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.

Targeting Organic Anion Transporter 3 with Probenecid as a Novel Anti-Influenza A Virus Strategy

“…Administration of probenecid alone reduced influenza A virus titer in agreement with the finding that OAT3 is important for influenza A virus replication. Additionally, probenecid has been previously reported to elevate plasma concentrations of an active oseltamivir metabolite, oseltamivir carboxylate; thus, its coadministration with oseltamivir has been suggested (19)(20)(21). This report shows that probenecid, the classical OAT3 inhibitor, can potentially be repositioned for a new anti-influenza A therapy.…”

Prediction of the Pharmacodynamically Linked Variable of Oseltamivir Carboxylate for Influenza A Virus Using an In Vitro Hollow-Fiber Infection Model System

“…Because of issues of availability of oseltamivir carboxylate in a pandemic situation, Holodny et al (22) examined everyother-day dosing of oseltamivir supplemented with q6h dosing of probenecid and daily dosing supplemented with q12h dosing of probenecid. There are no data on a minimum target value of AUC 0-24 for oseltamivir carboxylate to predict a high likelihood of a good clinical outcome.…”

“…Nonetheless, the finding that AUC/EC 50 is the pharmacodynamic driver for oseltamivir should give pause to the idea of employing dosing regimens that fall outside the "80-125 rule." In order to put the findings of the Holodny study (22) into perspective, it would be important to generate an AUC 0-24 /EC 50 target for outcome and to employ Monte Carlo simulation to ascertain how frequently the alternative regimens (including probenecid) attain such a target. Given the noted point estimates of the means and standard deviations, it is highly likely that such alternative FIG.…”

Oseltamivir and G6PD deficiency

“…Other metabolites-oseltamivir phosphate, D3-oseltamivir phosphate, and D3-oseltamivir carboxylate -have since been detected [2,3]. There is at present no information on the possible effects of these compounds on the G6PD pathway.…”

“…There is at present no information on the possible effects of these compounds on the G6PD pathway. As a result, G6PD-deficient individuals have been excluded during the pharmacokinetic studies of oseltamivir [2].…”