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Correlation between cerebral perfusion and pharmacokinetics of OXC and its metabolite 10-hidroxicarbazepina enantiomers in the plasma of healthy volunteers using non-linear hierarchical models

Grant number: 12/18175-9
Support Opportunities:Scholarships abroad - Research Internship - Doctorate
Effective date (Start): April 01, 2013
Effective date (End): March 31, 2014
Field of knowledge:Biological Sciences - Pharmacology - Clinical Pharmacology
Principal Investigator:Vera Lúcia Lanchote
Grantee:Natalícia de Jesus Antunes
Supervisor: Oscar E. Della Pasqua
Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Research place: Universiteit Leiden, Netherlands  
Associated to the scholarship:11/06887-1 - Influence of verapamil on the oxcarbazepine enantiomers and 10-hydroxycarbazepine pharmacokinetics and their relationships to cerebral perfusion in healthy volunteers, BP.DR

Abstract

Oxcarbazepine (OXC) is a second-generation antiepileptic drug indicated as monotherapy or adjunctive therapy for the treatment of partial seizures or generalized tonic-clonic seizures in adults and children. It suffers rapid pre-systemic reduction with formation of the active chiral metabolite S-(+) and R-(-)-10,11-dihydro-10-hydroxy-carbazepine (MHD), which have similar antiepileptic effects. Considering the MHD as a substrate of P-glycoprotein (Pgp) and verapamil as a Pgp inhibitor, the coadministration of verapamil would favor the distribution of the MHD in the central nervous system (CNS). Healthy volunteers (n=12) received oral doses of 300 mg/12 h of oxcarbazepine associated or not (Phase II) with 80 mg/8h of verapamil (Phase III). Serial blood samples were collected during the dose interval of 12 h and the cerebral perfusion was performed using the single-photon emission computed tomography (SPECT). Plasma concentrations of OXC and MHD enantiomers were performed by LC-MS/MS. The clinical and analytical phases of the study was developed in Brazil, while the pharmacokinetics and statistical phases will be developed at the University of Leiden. The study will be developed using non-linear hierarchical models (softwares NONMEN and R) aiming to characterize the distributional phenomena in parametric mode and consequently determine the possible clinical relevance of the inhibition of Pgp to therapeutic effect. (AU)

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
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. Population pharmacokinetics of oxcarbazepine and its metabolite 10-hydroxycarbazepine in healthy subjects. European Journal of Pharmaceutical Sciences, v. 109, p. 8-pg., . (11/06887-1, 12/18175-9)
PIANA, CHIARA; ANTUNES, NATALICIA DE JESUS; DELLA PASQUA, OSCAR. Implications of pharmacogenetics for the therapeutic use of antiepileptic drugs. EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY, v. 10, n. 3, p. 341-358, . (12/18175-9)
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. Population pharmacokinetics of oxcarbazepine and its metabolite 10-hydroxycarbazepine in healthy subjects. European Journal of Pharmaceutical Sciences, v. 109, n. S, SI, p. S116-S123, . (12/18175-9, 11/06887-1)

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