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

• Published in: International journal of clinical pharmacology and therapeutics Vol. 45; no. 2; p. 126
• Main Authors: Avramoff, A, Laor, A, Kitzes-Cohen, R, Farin, D, Domb, A J
• Format: Journal Article
• Language: English
• Published: Germany 01.02.2007
• Subjects: Administration, Oral; Adult; Area Under Curve; Capsules; Cross-Over Studies; Cyclosporine - administration & dosage; Cyclosporine - chemistry; Cyclosporine - pharmacokinetics; Gelatin; Humans; Immunosuppressive Agents - administration & dosage; Immunosuppressive Agents - chemistry; Immunosuppressive Agents - pharmacokinetics; Male; Metabolic Clearance Rate; Solubility; Therapeutic Equivalency
• ISSN: 0946-1965
• DOI: 10.5414/cpp45126

A study was conducted to establish the bioequivalence between a newly developed cyclosporin A (CsA) oral formulation, Deximune soft-gelatin capsules (Dexcel Ltd.) and Sandimmune Neoral (Novartis Inc.). 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. For both treatments, a mean maximum blood concentration (Cmax) of approximately 1,200 ng/ml was obtained at about 1.6 hours (tmax) 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 x h/ml. Bioequivalence was conclusively demonstrated for both rate (Cmax and tmax) 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. Based on the results, the two oral CsA formulations compared are bioequivalent and can be interchanged without need for dosage adjustment.