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 1200 mg 3 times daily than with the HGC formulation 600 mg 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 > or =2
nucleoside reverse transcriptase inhibitors (NRTIs), or
nelfinavir, or
nelfinavir plus 2 NRTIs or nonnucleoside
reverse transcriptase inhibitors (NNRTIs), markedly improved immunological and 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. In 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 antiretroviral
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 triple
therapy, 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: