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

Bruno Reigner, Susan Grange, Darren Bentley, Ludger Banken, Markus Abt, Richard Hughes, Emmanuel Scheubel, Theodor W Guentert, Bruno Reigner, Susan Grange, Darren Bentley, Ludger Banken, Markus Abt, Richard Hughes, Emmanuel Scheubel, Theodor W Guentert

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 (Cmax) 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 Cmax 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.

Figures

Figure 1.. Mean MPA plasma concentration vs.…
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.…
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…
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.

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