Population pharmacokinetics and pharmacogenetics of mycophenolic acid following administration of mycophenolate mofetil in de novo pediatric renal-transplant patients.
The objective was to develop a population pharmacokinetic-pharmacogenetic model of mycophenolic acid following administration of mycophenolate mofetil (MMF) in de novo pediatric renal-transplant patients and identify factors that explain variability. The pharmacokinetic samples were collected from 89 de novo pediatric renal-transplant patients treated with MMF and studied during the first 60 postoperative days. All patients were genotyped for UGT1A8-A9, UGT2B7, and ABCC2. Population pharmacokinetic analysis was performed with the NONMEM and was validated using bootstrap visual predictive check. The pharmacokinetic data were best described by a 2-compartment model with Erlang distribution to describe the absorption phase. The covariate analysis identified body weight as an individual factor influencing central volume of distribution and concomitant immunosuppressive medication and identified body weight and UGT2B7 802C>T genotype as individual factors influencing apparent oral clearance (CL/F) of MMF. CL/F in cyclosporine-MMF-treated patients was 33% higher than in tacrolimus-MMF-treated patients. The CL/F was significantly lower in patients with UGT2B7 802 C/C genotype compared with patients with UGT2B7 802 C/T and 802T/T genotypes, and this effect was independent of concomitant immunosuppressive medication or body weight. The population pharmacokinetic-pharmacogenetic model of mycophenolic acid was validated. Body weight, concomitant medication, and UGT2B7 genotype contribute significantly to the interindividual variability of MMF disposition in pediatric renal-transplant patients.
Department of Pediatric Pharmacology and Pharmacogenetics, Hôpital Robert Debré, Paris, France.
Wei
W
Zhao
May
M
Fakhoury
Georges
G
Deschênes
Gwenaelle
G
Roussey
Karine
K
Brochard
Patrick
P
Niaudet
Michel
M
Tsimaratos
Jean Luc
JL
André
Sylvie
S
Cloarec
Pierre
P
Cochat
Albert
A
Bensman
Saïd
S
Azougagh
Evelyne
E
Jacqz-Aigrain
D000293:Adolescent; D001835:Body Weight; D002648:Child; D002675:Child, Preschool; D016572:Cyclosporine / Q000008:administration & dosage / Q000627:therapeutic use; D005260:Female; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007223:Infant; D016030:Kidney Transplantation; D008297:Male; D008954:Models, Biological; D000089762:Multidrug Resistance-Associated Protein 2; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D017711:Nonlinear Dynamics; D010597:Pharmacogenetics; D011446:Prospective Studies; D016559:Tacrolimus / Q000008:administration & dosage / Q000627:therapeutic use; D014018:Tissue Distribution
C000715087:ABCC2 protein, human; D007166:Immunosuppressive Agents; D000089762:Multidrug Resistance-Associated Protein 2; D016572:Cyclosporine; C491474:UGT2B7 protein, human; D014453:Glucuronosyltransferase; D009173:Mycophenolic Acid; D016559:Tacrolimus