Comparative bioavailability of two oral formulations of mycophenolate mofetil in healthy adult Uruguayan subjects: a case of highly variable rate of drug absorption

Objective: To assess the bioequivalence and safety of a new formulation of mycophenolate mofetil (MMF) 500 mg (Suprimun (R), Clausen, Montevideo, Uruguay) marketed in Uruguay and other South American countries, and to test C-max/AUC as a characteristic of its absorption rate. Material and methods: A randomized, open-label, two-way, two-treatment, two-period crossover study in 24 healthy male volunteers was carried out. One tablet (500 mg) of each formulation was administered after an overnight fast. After dosing, serial blood samples were collected for a period of 36 hours. Plasma concentrations of MPA were determined by high-performance liquid chromatography and pharmacokinetic parameters were calculated. Analysis of variance was carried out using log-transformed AUC(0-36), C-max, and C-max/AUC(0-36). 90% confidence intervals and within-subject between-subject variance were calculated. The bioequivalence of the two formulations was established at the 80% - 125% acceptance limits and untransformed t(max) medians were compared using Wilcoxon test. Subjects were monitored for adverse events throughout the study. Results: The means (test and reference) were 21.14 and 20.86 mu g x h x ml(-1) for AUC(0-36), 24.92 and 24.18 mu g x h x ml(-1) for AUC(0-infinity), 11.86 and 10.76 mu g x ml(-1) for C-max and 0.51 and 0.54 h(-1) for C-max/AUC(0-36). The geometric mean ratios (confidence interval 90%) of Test/Reference were 1.00 (0.95 - 1.06) for AUC(0-36), 1.09 (0.96 - 1.24) for C-max and 1.04 (0.99 - 1.09) for C-max/AUC(0-36). The extra peaks observed are due to enterohepatic recycling of MPA. No serious or unexpected adverse events were observed during the study. Conclusions: The test formulation containing mycophenolate mofetil 500 mg met regulatory requirements for bioequivalence. Moreover, C-max/AUC shows interesting features as a putative metric to evaluate the absorption rate of highly variable drugs like