Single-dose, Two-way Crossover, Bioequivalence Study of Mycophenolate Mofetil 500 mg Tablet Under Fasting Conditions in Healthy Male Subjects

Abstract

Background Mycophenolate mofetil (MMF) is an immunosuppressant indicated for prophylaxis of acute organ transplant rejection. Generic MMF is less costly than the branded product, but European regulatory authorities require bioequivalence studies for the marketing of generics. Objectives The aims of the 2 studies reported were to assess the dissolution and bioavailability of a generic (test) and branded (reference) formulation of MMF 500 mg. Methods An in vitro analytical dissolution profile test was conducted comparing 500 mg MMF test drug with a reference drug. A separate single-dose, randomized, open-label, 2-way crossover study involving fasting, healthy, adult male volunteers was conducted. Two study periods—1 test drug period and 1 reference drug period—were separated by a 14-day washout period. Blood samples were collected for up to 60 hours after drug administration for the determination of MMF and mycophenolic acid (MPA) pharmacokinetics. Concentrations of the analytes were determined using a validated liquid chromatography–tandem mass spectrometry (LC-MS/MS) method; pharmacokinetic parameters were calculated using noncompartmental analysis; C max, AUC 0-t, and AUC 0-∞ were the primary evaluation criteria. Bioequivalence was assumed if the 90% confidence intervals (CIs) for the test/reference ratios of natural logarithm transformed values (obtained using ANOVA) were between 80% and 125%, per European regulations for bioequivalence. Tolerability was monitored throughout the study. Results The dissolution profiles of the test drug matched those of the reference drug at 4 pH levels. In the bioequivalence study, a total of 126 male subjects were dosed, and 117 subjects completed the study. The 90% CIs for MPA were C max, 94.13% to 116.46%; AUC 0-t, 98.26% to 102.36%; and AUC 0-∞, 97.85% to 101.99%. These values met with the European regulatory definition of bioequivalence. Reported adverse events were similar in both the test and reference drugs. Conclusions This single-dose study found that the test and reference MMF 500 mg tablets met the European regulatory criteria for assuming bioequivalence in fasting, healthy, male subjects. Both formulations were well tolerated. (Clinical Trials Registry - India [CTRI]: 2011/03/002211).