Bioequivalence of generic immunosuppressants in kidney transplants

Background: In solid organ transplants (SOT) generic immunosuppression dominates sales. There is a growing concern that properties of generic vs brand immunosuppression in healthy volunteers may not reflect those in SOTs. Bioequivalence studies in SOT recipients published post approval by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) are often disregarded, and the products remain on the market. This has been the case for Tacrolimus Accord (FDA) and Tacni^® by Teva (EMA). We aimed to simultaneously assess the bioequivalence of generic formulations of tacrolimus (Ascend) and mycophenolate mofetil (Accord) in stable kidney transplant recipients (KTR), using Prograf (Astellas) and CellCept (Roche) as reference products.
Methods: KTRs on Prograf^® (tacrolimus, Tac) and CellCept^® (mycophenolate mofetil, MMF) were randomized to one of four treatment sequences of original/generic Tac and MMF, using a single cross-over design. Two 12-hour pharmacokinetic investigations were performed, each collecting 14 blood samples for both Tac and mycophenolic acid (MPA) concentration determinations. In accordance with EMA bioequivalence guidelines, the primary endpoint was the ratio of generic to original AUC_0-12 and C_max. The 90% confidence interval (CI) boundaries for bioequivalence were 0.80-1.25, except for Tac AUC_0-12 which was 0.90 to 1.11 due to the narrow therapeutic index criteria in the guideline. 
Results: In total 38 KTR representative of the Norwegian KTR population (61% males, 44% >60 years, 17% early posttransplant) were included, and provided two evaluable pharmacokinetic investigations. No adverse events occurred during the study.
Generic Tac was not bioequivalent, showing AUC_0-12 and C_max ratios [90% CI] of 1.08 [1.02, 1.16] and 1.19 [1.1, 1.29], respectively. Importantly, the differences increased with increasing age. Tac C₀ was similar with a ratio of 1.01 [0.94, 1.08].
Generic MMF was bioequivalent with AUC_0-12 and C_max ratios of 1.07 [1.0, 1.13] and 1.12 [1.03, 1.21], respectively.
Conclusions: To our knowledge, this is the first simultaneous assessment of generic Tac and MMF in KTR. We were unable to demonstrate bioequivalence for the tested generic Tac, despite its EMA approval. Importantly, the discrepancy in Tac AUC_0-12 and C_max was not detected by traditional pre-dose (C₀) concentration monitoring. For the safety of the SOT population we strongly question current FDA and EMA requirements for market access of generic immunosuppressive drugs as these results adds to previous findings of failed bioequivalence in true patients and highlights the necessity of validating bioequivalence in a clinically relevant population.