Antiepileptic Drugs: Adult

Abstract

Abstract 1 Alaa M. Ahmad, 1 Frank D. Boudinot, 2 William H. Barr, 3 Ronald C. Reed, and 2 William R. Garnett ( 1 Pharmaceutics, Virginia Commonwealth University, Richmond, VA ; 2 Pharmacy, Virginia Commonwealth University, Richmond, VA ; and 3 Neuroscience, Abbott Laboratories Inc., Abbott Park, IL ) Rationale: Clinicians rely primarily on total valproic acid (VPA) concentrations for therapeutic monitoring. However, due to nonlinear plasma protein binding of VPA, dose titration is complicated by disproportionality between the total drug concentration and dose. The purpose of this report was to develop a nomogram for VPA based on total drug concentrations. Methods: Nine healthy volunteers were administered 500, 750 and 1000 mg VPA in a dose escalation study. Plasma protein binding of VPA was characterized for each volunteer in vitro. Results: A one-site saturable binding model provided an adequate description of the binding of VPA to albumin and yielded (mean,% standard error) 2.3 (4.5%) binding sites (N) and an equilibrium association constant (KA) of 6.7 (17.9%) (L/mM). Predictions for the increase in total concentration observed with dose escalation were based on individual and population pharmacokinetic parameters. There weren't significant statistical differences between the predictions based on individual and population estimates (based on root mean square error and mean absolute error). Conclusions: Using population estimates, a dosing nomogram for VPA was constructed. To minimize the risk of achieving toxic drug concentrations, the dose should not be increased more than 2 fold at a time. The nomogram should be used in conjunction with patient history and clinical response to aid clinicians in making informed decisions about dose-adjustments. The nomogram can be used for all VPA preparations and regardless of enzyme inducing or inhibiting co-medications. (Supported by Virginia Commonwealth University.) (1) [(A) Percent reduction of the number of seizures; (B) Percentage of seizure-free patients (ITT)]