Topiramate pharmacokinetics in infants and young children: contribution of population analysis.
OBJECTIVE
To determine the range of topiramate (TPM) concentrations obtained in children under 4 with the recommended dosage regimen (3-9 mg/kg/day) and to compare them to adult target ranges.


METHODS
The population pharmacokinetic model developed for TPM, with/without enzyme inducer antiepileptic drugs (EIAEDs) in children was used to determine dosage regimens providing AUC and trough concentrations (C(trough)s) within the adult ranges.


RESULTS
TPM pharmacokinetics was described by a one-compartment model. EIAEDs increased the apparent clearance (CL/F) and age and body weight increased the apparent distribution volume (Vd/F). Mean population estimates (% CV interindividual variability) were 0.608/1.15 L/h (13%) for CL/F without/with EIAEDs, 28.6L (0.2%) for Vd/F and 1.4h(-1) (124%) for the absorption rate constant. Mean AUC(0-12h) reached with a 2mg/kg/day dosing regimen was within described range. A 6-16 mg/kg/day dose depending on age allowed reaching target C(trough) range with the highest probability. Combined EIAEDs led to a 2- and 3-fold decrease in AUC and C(trough), respectively.


CONCLUSIONS
TPM dosage of 2/4 mg/kg/day (without/with EIEADs, respectively) provides the AUC reported in adults. In children under 4, alternative dosing regimen should be considered mainly when associated to EIAED to reach C(trough) comparable to adult values.
Inserm, U663, Paris F-75015, France. marion.bp@svp.aphp.fr
Marion
M
Bouillon-Pichault
Rima
R
Nabbout
Stephanie
S
Chhun
Elisabeth
E
Rey
Catherine
C
Chiron
Olivier
O
Dulac
Gerard
G
Pons
Vincent
V
Jullien
D000465:Algorithms; D000927:Anticonvulsants / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002675:Child, Preschool; D016208:Databases, Factual; D005260:Female; D005544:Forecasting; D005632:Fructose / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D006801:Humans; D007223:Infant; D008297:Male; D015233:Models, Statistical; D009010:Monte Carlo Method; D011153:Population; D000077236:Topiramate
D000927:Anticonvulsants; D000077236:Topiramate; D005632:Fructose