Generics in transplantation medicine: Randomized comparison of innovator and substitution products containing mycophenolate mofetil

Abstract

Objective: Mycophenolate mofetil (MMF) is widely used as an immunosuppressant for the prophylaxis of acute organ rejection in recipients of solid organ transplants.

Materials and methods: We have compared, in healthy subjects, the pharmacokinetics of mycophenolic acid when MMF was administered in the form of the innovator product CellCept (F. Hoffmann-La Roche Ltd.) or one of three commercially available generics, Renodapt (Biocon Ltd.), Mycept (Panacea Biotec), or Cellmune (Cipla Ltd.). The study was powered to detect a 20% difference in mean formulation performance measures, but not to formally evaluate bioequivalence. Geometric mean ratios of maximum concentrations (C_max) and areas under plasma concentration-time curves were calculated.

Results: Comparing generics against each other, the differences in point estimates of the geometric mean ratios of C_max of two of the comparisons were either borderline within (Renodapt/Cellmune) or clearly outside (Mycept/Cellmune) a region of 80 - 125% around the reference mean, indicating that bioequivalence between these generics may be difficult to show.

Conclusion: Physicians in the field of transplantation should be aware of the potential risk of altering the therapeutic outcome when switching from one preparation of MMF to another. ClinicalTrials.gov identifier: NCT02981290.

Figure 1.. Mean MPA plasma concentration vs. time profiles (0 – 6 hours; inset: 0 – 48 hours). MPA = mycophenolic acid.

Figure 2.. Mean MPAG plasma concentration vs. time profiles (0 – 6 hours; inset: 0 – 48 hours). MPAG = 7-O-glucuronide metabolite of mycophenolic acid.

Figure 3.. Dissolution profiles of the four MMF tablets in acetate pH 4.5 buffer at 50 rpm (adapted from Scheubel et al. [4]). MMF = mycophenolate mofetil.