Bioequivalence Study of Three Ciclosporin Capsule Formulations in Healthy Volunteers

Abstract

The study was conducted in order to assess the bioequivalence of three capsule formulations containing 100 mg of ciclosporin (CAS 59865-13-3). 24 Healthy volunteers, 20 to 37 years of age (mean 26, SD 5.3 years), weighing 51 to 76 kg (mean 65, SD 7.0 kg) and a body height of 1.5 to 1.83 m (mean 1.68, SD 0.07 m) were enrolled in the study. Each volunteer received a single oral dose of 300 mg (3 100 mg ciclosporin capsules) on three separate occasions according to a randomized, single-dose, three-way crossover design with three formulations of ciclosporin: Treatment I (reference formulation, capsules), Treatment II (test formulation 1, soft gel capsules), Treatment III (test formulation 2, hard gel capsules). Blood samples for the determination of ciclosporin were drawn at scheduled intervals up to 56 h after dosing. Ciclosporin concentrations in whole blood were determined by a specific HPLC method with ultraviolet detection. Quantitation of ciclosporin was validated for concentrations range from 25 to 1600 ng/ml. Since the 90% confidence intervals for the “test/reference” mean ratio of the Log-transformed pharmacokinetic variables C_max, AUC_0–t and AUC_0–∞ were clearly within the bioequivalence range of 80% to 125%, the treatments were considered bioequivalent in terms of both the rate and extent of absorption.

Key words

CAS 59865-13-3 - Ciclosporin, pharmacokinetics, bioequivalence - Immunosuppressants

• Literature

• 1 Borel JF. Ciclosporin and its future. Progress in Allergy. 1986; 38: 9-18
• 2 Kahan BD. Ciclosporin: nursing and paraprofessional aspects. Grune and Stratton. 1984;
• 3 Kahan BD. Ciclosporin: a revolution in transplantation. Transplantation Transplant Proc. 1999; Feb–Mar 31 (1–2A) 14S-15S
• 4 Thomas MD, Cook LJ. Fever associated with ciclosporin for treating atopic dermatitis. Br Med J. 1998; 317: 1291- (7 November)
• 5 Bach JF. The contribution of Ciclosporin A to the understanding and treatment of autoimmune diseases. Transplantation Proceedings. 1999; 31 Suppl (1/2A) 16S-18S
• 6 Perlik F, Masri MA, Rost M, Kamarad V. Pharmacokinetic conversion study of a new Ciclosporin formulation in stable adult renal transplant recipients. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2005; Dec 149 (2) 309-13
• 7 Min DI, Hwang GC, Bergstrom S, Madras PN, Shaffer D, Sahyoun AI et al Bioavailability and patient acceptance of Ciclosporin soft gelatin capsules in renal allograft recipients. Ann Pharmacother. 1992; Feb 26 (2) 175-9
• 8 Eadon H, Rose M, O’Neill R, Leaver N, Yacoub M. A pharmacokinetic comparison of ciclosporin oral solution and ciclosporin capsules in heart and lung transplant recipients. Transplant International. 1995; Jan-Feb 8 (l) 35-40
• 9 Kovarik JM, Mueller EA, van Bree JB, Tetzloff W, Kutz K. Reduced inter- and intraindividual variability in Ciclosporine pharmacokinetics from a microemulsion formulation. J Pharm Sci. 1994; Mar 83 (3) 444