Pharmacokinetic and pharmacodynamic markers and correlation studies as tools for the optimisation of anti-epileptic pharmacotherapy

Introduction:
Epilepsy is one of the most common neurological disorders. It has a prevalence of about 0.5 to 1% in the population (1).The prevention of pharmacoresistence is one of the major challenges in epilepsy treatment today. Indeed, despite antiepileptic drug (AED) therapy, epilepsy remains uncontrolled in a significant proportion of the patients, especially in patients with temporal lobe epilepsy (2). Therefore, research towards the development of innovative AEDs is important. Patients with refractory psychomotor epilepsy have an increased risk of developing psychiatric disorders like depression, anxiety, psychosis and schizophrenia (3). Moreover, co-medication with antidepressants and anxiolytic drugs is considered to disrupt the therapeutic efficacy of antiepileptic drugs (4). Research focussing on the elucidation of the common pathophysiological mechanisms behind these comorbid disorders is therefore clinically relevant. Finally, responders to pharmacological epilepsy treatment often suffer from numerous side-effects that are inherent to the currently available AEDs. The broad spectrum of known and unknown mechanisms of action of these drugs together with a limited personalisation of the therapeutic regimen is considered responsible.

Aim and objectives of the project:
The pharmacokinetic (PK) and pharmacodynamic (PD) expertise that was build up during the PhD project will be used in the current project to develop innovative antiepileptic therapies that meet with the current clinical needs.
1) In the past, dopamine (DA) and serotonin (5-HT) were considered to play only a limited modulatory role in the control of epileptic activity. However, recently we showed that both endogenous and exogenous DA and 5-HT mediate potent anticonvulsant effects via respectively D2 and 5-HT1A receptor activation (5). We therefore suggested that the monoaminergic system might be an interesting target for innovative pharmacological epilepsy treatment. Since deficiencies in DA-ergic and 5-HT-ergic transmission are considered to play an important role in the pathogenesis of depression, anxiety, psychosis and schizophrenia, we hypothesise that monoaminergic AEDs will especially be useful to simultaneously treat these neurological comorbid disorders. In the current project we intend to screen monoaminergic compounds, which are on the market or in development for the treatment of one of these comorbidities, in both the acute and chronic pilocarpine model for limbic psychomotor epilepsy. This way we will try to gather information concerning the anticonvulsant and antiepileptogenic properties of these compounds.
2) There is a growing recognition for the use of PK/PD modelling to interpret toxicokinetic and dose-response data in preclinical and clinical studies and for the recommendation of optimal doses and/or regimen (6). PK/PD modelling can even be used to extrapolate results from animal to man. During the PhD project increases in extracellular hippocampal DA and 5-HT levels were defined as PD markers for the anticonvulsant efficacy of 10,11-dihydro-10-hydroxy-carbamazepine (MHD) (i.e. the active metabolite of oxcarbazepine (OXC)) in the focal pilocarpine model. Moreover, following systemic administration of different doses, quantitative microdialysis was used to determine the PK properties of MHD in freely moving animals. In the present project we want to mathematically correlate these PK and PD data to obtain a PK/PD model describing the concentration/effect relationships for MHD. Since we do not have the necessary modelling expertise at our lab, I will model these data with the help of Prof. M. Danhof at his department. Prof. Danhof is a leading expert in the field of PK/PD correlations at the Leiden University. Introducing the know-how of PK/PD modelling into our lab will have an important impact on neuropharmacological research at the Vrije Universiteit Brussel.
3) Non-specific adaptive mechanisms are mainly considered responsible for pharmacoresistant epilepsy. It has been hypothesized that over-expression of efflux transporters at the blood-brain barrier (BBB), which prevents AEDs from reaching sufficiently high brain concentrations despite adequate plasma levels, could be one such mechanism (2,7). In the past co-therapy of AEDs with transporter blockers has been suggested as a possible strategy to counterbalance the effects of these active efflux systems. Since the recent development of highly selective transporter inhibitors, which only moderately interfere with hepatic metabolic processes (8-11), such co-medication strategies can be studied today. In the current project we therefore want to evaluate the impact of systemic administration of selective efflux transporter inhibitors on the BBB passage of AEDs by the use of in vivo microdialysis. Simultaneously the effects on extracellular hippocampal DA and 5-HT levels will be monitored and used as PD markers for the anticonvulsant efficacy of the AED applied in the study. This research will offer future perspectives for the treatment of refractory patients. __