title: Influence of donor-recipient CYP3A4/5 genotypes, age and fluconazole on tacrolimus pharmacokinetics in pediatric liver transplantation: a population approach.
abstract: OBJECTIVE
  To characterize the effect of donor and recipient CYP3A4, CYP3A5 and ABCB1 genotypes as well as relevant patient characteristics on tacrolimus pharmacokinetics in pediatric liver transplantation.
  
  
  METHODS
  Data from 114 pediatric liver transplant recipients were retrospectively collected during the first 3 months following transplantation. Population pharmacokinetic analysis was performed using nonlinear mixed effects modeling, including characterization of influential covariates.
  
  
  RESULTS
  A two-compartment model with first order elimination best fitted the data. Estimates of apparent volume of the central compartment, intestinal clearance, hepatic clearance and intercompartmental clearance were 79 l, 0.01 l/h, 10.9 l/h and 105 l/h, respectively. Time post-transplantation, recipient age, donor CYP3A5 and CYP3A4 genotypes and fluconazole administration significantly influenced tacrolimus apparent clearance while bodyweight influenced volume of distribution.
  
  
  CONCLUSIONS
  The proposed model displayed acceptable fitting performances and enabled identification of statistically significant and clinically relevant covariates on tacrolimus pharmacokinetics in the early pediatric post liver transplantation period.
authors.affiliation: Laboratory of Analytical Biochemistry, Cliniques Universitaires Saint-Luc & Louvain Centre for Toxicology & Applied Pharmacology (LTAP), UCL, Avenue Mounier 53, Box B1-52-12, 1200, Brussels, Belgium.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Guy-Viterbo
authors.forename: Henry
authors.initials: H
authors.lastname: Baudet
authors.forename: Laure
authors.initials: L
authors.lastname: Elens
authors.forename: Vincent
authors.initials: V
authors.lastname: Haufroid
authors.forename: Florence
authors.initials: F
authors.lastname: Lacaille
authors.forename: Muriel
authors.initials: M
authors.lastname: Girard
authors.forename: Dominique
authors.initials: D
authors.lastname: Debray
authors.forename: Christophe
authors.initials: C
authors.lastname: Chardot
authors.forename: Raymond
authors.initials: R
authors.lastname: Reding
authors.forename: Pierre
authors.initials: P
authors.lastname: Wallemacq
authors.forename: Flora
authors.initials: F
authors.lastname: Musuamba
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D065688:Cytochrome P-450 CYP2C9 Inhibitors / Q000627:therapeutic use; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D005260:Female; D015725:Fluconazole / Q000627:therapeutic use; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D007223:Infant; D007231:Infant, Newborn; D016031:Liver Transplantation / Q000379:methods; D008297:Male; D008657:Metabolic Clearance Rate / Q000235:genetics; D012189:Retrospective Studies; D016559:Tacrolimus / Q000493:pharmacokinetics* / Q000627:therapeutic use; D014019:Tissue Donors; D066027:Transplant Recipients
chemical_list: D065688:Cytochrome P-450 CYP2C9 Inhibitors; D007166:Immunosuppressive Agents; D015725:Fluconazole; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D016559:Tacrolimus
keywords: age; fluconazole; pediatric liver transplantation; pharmacogenetics; tacrolimus