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Population pharmacokinetic and pharmacogenomic analysis of tacrolimus in pediatric living‐donor liver transplant recipients
Author(s) -
Fukudo Masahide,
Yano Ikuko,
Masuda Satohiro,
Goto Maki,
Uesugi Miwa,
Katsura Toshiya,
Ogura Yasuhiro,
Oike Fumitaka,
Takada Yasutsugu,
Egawa Hiroto,
Uemoto Shinji,
Inui Kenichi
Publication year - 2006
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2006.06.008
Subject(s) - tacrolimus , cyp3a5 , pharmacokinetics , cyp3a4 , volume of distribution , liver transplantation , population , gastroenterology , medicine , nonmem , confidence interval , pharmacology , urology , transplantation , biology , endocrinology , genotype , cytochrome p450 , metabolism , gene , biochemistry , environmental health
Objective Our objective was to investigate the population pharmacokinetics of tacrolimus in pediatric living‐donor liver transplant recipients and examine the effects of the multidrug resistance 1 (MDR1) gene and the cytochrome P450 (CYP) genes CYP3A4 and CYP3A5 on the oral clearance of tacrolimus. Methods Data were collected retrospectively from 130 de novo pediatric liver transplant recipients treated with tacrolimus during the first 50 postoperative days. Pharmacogenomic data including both the CYP3A5*3 polymorphism and messenger ribonucleic acid (mRNA) expression levels of MDR1, CYP3A4, and CYP3A5 in the native intestine and the graft liver at transplantation were obtained from 65 of the recipients. Population pharmacokinetic analysis was performed with the nonlinear mixed‐effects modeling program NONMEM to estimate population mean parameters of apparent clearance (CL/F) and apparent volume of distribution (V/F). Results Both CL/F and V/F were allometrically related to body weight, and CL/F decreased when the AST value was elevated. CL/F increased linearly in the immediate postoperative period but did not change with time after postoperative day 21. The intestinal MDR1 mRNA level significantly influenced the initial CL/F ( P < .005). Furthermore, the increase in CL/F over time was 2 times higher (95% confidence interval, 1.19–2.81 times; P < .005) in recipients of a CYP3A5*1 ‐carrying graft liver than in patients with the hepatic CYP3A5*3/*3 genotype. The Bayesian prediction for tacrolimus concentrations was not significantly biased on any postoperative day, and the mean absolute prediction error was lower than 3 ng/mL after the first 2 weeks of transplantation. Conclusions The enterocyte MDR1 mRNA level and the CYP3A5*1 allele in the graft liver contribute differently to the interindividual variability in the oral clearance of tacrolimus after living‐donor liver transplantation. Clinical Pharmacology & Therapeutics (2006) 80 , 331–345; doi: 10.1016/j.clpt.2006.06.008