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.
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-infinity) , 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-infinity) 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.
Department of Pharmacology and Toxicology, Universidad Autóonoma de Nuevo León, Monterrey, México. bioequivalencia@i-pharma.com.mx
Alfredo
A
Piñeyro-López
Everardo
E
Piñeyro-Garza
Oscar
O
Torres-Alanís
Ratúl
R
Reyes-Araiza
Magdalena
M
Gómez-Silva
Noemí
N
Waksman
Martha
M
E Salazar-Leal
Rubén
R
Luján-Rangel
D000284:Administration, Oral; D000328:Adult; D000704:Analysis of Variance; D019540:Area Under Curve; D002214:Capsules; D002626:Chemistry, Pharmaceutical; D018592:Cross-Over Studies; D016572:Cyclosporine / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D004655:Emulsions; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D008297:Male; D008800:Mexico; D013810:Therapeutic Equivalency
D002214:Capsules; D004655:Emulsions; D007166:Immunosuppressive Agents; D016572:Cyclosporine