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Objectives: The amount of ritonavir needed to enhance saquinavir hard gel (hg) plasma concentrations is unclear. Reduced ritonavir dosing may help to reduce ritonavir-related side effects and costs. This study examined the pharmacokinetics of twice-daily saquinavir-hg (1000?mg) in the presence of ritonavir 100?mg, dosed twice-daily and once-daily on one single occasion.Methods: Eighteen HIV-infected adults taking saquinavir/ritonavir 1000/100?mg twice-daily underwent pharmacokinetic (PK) assessment of saquinavir/ritonavir on day 1 following a morning saquinavir/ritonavir dose. On day 2, PK assessment was repeated when subjects took saquinavir without ritonavir. Drug intake (with a standard meal containing 20?g of fat) was timed on days -1, 1 and 2. Geometric mean ratios (GMR) and 95% confidence intervals (CI) were calculated to assess changes in saquinavir PK parameters.Results: Geometric mean saquinavir AUC012, Ctrough, Cmax and elimination half-life on days 1 and 2 were 14 389 and 9590?ngh/mL, 331 and 234?ng/mL, 2503 and 1893?ng/mL and 2.80 and 2.82?h, respectively. The GMR (95% CI) for these parameters were 0.67 (0.530.84), 0.71 (0.481.04), 0.76 (0.580.98) and 1.01 (0.861.18), respectively.Conclusions: Withholding a ritonavir dose significantly reduces overall saquinavir exposure and Cmax, but had no impact on the elimination half-life. These data establish the need to administer saquinavir and ritonavir simultaneously. [ABSTRACT FROM AUTHOR]