Cognitive impairment is one of the most prevalent side effects associated with antiepileptic drugs and is a common reason for discontinuation of therapy, especially in the elderly. Due to individual variability in pharmacokinetics and sensitivity to adverse effects, it is difficult to predict which patients are at risk for developing a drug-induced deterioration in neuropsychological function. The goal of this project is to characterize the relationship among topiramate (TPM) pharmacokinetics, pharmacogenomics and cognitive functioning in order to forecast which patients are most likely to manifest significant cognitive deficits when placed on a regime that includes TPM. The effect of age and genotype on TPM pharmacokinetics will be determined using a novel, stable-labeled (non-radioactive) intravenous TPM formulation and the utility of a single point plasma concentration method to predict subsequent systemic drug exposure in an individual will be assessed. Cognitive function will be determined as an effect of age and duration of TPM therapy. Pharmacokinetic and neuropsychological measures will be correlated in order to identify factors that can be used to forecast risk for TPM induced cognitive impairment. This approach will not only aid in optimizing TPM therapy but may be applied to other AEDs and more broadly to other neuroactive medications. If successful, it will alter the common contemporary practice of pushing drugs to maximum tolerated doses.
