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

Autor(es)

Antunes, Natalicia de Jesus ; van Dijkman, Sven C. ; Lanchote, Vera Lucia ; Wichert-Ana, Lauro ; Coelho, Eduardo Barbosa ; Alexandre Junior, Veriano ; Takayanagui, Osvaldo Massaiti ; Tozatto, Eduardo ; van Hasselt, J. G. Coen ; Della Pasqua, Oscar

• Tipo de documento: Artigo Científico
• Fonte: European Journal of Pharmaceutical Sciences; v. 109, p. 8-pg., 2017-11-15.

Resumo

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 300 mg b.i.d. and 80 mg t.i.d., respectively. Blood samples (n = 185) were collected over a period of 12 h 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 84.9 L/h (69.5-100.3) for oxcarbazepine and 2.0 L/h (1.9-2.1) for both MHD enantiomers. The volume of distribution was much larger for oxcarbazepine (131 L (97-165)) as compared to R-(-)- and S-(+)-MHD (23.6 L (14.4-32.8) vs. 31.7 L (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. (AU)

• Processo FAPESP: 11/06887-1 - Influência do verapamil na farmacocinética da oxcarbazepina e dos enantiômeros da 10-hidroxicarbazepina e suas relações com a perfusão cerebral em voluntários sadios
• Beneficiário: Natalícia de Jesus Antunes
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 12/18175-9 - Correlação entre a perfusão cerebral e a farmacocinética da OXC e dos enantiômeros do seu metabólito 10-hidroxicarbazepina em plasma de voluntários sadios utilizando modelos hierárquicos não-lineares
• Beneficiário: Natalícia de Jesus Antunes
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Doutorado