Journal of Pharmaceutical Investigation

The Korean Society of Pharmaceutical Sciences and Technology (한국약제학회)
권호 표지
DOI QR코드

DOI QR Code

Bioequivalence of Cyclosporine A 100 mg Soft Capsules (Cipol-N® vs. Sandimmun Neoral®) in Healthy Korean Volunteers

  • Huh, Yong-Ho (Toxicology Lab., Bioanalysis and Biotransformation Research Center, Korea Institute of Science and Technology) ;
  • Park, Eun-A (Toxicology Lab., Bioanalysis and Biotransformation Research Center, Korea Institute of Science and Technology) ;
  • Chung, Youn-Bok (College of Pharmacy, Chungbuk National University) ;
  • Pyo, Hee-Soo (Toxicology Lab., Bioanalysis and Biotransformation Research Center, Korea Institute of Science and Technology) ;
  • Kwon, Oh-Seung (Toxicology Lab., Bioanalysis and Biotransformation Research Center, Korea Institute of Science and Technology)
  • Published : 2008.10.20
Download PDF
⟨ Previous Next ⟩

Abstract

The bioequivalence of two cyclosporine A (CyA) 100 mg soft capsules (Chong Kun Dang's $Cipol-N^{(R)}$ as the test drug; Korea Novartis' Sandimmun $Neoral^{(R)}$ as the reference drug) was assessed in healthy male Korean volunteers after oral administration of 200 mg CyA according to a randomized crossover design. The whole blood samples were analyzed for the determination of parent CyA in the blood by using a validated HPLC/diode array detector method. The mean $AUC_t$ values for reference and test products were $4095.3{\pm}1397.2$ and $3958.3{\pm}1138.2\;ng{\cdot}hr/mL$, respectively. The mean $C_{max}$ values were $1135.9{\pm}293.2\;ng/mL$ for the reference product, and $985.0{\pm}207.9\;ng/mL$ for the test product. $T_{max}$ was $1.6{\pm}0.4\;hr$ for the reference and $1.8{\pm}0.5\;hr$ for the test product. The differences of $AUC_t$, $C_{max}$ and $T_{max}$ were -3.35, -13.28 and +10.63%, respectively. The point estimates and 90% confidence intervals for $AUC_t$ and $C_{max}$ were 0.981 (0.9171 to 1.0514) and 0.876 (0.8229 to 0.9336), respectively. Based on the pharmacokinetic and statistical data, we conclude that these two products are bioequivalent and can be considered interchangeable in the medical practice.

Keywords

References

  1. White DJ, Plumb AM, Pawelec G and Brons G, Cyclosporine A, an immunosuppressive agent preferentially active against proliferating T cells, Transplantation, 27, 55-58 (1979) https://doi.org/10.1097/00007890-197901000-00014
  2. Fowler MB and Schroeder JS, Current status of cardiac transplantation, Mod. Concepts Cardiovasc. Dis., 55, 37-41 (1986)
  3. Kahan BD, Mickey R, Flechner SM, Lorber MI, Wideman CA, Kerman RH, Tersaki P and van Buren CT, Multivariate analysis of risk factors impacting on immediate and eventual cadaver allograft survival in cyclosporine-treated recipients, Transplantation, 43, 65-70 (1987) https://doi.org/10.1097/00007890-198701000-00015
  4. O'Grady JG, Forbes A, Rolles K, Calne RY and William R, An analysis of cyclosporine efficacy and toxicity after liver transplantation, Transplantation, 45, 575-579 (1988) https://doi.org/10.1097/00007890-198803000-00015
  5. Magnasco A, Rossi A, Cartasi P, Gusmano R, Ginevri F, Perfumo F and Ghiggeri GM, Cyclosporine and organ specific toxicity: clinical aspects, pharmacogenetics and perspectives, Curr. Clin. Pharamcol., 3, 166-173 (2008) https://doi.org/10.2174/157488408785747674
  6. Garcia-Escriq M, Martinez J, Fernandez-Ponsati J, Diaz J and Soto O, Severe central nervous system toxicity after chronic treatment with cyclosporine, Clin. Neuropharmacol., 17, 298-302 (1994)
  7. Kronbach T, Fischer V and Mever UA, Cyclosporine metabolism in human liver: identification of cytochrome P450III gene family as the major cyclosporine-metabolizing enzyme explains interaction of cyclosporine with other drugs, Clin. Pharmacol. Ther., 43, 630-635 (1988) https://doi.org/10.1038/clpt.1988.87
  8. Min DI, Lee M, Ru YM and Flanigan M, Gender-dependent racial difference in disposition of cyclosporine among healthy African, African American and White volunteers. Clin. Pharmacol. Ther., 68, 478- (2000) https://doi.org/10.1067/mcp.2000.111255
  9. Stein CM, Sadeque AJ, Murray JJ, Wandel C, Kim RB and Wood AJJ, Cyclosporine pharmacokinetics and pharmacodynamics in African American and White subjects, Clin. Pharmacol. Ther., 69, 317- (2001) https://doi.org/10.1067/mcp.2001.115073
  10. Brozmanova B., Grundmann M, Safarcik K and Jegorov A, High-performance liquid chromatographic method for therapeutic drug monitoring of cyclosporine A and its two metabolites in renal transplant patients, J. Chromatogr. B., 749, 93-100 (2000) https://doi.org/10.1016/S0378-4347(00)00384-4
  11. KFDA, 18. Cyclosporine, In "The Standard Protocols of Bioequivalence Tests", 94-98 (2002)
  12. EC, European Community, Investigation of Bioavailability and Bioequivalence, The Rules Governing Medicinal Products in European Community, Vol. III, 149-169, Addendum 2 (1991)
  13. KFDA, K-BE test for Window, Lee YJ, Chung SJ, and Shim CK, Version 1.2.1 (2002)
  14. KFDA, Notification No. 2005-31, The Standard Protocol of Bioequivalence Test (June 07, 2005)
  15. KFDA, Guidance for Industry. Statistical Approaches to Establishing Bioequivalence, Bioequivalence Division, Pharmacology Department, National Institute of Toxicology Department, http://www.kfda.go.kr (2005)
  16. FDA, Guidance for Industry. Statistical Approaches to Establishing Bioequivalence, U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and research (CDER). Office of Training and Communication, Division of Communications Management, Rockville, MD (January 2001)