title: Population pharmacokinetics of mycophenolic acid and dose optimization with limited sampling strategy in liver transplant children.
abstract: OBJECTIVE
  The aims were to estimate the mycophenolic acid (MPA) population pharmacokinetic parameters in paediatric liver transplant recipients, to identify the factors affecting MPA pharmacokinetics and to develop a limited sampling strategy to estimate individual MPA AUC(0,12 h).
  
  
  METHODS
  Twenty-eight children, 1.1 to 18.0 years old, received oral mycophenolate mofetil (MMF) therapy combined with either tacrolimus (n= 23) or ciclosporin (n= 5). The population parameters were estimated from a model-building set of 16 intensive pharmacokinetic datasets obtained from 16 children. The data were analyzed by nonlinear mixed effect modelling, using a one compartment model with first order absorption and first order elimination and random effects on the absorption rate (k(a)), the apparent volume of distribution (V/F) and apparent clearance (CL/F).
  
  
  RESULTS
  Two covariates, time since transplantation (≤ and >6 months) and age affected MPA pharmacokinetics. k(a), estimated at 1.7 h(-1) at age 8.7 years, exhibited large interindividual variability (308%). V/F, estimated at 64.7 l, increased about 2.3 times in children during the immediate post transplantation period. This increase was due to the increase in the unbound MPA fraction caused by the low albumin concentration. CL/F was estimated at 12.7 l h(-1). To estimate individual AUC(0,12 h), the pharmacokinetic parameters obtained with the final model, including covariates, were coded in Adapt II(®) software, using the Bayesian approach. The AUC(0,12 h) estimated from concentrations measured 0, 1 and 4 h after administration of MMF did not differ from reference values.
  
  
  CONCLUSIONS
  This study allowed the estimation of the population pharmacokinetic MPA parameters. A simple sampling procedure is suggested to help to optimize pediatric patient care.
authors.affiliation: Department of Clinical Pharmacy, Assistance Publique - Hôpitaux de Paris, Hôpitaux Universitaires Paris-Sud, Le Kremlin Bicêtre, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Barau
authors.forename: Valérie
authors.initials: V
authors.lastname: Furlan
authors.forename: Dominique
authors.initials: D
authors.lastname: Debray
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Taburet
authors.forename: Aurélie
authors.initials: A
authors.lastname: Barrail-Tran
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000367:Age Factors; D019540:Area Under Curve; D001499:Bayes Theorem; D002648:Child; D002675:Child, Preschool; D016572:Cyclosporine / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007223:Infant; D016031:Liver Transplantation; D008297:Male; D008954:Models, Biological; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D017711:Nonlinear Dynamics; D016559:Tacrolimus / Q000008:administration & dosage; D014018:Tissue Distribution
chemical_list: D007166:Immunosuppressive Agents; D016572:Cyclosporine; D009173:Mycophenolic Acid; D016559:Tacrolimus