Relationships between exposure to saquinavir monotherapy and antiviral response in HIV-positive patients

Objective: The aim of this study was to confirm the most appropriate dosage of a new soft gelatin capsule (SGC) formulation of the HIV protease inhibi tor saquinavir by investigating the relationships between systemic (plasma) exposure to saquinavir and plasma HIV RNA and CD4+ cell counts using empir ical mathematical modelling. Design and setting: A randomised, non-blind, multicentre, dose-ranging 8-we ek study of monotherapy with 400, 800 or 1200mg of saquinavir-SGC or 600mg of the hard gelatin capsule (HGC) formulation, both administered 3 times da ily, was carried out in protease inhibitor-naive, HIV-positive adults. Two surrogate markers of response, plasma HIV RNA level and CD4+ cell count, we re fitted to 2 measures of systemic drug exposure, the area under the plasm a concentration-time curve (AUC) and trough plasma concentration (C-min), u sing 6 exposure-response models of progressively increasing complexity. Aka ike and Schwarz model selection criteria were applied to determine the most effective pharmacokinetic;pharmacodynamic relationship. Results: A total of 88 patients were randomised; pharmacokinetic and pharma codynamic data were available for 84 patients. In. terms of plasma HIV RNA, pharmacokinetic-pharmacodynamic relationships were best described by a 2-p arameter maximum effect (E-max) model, which predicted a typical maximum re duction in viral load of 1.94 log(10) copies/ml [coefficient of variation ( CV) 12%], with a half-maximal antiviral response occurring at a Cmin Of 50 mu g/L (CV 40%). Saquinavir-SGC 1200mg administered 3 times daily produced a median AUC to 24 hours (AUC(24)) of approximately 20 000 mu g/L . h, corr esponding to 85% of the maximum achievable antiviral effect as defined by t he model. None of the models yielded a satisfactory fit for CD4+ cell count . Conclusion: Empirical mathematical modelling confirmed that, when administe red 3 times daily, the optimum dose of saquinavir-SGC is 1200mg, correspond ing to 3600 mg/day.