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
• Start date: April 01, 2013
• End date: 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
• Institution abroad: 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)

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, n. S, SI, p. S116-S123, NOV 15 2017. (12/18175-9, 11/06887-1)

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, MAR 2014. (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, p. 8-pg., 2017-11-15. (11/06887-1, 12/18175-9)