Su-jin Rhee(1), Jung-Won Shin(2), Sang Kun Lee(3), Kon Chu(3), In-Jin Jang(1)
(1)Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Korea; (2)Department of Neurology, CHA Bundang Medical Center, CHA University, Seongnam, Korea; (3)Department of Neurology, Laboratory of Neurotherapeutics, Comprehensive Epilepsy Center, Biomedical Research Institute Seoul National University College of Medicine and Hospital, Seoul, Korea
Objectives: Levetiracetam is commonly used as mono- or adjunctive therapy for the treatment of patient with partial and generalized epilepsy. The aims of this study were to develop a population pharmacokinetic model of levetiracetam, and to evaluate the demographic and physiologic determinants of plasma levetiracetam levels.
Methods: A population pharmacokinetic analysis was performed using 632 levetiracetam concentrations in 508 patients with epilepsy, who received multiple oral levetiracetam. The First-Order Conditional Estimation with Interaction estimation method implemented in NONMEM (version 7.2) was used, which was followed by model qualification using bootstrapping and visual predictive checks (VPCs).
Results: A one-compartment open linear model with first-order absorption and additive residual error adequately described the concentration–time profiles of levetiracetam. The typical population estimates of the absorption rate constant, apparent clearance, and volume of distribution were 2.44 h-1 (fixed), 3.99 L/h, and 64.98 L, respectively. The inter-individual variabilities were 18.9% for the apparent clearance and 57.9% for the volume of distribution, respectively. Bodyweight, age, sex, and creatinine clearance had a statistically significant effect on the apparent clearance of levetiracetam, while body weight only had a statistically significant effect on the volume of distribution. Concomitant intake of other anti-epileptic drugs had no significant effect on both apparent clearance and volume of distribution of levetiracetam. Model evaluation by bootstrapping and VPCs indicated that the proposed model was adequate, robust, and stable, and the parameters were estimated with a good precision.
Conclusions: The population pharmacokinetic parameters for oral levetiracetam were successfully estimated in the patients with epilepsy using sparse data. This population pharmacokinetic model can be utilized to evaluate the relationship between levetiracetam level and occurrence of adverse event or seizure.
Reference: PAGE 25 () Abstr 5843 [www.page-meeting.org/?abstract=5843]
Poster: Drug/Disease modeling - CNS