Evaluation of the bioequivalence of single 100-mg doses of two oral formulations of cyclosporin a microemulsion: A randomized, open-label, two-period crossover study in healthy adult male mexican volunteers

Abstract

Background: Cyclosporin A is widely used in Mexico as immunosuppressive therapy in organ transplantation and in the treatment of autoimmune disorders. Although several generic oral formulations of cyclosporin A are available in Mexico, information concerning the bioequivalence of these formulations in the Mexican population is not available in the published literature. Objective: The aim of this study was to compare the bioequivalence and tolerability of a generic (test) and a branded (reference) soft-gelatin capsule formulation of cyclosporin A microemulsion 100 mg available in Mexico. Methods: This randomized, open-label, 2-period cross-over study was performed at the Universidad Autónomade Nuevo León, Monterrey, México. Eligible subjects were healthy male volunteers who were randomly assigned to receive a single 100-mg dose of the test or reference formulation, followed by a 2-week washout period and administration of the alternate formulation. Doses were administered after a 12-hour overnight fast. For analysis of pharmacokinetic properties, including C max, AUC 0−t, and AUC 0−∞ , blood samples were obtained at intervals over the 48-hour period after dosing. The formulations were considered bioequivalent if the log-transformed ratios of Cma x and AUC were within the predetermined equivalence range (80%-125%). Tolerability was assessed by monitoring vital signs and laboratory tests (hematology, blood biochemistry, hepatic function, and urinalysis), and by questioning subjects about adverse events. Results: Thirty-six male subjects (mean age, 22.08 years [range, 18-29 years]; mean weight, 78.23 kg [range, 72-89 kg]; mean height, 177 cm [range, 169-185 cm]) were enrolled in the study, and 34 (17 each randomized to receive the test or reference formulation first) completed it. No period or sequence effect was observed. The 90% CIs for the log-transformed ratios of C max, AUC 0−t, and AUC 0−∞ were 85.12 to 92.85, 92.14 to 99.75, and 92.19 to 99.72, respectively (all, P <0.05). Similar results were found for the data without log-transformation. No adverse events occurred or were reported by patients during the study. Conclusions: In this small study in healthy adult male Mexican volunteers, a single 100-mg dose of the test formulation was bioequivalent to a single 100-mg dose of the reference formulation based on the regulatory definition (rate and extent of absorption). Both formulations were well tolerated.