir SGC in combination with either 2 NRTIs plus nelfinavir or 2 NRTIs than in patients treated with either saquinavir SGC plus nelfinavir or nelfinavir plus 2 NRTIs. Patients who were antiretroviral therapy-naive gained the most benefit from 4-drug combination therapy.
Saquinavir SGC 1200mg 3 times daily in combination with 2 NRTIs was more effective than saquinavir HGC 600mg plus 2 NRTIs in terms of reducing viral load in antiretroviral therapy-naive patients with HIV infection; plasma HIV RNA levels decreased to below the limit of detection (<400 copies/ml) in 80 and 43% of the SGC and HGC recipients, respectively, (p = 0.001) after 16 weeks.
Saquinavir SGC, given in combination with NRTIs and/or nelfinavir, is generally well tolerated in antiretroviral therapy-naive and -experienced adults with HIV infection. Limited data indicate that saquinavir SGC combination therapy is also well tolerated in children.
Gastrointestinal disturbances, including diarrhoea, abdominal discomfort, nausea and dyspepsia, were the most common events that occurred in HIV-infected patients receiving the drug in clinical trials. These events were typically mild in intensity. In a comparative trial, the incidence of adverse events was slightly higher in recipients of saquinavir SGC combination therapy than in patients treated with HGC combination therapy. Serious adverse events occurred in 5.6 and 2.5% of SGC and HGC recipients, respectively. 21 (5%) of 442 HIV-infected patients treated with saquinavir SGC combination therapy discontinued treatment because of adverse events in another trial.
Dosage and Administration
The recommended dosage of saquinavir SGC for patients with HIV infection is 1200mg 3 times daily in combination with NRTIs, taken ≤2 hours after a meal. Dosage reduction is required when saquinavir SGC is coadministered with the protease inhibitors ritonavir or nelfinavir, although formal recommendations are not yet available. Saquinavir SGC should not be given as monotherapy.
Patients should be monitored for biochemical abnormalities before and during treatment with saquinavir SGC. Since there are no data on the use of saquinavir SGC in patients with hepatic impairment, caution should be applied when administering the drug in this group. Drugs which are contraindicated in patients receiving saquinavir SGC therapy include terfenadine, astemizole, cisapride, triazolam, midazolam and ergot derivatives.
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