title: Development of a population pharmacokinetic model for parecoxib and its active metabolite valdecoxib after parenteral parecoxib administration in children.
abstract: BACKGROUND
  Parecoxib is a cyclooxygenase-2 selective inhibitor used in management of postoperative pain in adults. This study aimed to provide pediatric pharmacokinetic information for parecoxib and its active metabolite valdecoxib.
  
  
  METHODS
  Thirty-eight children undergoing surgery received parecoxib (1 mg/kg IV to a maximum of 40 mg) at induction of anesthesia, and plasma samples were collected for drug measurement. Population pharmacokinetic parameters were estimated using nonlinear mixed effects modeling. Area under the valdecoxib concentration-time curve and time above cyclooxygenase-2 in vitro 50% inhibitory concentration for free valdecoxib were simulated.
  
  
  RESULTS
  A three-compartment model best represented parecoxib disposition, whereas one compartment was adequate for valdecoxib. Age was linearly correlated with parecoxib clearance (5.0% increase/yr). There was a sigmoid relationship between age and both valdecoxib clearance and distribution volume. Time to 50% maturation was 87 weeks postmenstrual age for both. In simulations using allometric-based doses the 90% prediction interval of valdecoxib concentration-time curve in children 2-12.7 yr included the mean for adults given 40 mg parecoxib IV. Simulated free valdecoxib plasma concentration remained above the in vitro 50% inhibitory concentrations for more than 12 h. In children younger than 2 yr, a dose reduction is likely required due to ongoing metabolic maturation.
  
  
  CONCLUSIONS
  The final pharmacokinetic model gave a robust representation of parecoxib and valdecoxib disposition. Area under the valdecoxib concentration-time curve was similar to that in adults (40 mg), and simulated free valdecoxib concentration was above the cyclooxygenase-2 in vitro 50% inhibitory concentration for free valdecoxib for at least 12 h.
authors.affiliation: Department of Anaesthesiology, Princess Margaret Hospital for Children, Subiaco, Australia.
authors.forename: Bruce
authors.initials: B
authors.lastname: Hullett
authors.forename: Sam
authors.initials: S
authors.lastname: Salman
authors.forename: Sean J
authors.initials: SJ
authors.lastname: O'Halloran
authors.forename: Deborah
authors.initials: D
authors.lastname: Peirce
authors.forename: Kylie
authors.initials: K
authors.lastname: Davies
authors.forename: Kenneth F
authors.initials: KF
authors.lastname: Ilett
mesh_terms: D000328:Adult; D000367:Age Factors; D000465:Algorithms; D001711:Biotransformation; D002648:Child; D002675:Child, Preschool; D003198:Computer Simulation; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D003627:Data Interpretation, Statistical; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D006801:Humans; D007223:Infant; D007263:Infusions, Parenteral; D007555:Isoxazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D015233:Models, Statistical; D017711:Nonlinear Dynamics; D011153:Population; D011446:Prospective Studies; D015203:Reproducibility of Results; D013449:Sulfonamides / Q000097:blood; D000096926:Benzenesulfonamides
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D007555:Isoxazoles; D013449:Sulfonamides; C406224:valdecoxib; D000096926:Benzenesulfonamides; C409945:parecoxib