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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08NS040261-02
Application #
6394477
Study Section
Special Emphasis Panel (ZRG1-BDCN-5 (01))
Program Officer
Fureman, Brandy E
Project Start
2000-07-06
Project End
2004-06-30
Budget Start
2001-07-01
Budget End
2002-06-30
Support Year
2
Fiscal Year
2001
Total Cost
$125,010
Indirect Cost
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
Tang, Yang; Gilbert, Donald L; Glauser, Tracy A et al. (2005) Blood gene expression profiling of neurologic diseases: a pilot microarray study. Arch Neurol 62:210-5
Tang, Y; Glauser, T A; Gilbert, D L et al. (2004) Valproic acid blood genomic expression patterns in children with epilepsy - a pilot study. Acta Neurol Scand 109:159-68
Hershey, Andrew D; Tang, Yang; Powers, Scott W et al. (2004) Genomic abnormalities in patients with migraine and chronic migraine: preliminary blood gene expression suggests platelet abnormalities. Headache 44:994-1004
Tang, Yang; Schapiro, Mark B; Franz, David N et al. (2004) Blood expression profiles for tuberous sclerosis complex 2, neurofibromatosis type 1, and Down's syndrome. Ann Neurol 56:808-14
Nallani, Srikanth C; Glauser, Tracy A; Hariparsad, Niresh et al. (2003) Dose-dependent induction of cytochrome P450 (CYP) 3A4 and activation of pregnane X receptor by topiramate. Epilepsia 44:1521-8
Glauser, Tracy A (2002) Advancing the medical management of epilepsy: disease modification and pharmacogenetics. J Child Neurol 17 Suppl 1:S85-93
Glauser, Tracy A (2002) Integrating clinical trial data into clinical practice. Neurology 58:S6-12