Relative bioavailability of two formulations of nevirapine 200-mg tablets in healthy Chinese male volunteers: a single-dose, randomized-sequence, open-label, two-way crossover study.

摘要

BACKGROUND: Nevirapine was the first member of the nonnucleoside reverse transcriptase inhibitor class to be approved for the treatment of HIV infection. It binds directly to the allosteric site on the reverse transcriptase and inhibits the activity of both RNA- and DNA-dependent DNA polymerases. OBJECTIVE: This study compared the pharmacokinetics and relative bioavailability of a test and reference formulation of nevirapine 200-mg tablets after single oral doses in healthy Chinese men to meet regulatory criteria for marketing of the new generic formulation. METHODS: This single-dose, randomized-sequence, open-label, 2-way crossover study was conducted at the Nanjing First Hospital of Nanjing Medical University, Nanjing, China. Healthy male Chinese volunteers were randomized in a 1ratio1 ratio to receive a single 200-mg (3.2-mg/kg) tablet of the test or reference formulation, followed by a 2-week washout period and administration of the alternate formulation. The study drugs were administered after a 10-hour overnight fast. Concentrations of nevirapine were assayed using an HPLC-UV method. For analysis of nevirapine pharmacokinetic parameters, blood samples were obtained before dosing and at regularly scheduled intervals over 168 hours after administration. The 2 formulations would be assumed to be bioequivalent for regulatory purposes if the 90% CIs for the log-transformed ratios of nevirapine AUC and C(max) were within the range established by the US Food and Drug Administration (0.80-1.25). Tolerability was evaluated throughout the study based on vital signs, physical examinations, 12-lead ECGs, and subject interviews concerning adverse events (AEs). RESULTS: Twenty Chinese male subjects were enrolled in and completed the study. Their mean age was 23 years (range, 21-25 years), mean weight was 63 kg (range, 56-70 kg), and mean height was 171 cm (range, 166-176 cm). No period or sequence effect was observed. The mean (SD) t((1/2)) was 38.12 (2.23) hours for the test tablet and 36.79 (5.06) hours for the reference tablet; T(max) was 3.1 (0.7) and 3.0 (0.7) hours, respectively; C(max) was 2.52 (0.31) and 2.60 (0.48) mg . L(-1); AUC(0-168) was 155.66 (22.41) and 150.66 (22.11) mg . h . L(-1); and AUC(0-infinity) was 163.30 (22.88) and 157.75 (22.87) mg . h . L(-1). Mean relative bioavailability was 103.6% (8.6%). The 90% CIs for the log-transformed ratios of C(max) (93.51-102.13) and AUC(0-168) ( 99.84-106.74) were within the predetermined range for the assumption of bioequivalence. One subject reported mild headache after receiving the test formulation; the relationship of this AE to study drug was considered uncertain. No serious or clinically significant AEs were observed or reported during the study. CONCLUSIONS: In this single-dose study in healthy fasted Chinese males, the test tablet met the regulatory criterion for assumption of bioequivalence to the reference tablet. Both formulations were well tolerated in the population studied. SFDA registration no: 2009L04358.