title: Population pharmacokinetics and maximum a posteriori probability Bayesian estimator of abacavir: application of individualized therapy in HIV-infected infants and toddlers.
abstract: BACKGROUND
  Abacavir is used to treat HIV infection in both adults and children. The recommended paediatric dose is 8 mg kg(-1) twice daily up to a maximum of 300 mg twice daily. Weight was identified as the central covariate influencing pharmacokinetics of abacavir in children.
  
  
  CONCLUSIONS
  A population pharmacokinetic model was developed to describe both once and twice daily pharmacokinetic profiles of abacavir in infants and toddlers. Standard dosage regimen is associated with large interindividual variability in abacavir concentrations. A maximum a posteriori probability Bayesian estimator of AUC(0-) (t) based on three time points (0, 1 or 2, and 3 h) is proposed to support area under the concentration-time curve (AUC) targeted individualized therapy in infants and toddlers.
  
  
  OBJECTIVE
  To develop a population pharmacokinetic model for abacavir in HIV-infected infants and toddlers, which will be used to describe both once and twice daily pharmacokinetic profiles, identify covariates that explain variability and propose optimal time points to optimize the area under the concentration-time curve (AUC) targeted dosage and individualize therapy.
  
  
  METHODS
  The pharmacokinetics of abacavir was described with plasma concentrations from 23 patients using nonlinear mixed-effects modelling (NONMEM) software. A two-compartment model with first-order absorption and elimination was developed. The final model was validated using bootstrap, visual predictive check and normalized prediction distribution errors. The Bayesian estimator was validated using the cross-validation and simulation-estimation method.
  
  
  RESULTS
  The typical population pharmacokinetic parameters and relative standard errors (RSE) were apparent systemic clearance (CL) 13.4 () h−1 (RSE 6.3%), apparent central volume of distribution 4.94 () (RSE 28.7%), apparent peripheral volume of distribution 8.12 () (RSE14.2%), apparent intercompartment clearance 1.25 () h−1 (RSE 16.9%) and absorption rate constant 0.758 h−1 (RSE 5.8%). The covariate analysis identified weight as the individual factor influencing the apparent oral clearance: CL = 13.4 × (weight/12)1.14. The maximum a posteriori probability Bayesian estimator, based on three concentrations measured at 0, 1 or 2, and 3 h after drug intake allowed predicting individual AUC0–t.
  
  
  CONCLUSIONS
  The population pharmacokinetic model developed for abacavir in HIV-infected infants and toddlers accurately described both once and twice daily pharmacokinetic profiles. The maximum a posteriori probability Bayesian estimator of AUC(0-) (t) was developed from the final model and can be used routinely to optimize individual dosing.
authors: Department of Pediatric Pharmacology and Pharmacogenetics, Hôpital Robert Debré, Université Paris VII, 48 Boulevard Sérurier, Paris Cedex 19, France.
authors: Wei
authors: W
authors: Zhao
authors: Massimo
authors: M
authors: Cella
authors: Oscar
authors: O
authors: Della Pasqua
authors: David
authors: D
authors: Burger
authors: Evelyne
authors: E
authors: Jacqz-Aigrain
mesh_terms: D019380:Anti-HIV Agents / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001499:Bayes Theorem; D001835:Body Weight; D002675:Child, Preschool; D015224:Dideoxynucleosides / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D054796:Drug Dosage Calculations; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D007223:Infant; D008297:Male; D008954:Models, Biological; D000099227:Abacavir
chemical_list: D019380:Anti-HIV Agents; D015224:Dideoxynucleosides; D000099227:Abacavir