The goal of this project is to obtain population pharmacokinetic parameters of antiepileptic drugs (AEDs) in elderly nursing home patients using a sophisticated software tool, NONMEM (Non Linear Mixed Effects Models). This accurate knowledge will allow proper utilization of AEDs in the elderly patient population. Though there is information in patients older than 65 years. Thus, the initial doses used and the principles of optimization are extrapolated from a younger age group. Considering the profound physiologic changes which occur during the aging process, and the high number of medications elderly patients receive, it is highly likely there are profound changes in the pharmacokinetics of AEDs in elderly individuals. If so, the entire dosing plans in use today for the large population of elderly patients with epilepsy may be less than optimal. Through the use of NONMEM, a pharmacostatistical tool, this project will obtain these parameters from routinely collected clinical data from over 50,000 elderly patients residing in nursing homes and long term care facilities. In addition, their variability and identification of important patient characteristics that help define these pharmacokinetic estimates will be determined. These results will be compared to a gender matched set of younger patients from the current program project grant NONMEM database. The primary parameter of interest for drugs with first order elimination is Clearance. Secondary parameters are Volume of Distribution and absorption rate constant. For drugs with Michaelis-Menten type elimination (eg, phenytoin), Vmax and km will be determined. The initial drugs to be analyzed will be phenytoin, carbamazepine, valproic acid, and phenobarbital. Covariates that will be tested to determine their importance in estimating these parameters are: age, weight, gender, race, concomitant medications, and concomitant diagnoses. These variables will be obtained from the Minimum Data Set (MDS 2.0) form that is required for all Medicare certified nursing homes. The population pharmacokinetic parameters and their inter- and intra-individual variability determined from this project can form the basis of dosing guidelines that can be utilized prospectively in the elderly population.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Specialized Center (P50)
Project #
2P50NS016308-17A1
Application #
6243492
Study Section
Project Start
1997-07-15
Project End
1998-05-31
Budget Start
1996-10-01
Budget End
1997-09-30
Support Year
17
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Type
DUNS #
168559177
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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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
Conway, Jeannine M; Birnbaum, Angela K; Leppik, Ilo E et al. (2014) Safety of an intravenous formulation of lamotrigine. Seizure 23:390-2
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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
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
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
Punyawudho, Baralee; Ramsay, Eugene R; Brundage, Richard C et al. (2012) Population pharmacokinetics of carbamazepine in elderly patients. Ther Drug Monit 34:176-81
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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