Mycophenolate mofetil 500-mg tablet under fasting conditions: single-dose, randomized-sequence, open-label, four-way replicate crossover, bioequivalence study in healthy subjects.

BACKGROUND: Mycophenolate mofetil (MMF), a prodrug of mycophenolic acid (MPA), is an immunosuppressive agent indicated for the prophylaxis of organ rejection in allogeneic kidney, heart, or liver transplant recipients. The European regulatory authorities require bioequivalence studies for the marketing of generic products. OBJECTIVE: The aim of this study was to assess the bioequivalence of a generic (test) and branded (reference) formulation of MMF 500 mg and MPA. METHODS: This single-center, single-dose, randomized, open-label, 4-way crossover study was conducted at Anapharm's Clinical Research Facility, Québec, Québec, Canada. Healthy volunteers aged 18 to 55 years were eligible. Subjects were assigned to receive, in randomized order, a single dose of the test and reference formulations of MMF 500 mg under fasting conditions. Because the study design was 4-way replicate, there were 2 test periods and 2 reference periods. The 4 study periods were each separated by a 14-day washout period. Blood samples were collected over a period of 12 hours after administration for the determination of MMF pharmacokinetic properties, and over 48 (+/-0.5) hours, for MPA properties. Concentrations of the analytes were determined by reverse LC and detected using LC-MS/MS. Pharmacokinetic parameters were calculated from MMF and MPA concentration data using noncompartmental analysis. C(max) and AUC(0-t) were the primary evaluation criteria, while AUC(0-infinity) was a secondary parameter. The drugs were to be considered bioequivalent if the 90% CIs for the test/reference ratios of natural logarithm-transformed values of these parameters (obtained using ANOVA) were between 80% and 125%, per European regulations for bioequivalence. Tolerability was monitored using physical examination, including vital sign measurements, laboratory analysis, and adverse-events (AE) monitoring (including patient interview). RESULTS: A total of 103 subjects were enrolled (64 men, 39 women; 101 white, 2 black; mean [SD] age, 38 [10] years; weight, 68.2 [9.1] kg). The 90% CIs were as follows: MMF, C(max), 85.94% to 106.63%; AUC(0-t), 91.94% to 102.20%; and AUC(0-infinity), 93.15% to 105.48%; MPA, C(max), 92.03% to 105.82%; AUC(0-t), 97.42% to 100.59%; and AUC(0-infinity), 96.96% to 100.90%. These values met with the regulatory definition of bioequivalence. A total of 148 AEs were reported (68 in subjects who received the test treatment and 80 in subjects who received the reference treatment). The most commonly reported AEs were procedural pain (13/102 [12.7%] and 10/101 [9.9%] with the test and reference formulations, respectively), procedural site reaction (12 [11.8%] and 4 [4.0%]), and somnolence (7 [6.9%] and 14 [13.9%]). CONCLUSIONS: The generic and branded formulations of MMF 500 mg met the European regulatory criteria for assuming bioequivalence, based on the rate and extent of absorption of a single dose under fasting conditions. Both formulations were well tolerated in these healthy volunteers.