Pharmacokinetics of once-daily saquinavir/ritonavir in HIV-infected subjects: comparison with the standard twice-daily regimen

OBJECTIVE: To evaluate the steady-state pharmacokinetics and safety of two once-daily saquinavir/ritonavir (SQV/RTV) regimens, 1600/100 and 2000/100 mg, in HIV-positive patients. METHODS: Eighteen HIV-infected adults treated with the standard twice-daily SQV/RTV 1000/100 mg regimen were enrolled in this open-label, two-phase, crossover pharmacokinetic study. The steady-state pharmacokinetics of SQV administered with 100 mg RTV were investigated following once-daily doses of 1600 mg or 2000 mg or a twice-daily dose of 1000 mg. Plasma drug concentrations were determined by high performance liquid chromatography-tandem mass spectrometry and pharmacokinetic parameters were calculated using a non-compartmental model. RESULTS: Compared with SQV 1000 mg twice daily, the Cmax of SQV following a 1600 mg and 2000 mg dose increased in a dose-proportional manner [geometric mean (95% CI) 1915 (1656-2850) ng/ml for 1000 mg, 2782 (2249-4330) ng/ml for 1600 mg and 4179 (3429-6105) ng/ml for 2000 mg doses, respectively]. SQV Ctrough values were 539 (453-1011), 106 (76-223) and 231 (75-822) ng/ml, respectively. A SQV Ctrough value greater than 100 ng/ml was achieved in all subjects on the twice-daily regimen, in 9/18 (50%) subjects on the 1600/100 mg once-daily regimen, and in 14/17 (82%) subjects on the 2000/100 mg once-daily regimen. The once-daily regimens were well tolerated, with mild-to-moderate gastrointestinal symptoms being the only events reported by a small number of patients. CONCLUSION: This is the first study to evaluate the pharmacokinetics of once-daily SQV/RTV 2000/100 mg in HIV-infected subjects. Our findings suggest that this regimen may be an alternative to twice-daily 1000/100 mg doses and should be further evaluated in efficacy studies. The data indicate that most patients (14/17) on once-daily 2000/100 mg achieve trough concentrations above target values (determined for HIV wild-type) for efficacy of SQV with the use of just 100 mg RTV/day and with good tolerability.