Population pharmacokinetic and pharmacogenomic analysis of tacrolimus in pediatric living-donor liver transplant recipients.
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.
Fukudo
Masahide
M
Department of Pharmacy, Faculty of Medicine, Kyoto University Hospital, Kyoto University, Kyoto, Japan.
Yano
Ikuko
I
Masuda
Satohiro
S
Goto
Maki
M
Uesugi
Miwa
M
Katsura
Toshiya
T
Ogura
Yasuhiro
Y
Oike
Fumitaka
F
Takada
Yasutsugu
Y
Egawa
Hiroto
H
Uemoto
Shinji
S
Inui
Ken-ichi
K
D000293:Adolescent; D001499:Bayes Theorem; D002648:Child; D002675:Child, Preschool; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D005260:Female; D019450:Genes, MDR; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics*; D007223:Infant; D016031:Liver Transplantation; D019520:Living Donors; D008297:Male; D011110:Polymorphism, Genetic; D012333:RNA, Messenger; D012189:Retrospective Studies; D016559:Tacrolimus / Q000493:pharmacokinetics*
D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D003577:Cytochrome P-450 Enzyme System; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D016559:Tacrolimus