Dose-Finding Study of a Once-Daily Indinavir/Ritonavir Regimen

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Abstract
In antiretroviral therapy, to improve compliance the need is increasing to develop regimens that combine potency and safety with convenient dosing. The objective of our study was to find a once-daily dosing regimen of a HIV-protease inhibitor, indinavir (IDV), by combining it with ritonavir (RTV). In the study, 12 healthy volunteers took a single IDV dose of 800 mg on day 1. Plasma and urine sampling was done for 12 hours. From day 2 to day 21, participants took RTV liquid 200 mg (group A) or 400 mg (group B) once daily. Repeated pharmacokinetic sampling was performed over the course of 24 hours, after single doses of indinavir 400 mg (day 15), 800 mg (day 18), and 1200 mg (day 21). The best dosage regimen in this pharmacokinetic study was selected based on efficacy and tolerability criteria. The study comprised 10 male and 2 female healthy volunteers, mean age, 25 years (range, 18-50 years), mean weight, 70 kg (range, 52-83 kg). One male participant discontinued on day 8 due to influenza. All other participants completed the study without the occurrence of serious adverse events. RTV inhibited indinavir plasma clearance by 51% to 70%, leading to increased and prolonged IDV exposure. Renal clearance was influenced by the addition of RTV and dosage increments of IDV. The efficacy criterion was best fulfilled by 1200 mg IDV/400 mg RTV, whereas this combination performed most poorly on tolerability criteria. Based on the single dose data, a once-daily regimen of IDV with a low dose of RTV is possible. The best dosage regimen to start with among those studied here appears to be 1200 mg IDV/400 mg RTV, which could be decreased at steady state to 800 IDV/400 RTV or 1200 IDV/200 RTV if toxicity occurs. Steady-state pharmacokinetic data of once-daily IDV/RTV regimens in HIV-infected patients are warrante