Comparative in vivo bioequivalence and in vitro dissolution of two cyclosporin A soft gelatin capsule formulations

Objective: A study was conducted to establish the bioequivalence between a newly developed cyclosporin A (CsA) oral formulation, Deximune® soft-gel-atin capsules (Dexcel Ltd.) and Sandinimune Neoral® (Novartis Inc.). Materials and methods: The clinical investigation was designed as a randomized, open-labeled, two-period, two-treatment crossover study, in 24 healthy fasted male volunteers. The subjects were administered a single 200 mg CsA dose of either formulation. Serial venous blood samples were obtained over 24 hours after each administration to measure CsA in whole blood by a specific TDx-immunoassay. In addition, the comparative drug release rate was assessed using a dissolution apparatus test according to the USP-24 method. Results: For both treatments, a mean maximum blood concentration (C_max) of approximately 1,200 ng/ml was obtained at about 1.6 hours (t_max) after administration and the geometric mean of the area under the blood concentration-time curve (AUC) both for test and reference was approximately 4,900 ng × h/ml. Bioequivalence was conclusively demonstrated for both rate (C_max and t_max) and extent (AUC) of CsA absorption, between the two treatments. Moreover, the CsA blood concentration measurement at 2 hours after administration (C₂), demonstrated equivalent results between the two products. The point estimates and their 90% confidence intervals were within the respective equivalence ranges for the pharmacokinetic parameters and were included in the range for drugs with a narrow therapeutic index. The comparative dissolution test for both formulations showed an in vitro release rate of more than 90% within 15 minutes. Conclusions: Based on the results, the two oral CsA formulations compared are bioequivalent and can be interchanged without need for dosage adjustment.