Pharmacokinetics and Bioequivalence Evaluation of Two Voriconazole tablets: an Open-Label, Single-Dose, Randomized, Two-Way Crossover Study in Healthy Chinese Male Volunteers

Abstract

The aim of this study was to assess and compare the pharmacokinetic properties, bioavailability, and bioequivalence of a newly developed tablet of voriconazole with those of an established branded formulation in healthy Chinese adult male volunteers. An open-label, single-dose, randomized, 2-way crossover study was conducted in fasted healthy Chinese male volunteers. Eligible participants were randomly assigned in a 1:1 ratio to receive one tablet (200 mg) of the test or reference formulations, followed by a 1-week washout period and administration of the alternate formulations. Plasma samples were collected over 36 hours and analyzed by HPLC. The Voriconazole plasma concentration–time curves were used to obtain pharmacokinetic parameters including AUC0–t, AUC0–∞, Cmax and Tmax. The criteria for bioequivalence were 90% CIs of 80% to 125% for AUC and 70% to 143% for Cmax, and no significant differences for Tmax with a non-parameter test, according to guidelines of the SFDA of China. Tolerability was based on the recording of Adverse Events (AEs). A total of 19 volunteers were included in the study. The mean (SD) Cmax, Tmax, AUC0–t, and AUC0–∞ values after administration of the test and reference formulation, respectively, were as follows: 925.73(356.11) versus 1040.25(448.93) ng/mL, 1.57(0.98) vs 1.38(0.96) hours, 5304.97(3072.25) vs 5141.63(2976.92) ng/mL/h, and 5783.21(3266.86) vs 5520.69(3148.42) ng/mL/h. The relative bioavailability of the test formulation was 103.2% by mean AUC0–t and 104.8% by mean AUC0−∞. The 90% CIs for the ratios of Cmax, AUC0–t, and AUC0−∞ were 77.3% to 122.7%, 85.7% to 114.3%, and 83.6% to 116.4%, respectively, meeting the predetermined criteria for bioequivalence. No drug-related AEs were observed. In this study the test and reference formulations had similar PK parameters and similar plasma concentrationtime profiles and the test formulations met the regulatory criteria for bioequivalence to the established reference formulations based on the rate and extent of absorption. Both formulations were well tolerated.