Relationships Between Exposure to Saquinavir Monotherapy and Antiviral Response in HIV-Positive Patients

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Abstract
The aim of this study was to confirm the most appropriate dosage of a new soft gelatin capsule (SGC) formulation of the HIV protease inhibitor saquinavir by investigating the relationships between systemic (plasma) exposure to saquinavir and plasma HIV RNA and CD4+ cell counts using empirical mathematical modelling. A randomised, non-blind, multicentre, dose-ranging 8-week study of monotherapy with 400, 800 or 1200mg of saquinavir-SGC or 600mg of the hard gelatin capsule (HGC) formulation, both administered 3 times daily, was carried out in protease inhibitor-naive, HIV-positive adults. Two surrogate markers of response, plasma HIV RNA level and CD4+ cell count, were fitted to 2 measures of systemic drug exposure, the area under the plasma concentration-time curve (AUC) and trough plasma concentration (Cmin), using 6 exposure-response models of progressively increasing complexity. Akaike and Schwarz model selection criteria were applied to determine the most effective pharmacokinetic-pharmacodynamic relationship. A total of 88 patients were randomised; pharmacokinetic and pharmacodynamic data were available for 84 patients. In terms of plasma HIV RNA, pharmacokinetic-pharmacodynamic relationships were best described by a 2-parameter maximum effect (Emax) model, which predicted a typical maximum reduction in viral load of 1.94 log10 copies/ml [coefficient of variation (CV) 12%], with a half-maximal antiviral response occurring at a Cmin of 50 μ g/L (CV 40%). Saquinavir-SGC 1200mg administered 3 times daily produced a median AUC to 24 hours (AUC24) of approximately 20 000 μg/L · h, corresponding to 85% of the maximum achievable antiviral effect as defined by the model. None of the models yielded a satisfactory fit for CD4+ cell count. Empirical mathematical modelling confirmed that, when administered 3 times daily, the optimum dose of saquinavir-SGC is 1200mg, corresponding to 3600 mg/day.