The effect of ritonavir on saquinavir plasma concentration is independent of ritonavir dosage: combined analysis of pharmacokinetic data from 97 subjects

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Abstract
Objective To determine the correlation between ritonavir (RTV) dose and the degree of enhancement of saquinavir (SQV) exposure. Methods Combined analysis of pharmacokinetic data at steady state obtained from two open‐label, randomized, parallel‐group, multiple‐dose, single‐centre studies involving healthy volunteers. Plasma samples for SQV assay were obtained from 97 healthy subjects following multiple dosing of a range of SQV (400–1800 mg) plus RTV (100–400 mg) dosages for 13–14 days. The pharmacokinetics of SQV were derived by model‐independent, noncompartmental methods. Data were analysed by multivariate regression of log transformed Cmin and Cmax (geometric means) of SQV dosage as the dependent variable and independent variables of SQV and RTV dosage. Ritonavir was fitted as both a continuous and a categorical variable. Results There is a strong effect of any dose of RTV on Cmax and Cmin of SQV (P < 0.0001 for both parameters), but no greater effect of higher vs. lower RTV dosages on either parameter (Cmax: P=0.4373; Cmin: P=0.3393). Higher SQV dosage correlates linearly with higher Cmax (P=0.0093) and Cmin (P=0.0010), but the effects of increasing SQV dosages are less than with the addition of any RTV dose. Conclusions RTV enhances SQV concentrations to increase Cmax and Cmin. This effect is similar for RTV dosages of 100–400 mg twice daily. Based on this concept of ‘mini‐dose’ RTV, once‐daily dosing of 1600 mg SQV/100 mg RTV and twice‐daily 1000 mg SQV/100 mg RTV are currently being evaluated in clinical trials.