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.
Highlights
IntroductionThe bioavailability of orally administered fluconazole is over 90% compared with intravenous administration
Fluconazole is an orally active bistriazole antifungal agent which is used in the treatment of topical and systemic candidiasis and in the treatment of cryptococcal infections in patients with AIDS
Using a power analysis (β = 0.2), it was determined that the power of the analysis of variance (ANOVA) was >0.8 at a 90%
Summary
The bioavailability of orally administered fluconazole is over 90% compared with intravenous administration. Peak plasma concentrations occur between 1 and 2 hours post dose with a terminal plasma elimination half-life of approximately 30 hours (range 20-50 hours). Plasma concentrations are proportional to dose and steady-state levels are reached within 5-10 days with oral doses of 50-400 mg once daily (Debruyne and Ryckelynck, 1993; Al-Gaai et al, 2005; Jovanović et al, 2005; Portolés et al, 2004; Porta et al, 2005; Pereira et al, 2004; Manorot et al, 2000). Steady-state levels are approximately 2.5 times higher the levels achieved with single doses. Administration of loading dose (on day 1) of twice the usual daily dose enables plasma levels to approximate to 90% steady-state levels by day 2. Fluconazole is a triazole antifungal agent labeled for use in the treatment of oropharyngeal and esophageal candidiasis and cryptococcal meningitis, marketed in Mexico in several generic trade names
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