Population pharmacokinetics of cyclosporine A in Japanese renal transplant patients: comprehensive analysis in a single center

Akira Okada, Hidetaka Ushigome, Misaki Kanamori, Aya Morikochi, Hidefumi Kasai, Tadashi Kosaka, Takatoshi Kokuhu, Asako Nishimura, Nobuhito Shibata, Keizo Fukushima, Norio Yoshimura, Nobuyuki Sugioka

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Purpose: Cyclosporine A (CyA), a potent immunosuppressive agent used in renal transplantation, has a narrow therapeutic window and a large variability in blood concentrations. This study aimed to develop a population pharmacokinetic (PPK) model of CyA in living-donor renal transplant patients at a single center and identify factors influencing CyA pharmacokinetics (PK). Methods: A total of 660 points (preoperative) and 4785 points (postoperative) of blood concentration data from 98 patients who underwent renal transplantation were used. Pre- and postoperative CyA model structure and PPK parameters were separately estimated with a non-linear mixed-effect model, and subsequently, covariate analysis of postoperative data were comprehensively estimated, including preoperative PK parameters. Results: A two-compartment model with first-order absorption and absorption lag time was selected in this study. Aspartate aminotransferase, body surface area (BSA), pretransplant area under the whole blood concentration–time curve/dose, and postoperative days were identified as the covariates on oral clearance. BSA was selected as a covariate of the distribution volume of the central compartment. In addition, diabetes mellitus was selected as a covariate of the first-order absorption rate. Conclusions: This PPK study used the largest number of blood concentration data among previous reports of living-donor renal transplant patients. Moreover, all patients received the same immunosuppressive regimen in a single center. Therefore, the validity of the selected covariates is reliable with high precision. The developed PPK model and selected covariates provide useful information about factors influencing CyA PK and greatly contributes to the identification of the most suitable dosing regimen for CyA.

Original languageEnglish
Pages (from-to)1111-1119
Number of pages9
JournalEuropean Journal of Clinical Pharmacology
Volume73
Issue number9
DOIs
Publication statusPublished - 2017 Sep 1
Externally publishedYes

Keywords

  • Covariate analysis
  • Cyclosporine
  • Population pharmacokinetics
  • Renal transplantation

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Fingerprint Dive into the research topics of 'Population pharmacokinetics of cyclosporine A in Japanese renal transplant patients: comprehensive analysis in a single center'. Together they form a unique fingerprint.

  • Cite this

    Okada, A., Ushigome, H., Kanamori, M., Morikochi, A., Kasai, H., Kosaka, T., Kokuhu, T., Nishimura, A., Shibata, N., Fukushima, K., Yoshimura, N., & Sugioka, N. (2017). Population pharmacokinetics of cyclosporine A in Japanese renal transplant patients: comprehensive analysis in a single center. European Journal of Clinical Pharmacology, 73(9), 1111-1119. https://doi.org/10.1007/s00228-017-2279-2