Epilepsy is the most common chronic neurologic condition of infancy and childhood. Seizure freedom is associated with the best long-term outcome and is the goal of therapy. Unfortunately, a significant number of infants and children with partial seizures do not become seizure free using antiepileptic medications. There exists a significant need for more pediatric epilepsy specialists to be trained as clinical pharmacologists to (1) assess efficacy, safety, and pharmacokinetics of new therapeutic options for this population and to (2) assess mechanisms underlying individual variations in therapeutic efficacy or adverse drug reactions. These two lines of research will lead to improved care for infants and children with epilepsy. The objectives of this proposal are (1) to propose a didactic and experiential course of learning designed to train the candidate as a clinical pharmacologist, (2) to use a novel concentration response design in this age group to establish the safety, efficacy and pharmacokinetics of a newer antiepileptic medication (topiramate) as first line monotherapy in infants and children with partial seizures and (3) assess the pharmacogenetic relationship between differences in topiramate's metabolism and its clinical tolerability. These objectives would be examined through the following Specific aims (1a): Compare the efficacy and safety of two serum concentrations of topiramate in infants and children with new onset epilepsy characterized by partial seizures, (1b): determine topiramate's pharmacokinetic parameters along with the profile of topiramate metabolites in infants and children (2): Determine the pharmacodynamic effects of topiramate metabolites and examine the relationship between clinical differences in topiramate tolerability, topiramate metabolite concentrations and CYP gene polymorphisms, (3): Demonstrate that saliva monitoring of topiramate serum concentrations is useful and feasible as a technique to perform concentration response studies in children.
These specific aims combined with the didactic and experiential course of learning will help the candidate achieve his three goals and career objectives: (1) acquire expertise in clinical pharmacology and translational pharmacology research leading to Board Certification in Clinical Pharmacology, (2) acquire expertise in design and analysis of antiepileptic drug clinical trials in children with epilepsy and (3) acquire expertise needed to identify fundamental mechanisms associated with individual variations in antiepileptic drug response.
