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

  • Pharmacokinetics and Disposition
  • Published:
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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.

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Acknowledgements

This study was supported by Nagai Memorial Research Scholarship from the Pharmaceutical Society of Japan (AO).

Author information

Authors and Affiliations

  1. Department of Clinical Pharmacokinetics, Faculty of Pharmaceutical Sciences, Kobe Gakuin University, 1–1–3 Minatojima, Chuo–ku, Kobe, 650–8586, Japan

    Akira Okada, Misaki Kanamori, Aya Morikochi, Keizo Fukushima & Nobuyuki Sugioka

  2. Department of Transplantation and Regenerative Surgery, Kyoto Prefectural University of Medicine, 465 Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan

    Hidetaka Ushigome & Norio Yoshimura

  3. Certara G.K, 4-2-12, Toranomon, Minato-ku, 105-0001, Japan

    Hidefumi Kasai

  4. Department of Hospital Pharmacy, Kyoto Prefectural University of Medicine, 465 Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan

    Tadashi Kosaka

  5. Depertment of Pharmacy, Japan Community Health Care Organization Kyoto Kuramaguchi Medical Center, 27 Koyama Shimofusa-cho, Kita-ku, Kyoto, 603-8151, Japan

    Takatoshi Kokuhu

  6. Depertment of Biopharmaceutics, Faculty of Pharmaceutical Science, Doshisha Women’s College of Liberal Arts, 97-1 Kodo, Kyo-tanabe, Kyoto, 610-0395, Japan

    Asako Nishimura & Nobuhito Shibata

Authors
  1. Akira Okada
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  2. Hidetaka Ushigome
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  3. Misaki Kanamori
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  4. Aya Morikochi
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  5. Hidefumi Kasai
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  6. Tadashi Kosaka
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  7. Takatoshi Kokuhu
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  8. Asako Nishimura
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  9. Nobuhito Shibata
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  10. Keizo Fukushima
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  11. Norio Yoshimura
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  12. Nobuyuki Sugioka
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Contributions

AO, HU, Tadashi K, Takatoshi K, KF, NY, and Nobuyuki S equally contributed to the conception, design of the research, and acquisition of the data; AO, MK, AM, HK, AN, Nobuhito S, and KF contributed to the analysis of the data. All the authors critically revised the manuscript, read, and approved the final manuscript and agree to be fully accountable for ensuring the integrity and accuracy of the work.

Corresponding author

Correspondence to Nobuyuki Sugioka.

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The authors declare that they have no conflict of interest.

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Okada, A., Ushigome, H., Kanamori, M. et al. Population pharmacokinetics of cyclosporine A in Japanese renal transplant patients: comprehensive analysis in a single center. Eur J Clin Pharmacol 73, 1111–1119 (2017). https://doi.org/10.1007/s00228-017-2279-2

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  • DOI: https://doi.org/10.1007/s00228-017-2279-2

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