Format

Send to

Choose Destination
Br J Clin Pharmacol. 2017 Dec;83(12):2695-2708. doi: 10.1111/bcp.13392. Epub 2017 Sep 20.

Population pharmacokinetics of oxcarbazepine and its monohydroxy derivative in epileptic children.

Rodrigues C1,2, Chiron C1,2, Rey E1,2, Dulac O1,2, Comets E3,4, Pons G1,2, Jullien V1,2,5.

Author information

1
INSERM U1129, Paris, France.
2
Paris Descartes University, CEA, Gif-sur-Yvette, France.
3
INSERM, IAME, UMR1137, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
4
INSERM, CIC 1414, Université Rennes 1, Rennes, France.
5
Service de Pharmacologie, Hôpital Européen Georges Pompidou, 20 rue Leblanc, 75015, Paris, France.

Abstract

AIMS:

Oxcarbazepine is an antiepileptic drug with an activity mostly due to its monohydroxy derivative metabolite (MHD). A parent-metabolite population pharmacokinetic model in children was developed to evaluate the consistency between the recommended paediatric doses and the reference range for trough concentration (Ctrough ) of MHD (3-35 mg l-1 ).

METHODS:

A total of 279 plasma samples were obtained from 31 epileptic children (age 2-12 years) after a single dose of oxcarbazepine. Concentration-time data were analysed with Monolix 4.3.2. The probability to obtain Ctrough between 3-35 mg l-1 was determined by Monte Carlo simulations for doses ranging from 10 to 90 mg kg-1  day-1 .

RESULTS:

A parent-metabolite model with two compartments for oxcarbazepine and one compartment for MHD best described the data. Typical values for oxcarbazepine clearance, central and peripheral distribution volume and distribution clearance were 140 l h-1  70 kg-1 , 337 l 70 kg-1 , 60.7 l and 62.5 l h-1 , respectively. Typical values for MHD clearance and distribution volume were 4.11 l h-1  70 kg-1 and 54.8 l 70 kg-1 respectively. Clearances and distribution volumes of oxcarbazepine and MHD were related to body weight via empirical allometric models. Enzyme-inducing antiepileptic drugs (EIAEDs) increased MHD clearance by 29.3%. Fifty-kg children without EIAEDs may need 20-30 mg kg-1  day-1 instead of the recommended target maintenance dose (30-45 mg kg-1  day-1 ) to obtain Ctrough within the reference range. By contrast, 10-kg children with EIAEDs would need 90 mg kg-1  day-1 instead of the maximum recommended dose of 60 mg kg-1  day-1 .

CONCLUSION:

This population pharmacokinetic model of oxcarbazepine supports current dose recommendations, except for 10-kg children with concomitant EIAEDs and 50-kg children without EIAEDs.

KEYWORDS:

childhood epilepsy; monohydroxy derivative; oxcarbazepine; population pharmacokinetics

PMID:
28771787
PMCID:
PMC5698580
[Available on 2018-12-01]
DOI:
10.1111/bcp.13392
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for Wiley Icon for HAL archives ouvertes
Loading ...
Support Center