Effect of high-dose vitamin C on the steady-state pharmacokinetics of the protease inhibitor indinavir in healthy volunteers

Study Objective. To determine whether daily high-dose vitamin C alters the steady-state pharmacokinetics of indinavir, a protease inhibitor indicated for treatment of the human immunodeficiency virus type 1. Design. Prospective, open-label, longitudinal, two-period time series. Setting. University medical center. Subjects. Seven healthy volunteers. Intervention. Indinavir 800 mg every 8 hours was given to subjects for four doses on days 1 and 2. Plasma samples were then collected for indinavir pharmacokinetic determination. After a 7-day washout period, subjects were given vitamin C 1000 mg/day for 7 days. Beginning on day 6 of vitamin C administration, indinavir 800 mg every 8 hours was restarted for four doses. Plasma was then collected from subjects to determine indinavir pharmacokinetics. All subjects were given a vitamin C content-controlled diet for I week before the study began and throughout the study period. Measurements and Main Results. Steady-state plasma samples were collected before dosing (0 hr) and 0.5, 1, 2, 3, 4, and 5 hours after dosing to determine indinavir pharmacokinetics. Parameters of interest were maximum plasma concentration (C-max), time to C-max, area under the plasma concentration-time curve from 0-5 hours after the dose (AUC(0-5)), an extrapolated 8-hour AUC (AUC(0-8)), trough (minimum) plasma concentration (C-min), and oral clearance. Mean steady-state indinavir C-max was significantly reduced (20%) after 7 days of vitamin C administration (10.3 +/- 1.5 vs 8.2 +/- 2.9 mug/ml, p=0.04). The corresponding mean AUC(0-8) was also significantly decreased (14%; 26.4 +/- 7.2 vs; 22.7 +/- 8.1 mug.hr/ml, p=0.05). Although not statistically significant, the mean indinavir C-min was 32% lower in the presence of vitamin C (0.27 +/- 0.17 C vs 0.18 +/- 0.08 mug/ml, p=0.09). Indinavir oral clearance and half-life were not significantly different. Conclusion. Concomitant administration of high doses of vitamin C can reduce steady-state indinavir plasma concentrations. Subtherapeutic concentrations of antiretroviral agents have been associated with viral resistance and regimen failure, but the clinical significance of our findings remains to be established.