title: Brivaracetam population pharmacokinetics in children with epilepsy aged 1 month to 16 years.
abstract: OBJECTIVE
  The aims of the study were to develop a population pharmacokinetic model of orally administered brivaracetam in paediatric patients and to provide dosing suggestions.
  
  
  METHODS
  Analysis included 600 brivaracetam plasma concentrations from a phase 2a study (NCT00422422; N01263) in 96 paediatric patients with epilepsy aged 1 month to 16 years, taking one to three concomitant antiepileptic drugs (AEDs). Pharmacokinetic analysis was performed using non-linear mixed effects modelling, and a stepwise covariate search was used to determine factors influencing brivaracetam clearance. Simulations were performed to investigate dosing regimens.
  
  
  RESULTS
  The final model consisted of first-order absorption, single compartment distribution and first-order elimination components with allometric scaling of clearance and volume using lean body weight and fixed allometric exponents. Co-administration with phenobarbital or carbamazepine was associated with a 29% (95%CI 17%/39%) and 32% (22%/42%) decrease in exposure, respectively. Co-administration with valproate was associated with an 11% (1%/23%) increase in exposure. Simulations demonstrated that the majority of children were predicted to have an exposure similar to that in adults, using an age-independent dosing regimen of 2.0 mg/kg bid with a maximum of 100 mg bid for body weight >50 kg.
  
  
  CONCLUSIONS
  A paediatric dose adaptation of 2.0 mg/kg twice daily with a maximum of 100 mg twice daily for body weight >50 kg is predicted to ensure steady-state plasma concentrations in the same range as in adult patients receiving 100 mg twice daily (highest recommended dose). Data suggest no need to change brivaracetam dosing when used concomitantly with carbamazepine, phenobarbital or valproate.
authors.affiliation: SGS Exprimo, Mechelen, Belgium. rik.schoemaker@occams.com.|Occams, Malandolaan 10, 1187, HE, Amstelveen, The Netherlands. rik.schoemaker@occams.com.
authors.forename: Rik
authors.identifier: http://orcid.org/0000-0002-7538-3005
authors.initials: R
authors.lastname: Schoemaker
authors.affiliation: SGS Exprimo, Mechelen, Belgium.|Occams, Malandolaan 10, 1187, HE, Amstelveen, The Netherlands.
authors.forename: Janet R
authors.initials: JR
authors.lastname: Wade
authors.affiliation: Clinical Pharmacology, UCB Pharma, Braine l'Alleud, Belgium.
authors.forename: Armel
authors.initials: A
authors.lastname: Stockis
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000367:Age Factors; D000927:Anticonvulsants / Q000008:administration & dosage* / Q000493:pharmacokinetics; D002220:Carbamazepine / Q000008:administration & dosage; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D004827:Epilepsy / Q000188:drug therapy*; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008954:Models, Biological; D017711:Nonlinear Dynamics; D010634:Phenobarbital / Q000008:administration & dosage; D011760:Pyrrolidinones / Q000008:administration & dosage* / Q000493:pharmacokinetics; D014635:Valproic Acid / Q000008:administration & dosage
chemical_list: D000927:Anticonvulsants; D011760:Pyrrolidinones; D002220:Carbamazepine; D014635:Valproic Acid; C482793:brivaracetam; D010634:Phenobarbital
keywords: Brivaracetam; Epilepsy; NONMEM; Paediatrics; Population pharmacokinetics