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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
7K01NS050309-02
Application #
7187604
Study Section
NST-2 Subcommittee (NST)
Program Officer
Babcock, Debra J
Project Start
2005-08-11
Project End
2009-05-31
Budget Start
2006-01-01
Budget End
2006-05-31
Support Year
2
Fiscal Year
2005
Total Cost
$92,545
Indirect Cost
Name
University of Florida
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
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Patel, Sima I; Birnbaum, Angela K; Cloyd, James C et al. (2015) Intravenous and Intramuscular Formulations of Antiseizure Drugs in the Treatment of Epilepsy. CNS Drugs 29:1009-22
Ahmed, Ghada F; Marino, Susan E; Brundage, Richard C et al. (2015) Pharmacokinetic-pharmacodynamic modelling of intravenous and oral topiramate and its effect on phonemic fluency in adult healthy volunteers. Br J Clin Pharmacol 79:820-30
Ahmed, Ghada F; Brundage, Richard C; Marino, Susan E et al. (2013) Population pharmacokinetics of unbound and total drug concentrations following intravenously administered carbamazepine in elderly and younger adult patients with epilepsy. J Clin Pharmacol 53:276-84
Puranik, Yogita Ghodke; Birnbaum, Angela K; Marino, Susan E et al. (2013) Association of carbamazepine major metabolism and transport pathway gene polymorphisms and pharmacokinetics in patients with epilepsy. Pharmacogenomics 14:35-45
Conway, Jeannine M; Birnbaum, Angela K; Marino, Susan E et al. (2012) A sensitive capillary GC-MS method for analysis of topiramate from plasma obtained from single-dose studies. Biomed Chromatogr 26:1071-6
Marino, S E; Birnbaum, A K; Leppik, I E et al. (2012) Steady-state carbamazepine pharmacokinetics following oral and stable-labeled intravenous administration in epilepsy patients: effects of race and sex. Clin Pharmacol Ther 91:483-8
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Marino, S E; Pakhomov, S V S; Han, S et al. (2012) The effect of topiramate plasma concentration on linguistic behavior, verbal recall and working memory. Epilepsy Behav 24:365-72
Marino, S E; Meador, K J; Loring, D W et al. (2009) Subjective perception of cognition is related to mood and not performance. Epilepsy Behav 14:459-64