Once-daily dosing of saquinavir and low-dose ritonavir in HIV-1-infected individuals: a pharmacokinetic pilot study

Objective: To investigate the steady-state pharmacokinetics of a once-daily dosing regimen of saquinavir soft gelatin capsules in combination with a l ow dose of ritonavir in HIV-l-infected individuals. Design: Open-label, multi-dose, pharmacokinetic pilot study. Patients: Seven HIV-l-infected individuals who were treated with saquinavir hard gelatin capsules 400 mg twice daily + ritonavir liquid formulation 40 0 mg twice daily were switched to saquinavir soft gelatin formulation 1600 mg once daily in combination with ritonavir liquid formulation 200 mg once daily (day 0). Patients were instructed to ingest saquinavir and ritonavir simultaneously in the morning and with a meal. Methods: Steady-state pharmacokinetics of saquinavir and ritonavir were ass essed during a 24 h dosing interval after 2 weeks of continued therapy (day 14). Plasma saquinavir and ritonavir concentrations were measured using a validated high performance liquid chromatography assay. in addition, plasma HIV-1 RNA, and fasting total cholesterol, high-density lipoprotein, low-de nsity lipoprotein, and triglyceride levels were measured on days 0 and 14. A non-compartmental pharmacokinetic method was used to calculate the area u nder the plasma concentration versus time curve (AUC([0-24h])), the maximum and trough plasma concentrations (C-max and C-min), the time to reach C-ma x (T-max), the elimination halflife (t(1/2)), the apparent clearance (Cl/F) , and the apparent volume of distribution (V/F). Results: Median (range) values of the pharmacokinetic parameters for saquin avir after 2 weeks of treatment were: AUC([0-24h]), 19 802h*ng/ml (3720-74 016); C-max, 2936 ng/ml (573-6848); C-min, 84 ng/ml (11-854); T-max, 3.5 h (3.0-4.0), t(1/2), 6.8 h (4.6-10.2); Cl/F 81 l/h (22-430); V/F, 11891 (215- 3086). Ritonavir concentrations were always below the 90% effective concent ration of 2100 ng/ml (median C-max, 1323 ng/ml; range, 692-1528 ng/ml). No significant changes were observed for total serum cholesterol, high-density lipoprotein, and low-density lipoprotein levels between days 0 and 14 (P g reater than or equal to 0.24). In six out of seven patients the fasting ser um triglyceride levels were lower 2 weeks after the treatment switch (media n decrease was 32%, P= 0.03). No significant changes in plasma HIV-1 RNA co ncentrations were observed between days 0 and 14. The regimen was generally well tolerated. Conclusions: This pharmacokinetic study indicates that the combination of 1 600 mg of saquinavir (soft gelatin capsules) and 200 mg of ritonavir (liqui d formulation) in a once-daily dosing regimen generally results in therapeu tic plasma concentrations of saquinavir. Due to the large interindividual v ariation in saquinavir exposure, the monitoring of saquinavir concentration s in plasma is warranted. These pharmacokinetic findings rationalize the fu rther clinical evaluation of once-daily dosing of this combination of prote ase inhibitors. (C) 2000 Lippincott Williams & Wilkins.