Generic cyclosporine: a word of caution.

Cyclosporine (CsA) has been the cornerstone of immunosuppression for organ transplantation since its introduction. However, CsA is a critical drug as it has low therapeutic index and high inter- and intra-individual variations in bioavailability. The new microemulsion Neoral has increased bioavailability and is not influenced by bile or food. When compared with the old formulation, Neoral was able to significantly reduce rejection and to allow a better long-term graft survival in renal transplant patients. Moreover, the measurement of CsA at peak, around 2 hours after Neoral administration, proved to be a reliable index of the drug exposure, thus allowing efficient drug monitoring. Recently, different CsA galenics have been approved on the basis of bioequivalence tests performed in a small number of healthy volunteers after a single administration. Transplant experts expressed their concern about the adequacy of these tests in organ transplantation. The few short-term studies of bioequivalence in renal transplant recipients reported conflicting results. Certainly, the bioequivalence tests used, cannot capture a subset of low-absorbers who are exposed to the risk of underimmunosuppression. Another matter of concern is the lack of studies with galenic CsA to evaluate the role of C2 measurement for therapeutic drug monitoring. Observational studies reported a lower 1-year renal allograft survival in patients treated with galenic CsA than in patients given Neoral. A main problem is the absence of long-term studies with generic CsA, in the complex setting of organ transplantation.