Impact of Seizures and Efflux Mechanisms on the Biophase Kinetics and CNS Effects of Anticonvulsant Drugs
V.L. Di Iorio(1), R. Clinckers(1,2), I. Smolders(2), Y. Michotte(2), E.C. de Lange(1), M. Danhof(1), R.A. Voskuyl(1), O. Della Pasqua(1)
(1) Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden, The Netherlands; (2) Department of Pharmaceutical Chemistry and Drug Analysis, Faculty of Medicine and Pharmacy, Vrije Universiteit, Brussels, Belgium
Background: Several classes of efflux transporters are present at the blood-brain barrier (BBB). They are considered to act in tandem in hindering efficient drug delivery to the brain. Over-expression of active efflux mechanisms has been described in epileptic brain areas and is suggested to play a substantial role in pharmacoresistance to antiepileptic drugs. In addition, during seizures the integrity and selective permeability of the BBB is compromised causing regional drug concentration differences within the brain.
Objectives: The aim of this work was to develop a PKPD model to describe the impact of seizures and active efflux mechanism on the biophase kinetics and CNS effects of antiepileptic drugs.
Methods: Recently, an integrated pharmacokinetic (PK) model has been developed, which simultaneously describes the pharmacokinetics of 10-hydroxycarbazepine (MHD), the active metabolite of oxcarbazepine, in plasma and brain during seizures and p-glycoprotein inhibition. Like many other antiepileptic drugs, MHD was shown to stimulate hippocampal dopaminergic and serotoninergic neurotransmission and these neurotransmitter modulations were demonstrated to be partly responsible for the anticonvulsant effects. In the current investigation, we have used these monoamine transmitters as pharmacodynamic (PD) markers for the efficacy of MHD. An integrated PKPD model was built to characterise the effects of MHD on extracellular hippocampal dopamine and serotonin levels using nonlinear mixed effects modelling. Concomitantly, the impact of acute seizures and efflux transport mechanisms on the PD of MHD was quantified. Data analysis was performed in NONMEM v6.2. R was used for data manipulation, statistical and graphical summaries. Model validation procedures consisted of mirror plots, visual predictive check (VPC) and bootstrap.
Results: A sigmoid Emax model could best describe the increase in hippocampal dopamine and serotonin. Furthermore, our findings show that biophase disposition of antiepileptic drugs can differ significantly from plasma pharmacokinetics and that seizure-induced regional changes in drug disposition are often not correlated to alterations in plasma kinetics.
Conclusions: These experiments demonstrate that the PD effects of MHD are highly affected by seizures and active efflux transport blockade. These results also highlight that knowledge of the biophase kinetics is imperative to accurately describe drug effects under disease conditions.
 R. Clinckers, I. Smolders, A. Meurs, G. Ebinger, Y. Michotte. Hippocampal dopamine and serotonin elevations as pharmacodynamic markers for the anticonvulsant efficacy of oxcarbazepine and 10,11-dihydro-10-hydroxycarbamazepine. Neurosci Lett.;390(1):48-53, 2005.
 R. Clinckers, I. Smolders, Y. Michotte, G. Ebinger, M. Danhof, R.A. Voskuyl, O. Della Pasqua. Impact of efflux transporters and of seizures on the pharmacokinetics of oxcarbazepine metabolite in the rat brain. Br J Pharmacol.,155(7):1127-38, 2008.