Bioequivalence of two oseltamivir formulations in healthy Chinese volunteers .

Abstract

The aim of this study was to compare the bioavailability of a new generic formulation of oseltamivir 75-mg capsule (test) and a branded formulation Tamiflu® (reference) to meet regulatory criteria for marketing the test product in healthy Chinese male volunteers. This single-dose, randomized-sequence, open-label, two-period crossover study was conducted in fasted healthy Chinese male volunteers, who first received a single oral dose of the test or reference formulation with a 7-day washout period, and then the alternative formulation. The study drug was administered after a 10-hour overnight fast. Blood samples were collected at baseline and at 0.25, 0.5, 0.75, 1.0, 1.5, 2, 4, 6, 8, 10, 12, 24, and 36 hours after administration of the study drug. Plasma concentrations of the parent oseltamivir and its metabolite oseltamivir carboxylate were determined using an LC-MS/MS method. The formulations were considered bioequivalent if the 90% confidence intervals (CIs) for the log-transformed values were within the predetermined equivalence range (70-143% for Cmax, 80-125% for AUC) according to the guidelines of the State Food and Drug Administration of China. Adverse events (AEs) were monitored throughout the study based on clinical parameters and patient reports. Characteristics of the 20 male volunteers included were as follows: mean age 23 (±0.7, SD) years (range 21-24 years); weight 69 (±7.1) kg (range 60-88 kg); height 177 (± 5.9) cm (range 168-192 cm). All included subjects completed the study. The mean geometric ratio between the test and reference formulations of oseltamivir was 99.5% (90% CI), 86.3-114.8%) for Cmax, 104.4% (95.7-113.9%) for AUC0-t, and 104.4% (95.6-113.9%) for AUC0-∞. That of oseltamivir carboxylate was 103.7% (90% CI, 95.3-112.8%) for Cmax, 101.7% (96.6-107.1%) for AUC0-t, and 101.4% (96.5-106.5%) for AUC0-∞. There was no significant difference in pharmacokinetic parameters between the two groups. Only 1 AE (nausea) occurred in 1 subject who received the test formulation; the AE resolved without any treatment. The result of this single-dose study indicated that the test formulation of oseltamivir capsule met the Chinese regulatory criteria for bioequivalence vs. the reference formulation in fasted healthy Chinese male volunteers. .