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-gelatin capsules (Dexcel Ltd.) and Sandimmune Neoral (Novartis Inc.).


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 (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.


CONCLUSIONS
Based on the results, the two oral CsA formulations compared are bioequivalent and can be interchanged without need for dosage adjustment.
Avramoff
A
A
Department of Medicinal Chemistry and Natural Products, School of Pharmacy-Faculty of Medicine, The Hebrew University, Jerusalem, Israel. rnd@dexxon.co.il
Laor
A
A
Kitzes-Cohen
R
R
Farin
D
D
Domb
A J
AJ
D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D002214:Capsules; D018592:Cross-Over Studies; D016572:Cyclosporine / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D005780:Gelatin; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D008297:Male; D008657:Metabolic Clearance Rate; D012995:Solubility; D013810:Therapeutic Equivalency
D002214:Capsules; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D005780:Gelatin