Bioequivalence of Two Oral Fluconazole Formulations in Healthy Subjects: a Single Dose, Open-Label, Randomized, Two-Period Crossover Study

Abstract

Background: Fluconazole is a triazole antifungal agent labeled for use in the treatment of oropharyngeal and esoph- ageal candidiasis and cryptococcal meningitis, marketed in Mexico in several generic trade names. Objective: The aim of this study was to compare the bioavailability and determine the bioequivalence of one test formulation (fluconazole oral tablet) with its correspond- ing list reference-drug formulation in Mexico (a list issued by Mexican Health Authorities). Methods: A single dose, randomized, open-label, 2-pe- riod crossover, postmarketing study was conducted. Eli- gible subjects was selected comprising healthy Mexican adults of either sex, and subjects were randomly assigned to receive 1 test formulation of fluconazole followed by the corresponding reference drug formulation, or viceversa, with a 1-week washout period between doses. After a 12- hour (overnight) fast, subjects received a single capsule of fluconazole 150 mg tablet formulation. For the analysis of bioequivalence, including C max , AUC from time 0 (baseline) to time t (AUC 0-t ), and AUC from baseline to infinity (AUC 0- ∞ ), blood samples were collected at baseline, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 48, 72 and 96 hours after dosing. The formulation was considered bioequivalent if the geometric mean ratios (test/reference) of the C max and AUC were within the predetermined range of 80% to 125%. Tolerability was determined by clinical assessment, monitoring vital signs, laboratory analysis results, and sub- ject interviews regarding adverse events. Results: A total of 24 subjects were enrolled in the study The bioequivalence test drug values were C max of 4.44 ± 0.79 μg/mL, t max of 2.59 ± 1.03 h, AUC 0-t of 152.21 ± 28.89 h. μg/mL, AUC 0- ∞ of 175.13 ± 48.98 h. μg/mL, and refer- ence drug values of C max of 4.38 ± 0.83 μg/mL, t max of 2.70 ± 1.15 h, AUC 0-t of 154.67 ± 26.10 r. μg/mL, AUC 0- ∞ of 174.33 ± 31.10 hr. μg/mL. Conclusions: In this study in healthy Mexican adult sub- jects, a single dose of fluconazole 150 mg of the test for- mulation was found to be bioequivalent to the correspond- ing reference formulation according to the regulatory defi- nition of bioequivalence based on the rate and extent of absorption. Both formulations were generally well toler- ated.