Population pharmacokinetics and pharmacogenetics of tacrolimus in de novo pediatric kidney transplant recipients.
The aim of this study was to develop a population pharmacokinetic model of tacrolimus in pediatric kidney transplant patients, identify factors that explain variability, and determine dosage regimens. Pharmacokinetic samples were collected from 50 de novo pediatric kidney transplant patients (age 2-18 years) who were on tacrolimus treatment. Population pharmacokinetic analysis of tacrolimus was performed using NONMEM, and the impact of variables (demographic and clinical factors, and CYP3A4-A5, ABCB1, and ABCC2 polymorphisms) was tested. The pharmacokinetic data were described by a two-compartment model that incorporated first-order absorption and lag time. The apparent oral clearance (CL/F) was significantly related to body weight (allometric scaling); in addition, it was higher in patients with low hematocrit levels and lower in patients with CYP3A5*3/*3. The population pharmacokinetic-pharmacogenetic model developed in de novo pediatric kidney transplant patients demonstrated that, in children, tacrolimus dosage should be based on weight, hematocrit levels, and CYP3A5 polymorphism. Individualization of therapy will enable the optimization of tacrolimus exposure, with resultant beneficial effects on kidney function in the initial post-transplantation period.
Zhao
W
W
Department of Pediatric Pharmacology and Pharmacogenetics, Hôpital Robert Debré, Paris, France.
Elie
V
V
Roussey
G
G
Brochard
K
K
Niaudet
P
P
Leroy
V
V
Loirat
C
C
Cochat
P
P
Cloarec
S
S
André
J L
JL
Garaix
F
F
Bensman
A
A
Fakhoury
M
M
Jacqz-Aigrain
E
E
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D000293:Adolescent; D000367:Age Factors; D001835:Body Weight; D002648:Child; D002675:Child, Preschool; D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000378:metabolism; D054796:Drug Dosage Calculations; D016903:Drug Monitoring; D004359:Drug Therapy, Combination; D005260:Female; D005602:France; D006400:Hematocrit; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016030:Kidney Transplantation; D008297:Male; D008954:Models, Biological; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism; D011110:Polymorphism, Genetic; D015203:Reproducibility of Results; D016559:Tacrolimus / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016896:Treatment Outcome
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D051544:Cytochrome P-450 CYP3A; D007166:Immunosuppressive Agents; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D016559:Tacrolimus; C513055:ABCB1 protein, human; C000715087:ABCC2 protein, human; C510164:CYP3A5 protein, human; C510163:CYP3A4 protein, human