title: Population pharmacokinetics and Bayesian estimation of tacrolimus exposure in paediatric liver transplant recipients.
abstract: OBJECTIVE
  The objectives of this study were to develop a population pharmacokinetic (PopPK) model for tacrolimus in paediatric liver transplant patients and determine optimal sampling strategies to estimate tacrolimus exposure accurately.
  
  
  METHODS
  Twelve hour intensive pharmacokinetic profiles from 30 patients (age 0.4-18.4 years) receiving tacrolimus orally were analysed. The PopPK model explored the following covariates: weight, age, sex, type of transplant, age of liver donor, liver function tests, albumin, haematocrit, drug interactions, drug formulation and time post-transplantation. Optimal sampling strategies were developed and validated with jackknife.
  
  
  RESULTS
  A two-compartment model with first-order absorption and elimination and lag time described the data. Weight was included on all pharmacokinetic parameters. Typical apparent clearance and central volume of distribution were 12.1 l h(-1) and 31.3 l, respectively. The PopPK approach led to the development of optimal sampling strategies, which allowed estimation of tacrolimus pharmacokinetics and area under the concentration–time curve (AUC) on the basis of practical sampling schedules (three or four sampling times within 4 h) with clinically acceptable prediction error limit. The mean bias and precision of the Bayesian vs. reference (trapezoidal) AUCs ranged from -2.8 to -1.9% and from 7.4 to 12.5%, respectively.
  
  
  CONCLUSIONS
  The PopPK of tacrolimus and empirical Bayesian estimates represent an accurate and convenient method to predict tacrolimus AUC(0-12) in paediatric liver transplant recipients, despite high between-subject variability in pharmacokinetics and patient demographics. The developed optimal sampling strategies will allow the undertaking of prospective trials to define the tacrolimus AUC-based therapeutic window and dosing guidelines in this population.
authors: Nastya
authors: N
authors: Kassir
authors: Line
authors: L
authors: Labbé
authors: Jean-Romain
authors: JR
authors: Delaloye
authors: Mohamad-Samer
authors: MS
authors: Mouksassi
authors: Anne-Laure
authors: AL
authors: Lapeyraque
authors: Fernando
authors: F
authors: Alvarez
authors: Michel
authors: M
authors: Lallier
authors: Mona
authors: M
authors: Beaunoyer
authors: Yves
authors: Y
authors: Théorêt
authors: Catherine
authors: C
authors: Litalien
mesh_terms: D000293:Adolescent; D001499:Bayes Theorem; D002648:Child; D002675:Child, Preschool; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics*; D007223:Infant; D016031:Liver Transplantation; D008297:Male; D008954:Models, Biological; D012189:Retrospective Studies; D016559:Tacrolimus / Q000493:pharmacokinetics*
chemical_list: D007166:Immunosuppressive Agents; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus