The goal of Project I is to identify clinically significant factors that affect antiepileptic drug (AED) pharmacokinetics and response in the eldedy and to develop methods that can be used to tailor therapy to the individual. The standard practice in medicine is a """"""""one dose fits air' approach to drug therapy. This approach results in an increased incidence of adverse effects and diminished therapeutic effect for patients such as the eldedy who require individualized therapy. AEDs are commonly prescribed for elderly patients, but are associated with a disproportionately high rate of adverse events and drug interactions. Emerging evidence indicates that advanced age, gender, race, and genotype each significantly affect AED pharmacokinetics and therapeutic response. The proposed studies, which build on the current project (1997-2002), will determine if carbamazepine (CBZ) metabolism, primarily mediated by cytochrome P450 (CYP) isoenzymes 3A4/5 is altered in the elderly, women and African Americans. Preliminary studies will also be initiated with topiramate (TPM), a newer AED substantially metabolized by CYP enzymes, to determine if its pharmacokinetics change with advancing age. Three epilepsy centers with diverse patient demographics will participate in the project to ensure an adequate subject pool. A novel intravenous formulation of stable-labeled (non-radioactive) CBZ has been developed during the present project and a similar approach will be used for TPM. Use of intravenously administered isotopes is the only available method to rigorously characterized pharmacokinetics under steady-state conditions The CBZ or TPM isotope will be administered to patients as part of their daily dose. CBZ or TPM and their metabolites from labeled and unlabeled drug will be measured by liquid or gas chromatography-mass spectrometry. Carbamazepine pharmacokinetics will be characterized in 40 elderly (->65 yrs) patients and 50 Caucasian and 50 African-American men and women age18-50 yrs. Subjects will also be genotyped for the presence of a CYP3A5*1 polymorphism that may significantly increase CBZ metabolism, particularly in African Americans. The pharmacokinetic and genotype results will be compared between elderly and younger adults, men and women, and Afdcan Americans and Caucasians. A subgroup of eldedy and adult patients will be re-studied following CBZ discontinuation to measure the effect of age on the rate and extent of enzyme induction. The effect of advancing age on TPM pharmacokinetics and metabolism will be studied in 12 elderly and 12 adult patients. Unique aspects of this proposal include the first ever use of an intravenous CBZ and TPM formulations in humans, investigation of the relationship of CBZ pharrnacoldnetics and gender, race and/or genotype, and use of a TPM stable-labeled isotope for human pharmacokinetic studies. The combined results from Projects 1,2, 3, and 4 will provide information that clinicians can use to individualize drug therapy, supports the design of controlled trials in the elderly and other populations, and will serve as evidence that professional organizations can use for the development recommendations on the use of AEDs in the eldedy.
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