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Population pharmacokinetics of oxcarbazepine and its metabolite 10-hydroxycarbazepine in healthy subjects

De Jesus Antunes, N; Van Dijkman, SC; Lanchote, VL; Wichert-Ana, L; Coelho, EB; Alexandre Junior, V; Takayanagui, OM; ... Della Pasqua, O; + view all (2017) Population pharmacokinetics of oxcarbazepine and its metabolite 10-hydroxycarbazepine in healthy subjects. European Journal of Pharmaceutical Sciences , 109 (Supp) S116-S123. 10.1016/j.ejps.2017.05.034. Green open access

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Abstract

Oxcarbazepine is indicated for the treatment of partial or generalised tonic-clonic seizures. Most of the absorbed oxcarbazepine is converted into its active metabolite, 10-hydroxycarbazepine (MHD), which can exist as R-(-)- and S-(+)-MHD enantiomers. Here we describe the influence of the P-glycoprotein (P-gp) inhibitor verapamil, on the disposition of oxcarbazepine and MHD enantiomers, both of which are P-gp substrates. Healthy subjects (n=12) were randomised to oxcarbazepine or oxcarbazepine combined with verapamil at doses of 300mg b.i.d. and 80mg t.i.d., respectively. Blood samples (n=185) were collected over a period of 12h post oxcarbazepine dose. An integrated PK model was developed using nonlinear mixed effects modelling using a meta-analytical approach. The pharmacokinetics of oxcarbazepine was described by a two-compartment model with absorption transit compartments and first-order elimination. The concentration-time profiles of both MHD enantiomers were characterised by a one-compartment distribution model. Clearance estimates (95% CI) were 84.9L/h (69.5-100.3) for oxcarbazepine and 2.0L/h (1.9-2.1) for both MHD enantiomers. The volume of distribution was much larger for oxcarbazepine (131L (97-165)) as compared to R-(-)- and S-(+)-MHD (23.6L (14.4-32.8) vs. 31.7L (22.5-40.9), respectively). Co-administration of verapamil resulted in a modest increase of the apparent bioavailability of oxcarbazepine by 12% (10-28), but did not affect parent or metabolite clearances. Despite the evidence of comparable systemic levels of OXC and MHD following administration of verapamil, differences in brain exposure to both moieties cannot be excluded after P-glycoprotein inhibition.

Type: Article
Title: Population pharmacokinetics of oxcarbazepine and its metabolite 10-hydroxycarbazepine in healthy subjects
Location: Netherlands
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.ejps.2017.05.034
Publisher version: http://dx.doi.org/10.1016/j.ejps.2017.05.034
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: 10-Hydroxycarbazepine, Oxcarbazepine, P-glycoprotein, Population pharmacokinetics, Verapamil
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharmacology
URI: http://discovery.ucl.ac.uk/id/eprint/1558527
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