Akira Okada1, Hidetaka Ushigome2, Misaki Kanamori1, Aya Morikochi1, Hidefumi Kasai3, Tadashi Kosaka4, Takatoshi Kokuhu5, Asako Nishimura6, Nobuhito Shibata6, Keizo Fukushima1, Norio Yoshimura2, Nobuyuki Sugioka7. 1. Department of Clinical Pharmacokinetics, Faculty of Pharmaceutical Sciences, Kobe Gakuin University, 1-1-3 Minatojima, Chuo-ku, Kobe, 650-8586, Japan. 2. Department of Transplantation and Regenerative Surgery, Kyoto Prefectural University of Medicine, 465 Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan. 3. Certara G.K, 4-2-12, Toranomon, Minato-ku, 105-0001, Japan. 4. Department of Hospital Pharmacy, Kyoto Prefectural University of Medicine, 465 Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan. 5. Depertment of Pharmacy, Japan Community Health Care Organization Kyoto Kuramaguchi Medical Center, 27 Koyama Shimofusa-cho, Kita-ku, Kyoto, 603-8151, Japan. 6. Depertment of Biopharmaceutics, Faculty of Pharmaceutical Science, Doshisha Women's College of Liberal Arts, 97-1 Kodo, Kyo-tanabe, Kyoto, 610-0395, Japan. 7. Department of Clinical Pharmacokinetics, Faculty of Pharmaceutical Sciences, Kobe Gakuin University, 1-1-3 Minatojima, Chuo-ku, Kobe, 650-8586, Japan. nsugioka@pharm.kobegakuin.ac.jp.
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.
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.
Entities:
Keywords:
Covariate analysis; Cyclosporine; Population pharmacokinetics; Renal transplantation
Authors: H J Eisen; R E Hobbs; S F Davis; M Carrier; D M Mancini; A Smith; H Valantine; H Ventura; M Mehra; J L Vachiery; B K Rayburn; C C Canver; G Laufer; M R Costanzo; J Copeland; G Dureau; O H Frazier; R Dorent; P J Hauptman; C Kells; R Masters; J L Michaud; I Paradis; D G Renlund; J Vanhaecke; B Mellein; E A Mueller Journal: Transplantation Date: 2001-01-15 Impact factor: 4.939