Recommendations for bioequivalence testing of cyclosporine generics revisited.

The immunosuppressant cyclosporine is generally considered a critical-dose drug. The validity of standard criteria to establish bioequivalence between cyclosporine formulations has recently been challenged. Recommendations included establishment of individual bioequivalence rather than average bioequivalence, establishment of bioequivalence in transplant patients and in subgroups known to be poor absorbers, as well as long-term efficacy and safety studies in transplant patients. However, at the moment individual bioequivalence is a theoretical concept, the practical benefits of which have not statistically been proven. The proposed patient pharmacodynamic studies can be expected to require an unrealistically high number of subjects to achieve sufficient statistical power. It is well established that the common practice of blood-concentration-guided dosing of cyclosporine efficiently compensates for interindividual and intraindividual variability and allows for safely switching cyclosporine formulations as bioinequivalent as Sandimmune and Neoral. Recent studies comparing the generic cyclosporine formulation SangCya with Neoral, including individual bioequivalence, bioequivalence in transplant patients, and long-term safety after switching from Sandimmune to SangCya, confirmed that it was valid to conclude bioequivalence of both cyclosporine formulations based on standard average bioequivalence criteria. Present FDA guidelines for approving bioequivalence can be considered adequate and sufficient for generic cyclosporine formulations.