Pharmacokinetics and tolerability of oseltamivir combined with probenecid

Abstract

Oseltamivir is an inhibitor of influenza virus neuraminidase, which is approved for use for the treatment and prophylaxis of influenza A and B virus infections. In the event of an influenza pandemic, oseltamivir supplies may be limited; thus, alternative dosing strategies for oseltamivir prophylaxis should be explored. Healthy volunteers were randomized to a three-arm, open-label study and given 75 mg oral oseltamivir every 24 h (group 1), 75 mg oseltamivir every 48 h (q48h) combined with 500 mg probenecid four times a day (group 2), or 75 mg oseltamivir q48h combined with 500 mg probenecid twice a day (group 3) for 15 days. Pharmacokinetic data, obtained by noncompartmental methods, and safety data are reported. Forty-eight subjects completed the pharmacokinetic analysis. The study drugs were generally well tolerated, except for one case of reversible grade 4 thrombocytopenia in a subject in group 2. The calculated 90% confidence intervals (CIs) for the geometric mean ratios between groups 2 and 3 and group 1 were outside the bioequivalence criteria boundary (0.80 to 1.25) at 0.63 to 0.89 for group 2 versus group 1 and 0.57 to 0.90 for group 3 versus group 1. The steady-state apparent oral clearance of oseltamivir carboxylate was significantly less in groups 2 (7.4 liters/h; 90% CI, 6.08 to 8.71) and 3 (7.19 liters/h; 90% CI, 6.41 to 7.98) than in group 1 (9.75 liters/h; 90% CI, 6.91 to 12.60) (P < 0.05 for both comparisons by analysis of variance). The (arithmetic) mean concentration at 48 h for group 2 was not significantly different from the mean concentration at 24 h for group 1 (42 +/- 76 and 81 +/- 54 ng/ml, respectively; P = 0.194), but the mean concentration at 48 h for group 3 was significantly less than the mean concentration at 24 h for group 1 (23 +/- 26 and 81 +/- 54 ng/ml, respectively; P = 0.012). Alternate-day dosing of oseltamivir plus dosing with probenecid four times daily achieved trough oseltamivir carboxylate concentrations adequate for neuraminidase inhibition in vitro, and this combination should be studied further.

Figures

FIG. 1.

Mean plasma oseltamivir concentrations (± standard error of the mean) versus time in 18 subjects receiving oseltamivir 75 mg daily for 2 weeks.

FIG. 2.

Mean plasma probenecid concentrations (± standard error of the mean) versus time in subjects receiving probenecid 500 mg QID for 2 weeks (group 2; open diamonds) and 500 mg BID for 2 weeks (group 3; closed squares).

FIG. 3.

Mean plasma oseltamivir carboxylate concentrations (± standard error of the mean) versus time in three groups of healthy human subjects after 2 weeks of oseltamivir administration. Group 1 (solid diamonds, dashed line) received oseltamivir 75 mg q24h; group 2 (solid squares, solid line) received oseltamivir 75 mg q48h plus probenecid 500 mg QID; and group 3 (open triangles, solid line) received oseltamivir 75 mg q48h plus probenecid 500 mg BID. Error bars indicate standard errors of the means.