Population Pharmacokinetic Analysis of Levetiracetam in Adult Malaysian Patients with Epilepsy

Aims: To determine the pharmacokinetic parameters of levetiracetam (LEV), a third-generation antiepileptic drug, and its metabolite, etiracetam carboxylic acid (UCB L057) in adult Malaysian patients with epilepsy, and to identify any covariates predictive of the pharmacokinetic properties of LEV or UCB L057.

Methods: This study includes adult Malaysian patients with various types of epilepsy, receiving a stable oral LEV dose for at least 2 weeks. Demographic and clinical data, as well as serial blood samples, were collected prospectively on routine epilepsy clinic appointment days, at the University of Malaya Medical Centre. The plasma concentrations of LEV and UCB L057 were measured simultaneously by a locally developed and validated liquid chromatography-tandem mass spectrometry assay method(1). Pharmacokinetic analyses were performed using a nonlinear mixed-effects model approach. Population pharmacokinetic (PopPK) model of LEV was constructed using the plasma concentration-time data of LEV and UCB L057 simultaneously. Potential covariates for the popPK model were assessed using standard approach. The predictive performance of the population pharmacokinetic model was evaluated by visual predictive checks and nonparametric bootstrapping with replacement.

Results: Forty-eight adult patients who received LEV tablets as monotherapy or adjunctive therapy were enrolled in this study. Patients of Chinese descents made up 66.6% of the total number of study subjects, followed by an equal number of Malays and Indians. A one-compartment open model plus a gut compartment for oral LEV, and a metabolite compartment were fitted to 602 plasma concentrations-time points of LEV and UCB L057. The estimated total clearance of LEV is 3.24 L/h per 70 kg, while the population apparent clearance of LEV to UCB L057 (CLLU) via hydrolysis reaction is 1.21 L/h per 70 kg. The value of CLLU is influenced by body size and sex; with a multiplication factor of 1 for male, and 0.85 for female. The typical clearance of parent compound LEV via other routes besides hydrolysis reaction (CLLO), for example via oxidative biotransformation pathway, is 2.03 L/h per 70 kg. Body weight, the presence of a metabolic enzyme inducer or inhibitor, and ethnicity, significantly influence the CLLO value. The clearance of UCB L057 (CLU) is estimated to be 11.7 L/h. The volume of distribution of LEV (VL) is 34.2 L per 70 kg, and the absorption rate constant (ka) of LEV is 1.46 per h.

Conclusion: The total clearance, the volume of distribution and the absorption rate constant of LEV in Malaysian patients are comparable to those of previously reported (2-5). The apparent clearance of metabolite UCB L057 that has not been previously estimated is 11.7 L/h. This study supports the hypothesis that concomitant antiepileptic agents that are cytochrome enzyme inducers could stimulate the oxidative biotransformation pathway but not the hydrolysis pathway of LEV, although the former accounts for less than 3% of the total LEV disposition in the absence of any cytochrome enzyme inducer or inhibitor (6).

References: 1. Yeap LL, Lo YL. Rapid and simultaneous quantification of levetiracetam and its carboxylic metabolite in human plasma by liquid chromatography tandem mass spectrometry. PLoS One. 2014;9(11):e111544. 2. Uges JWF, Van Huizen MD, Engelsman J, Wilms EB, Touw DJ, Peeters E, et al. Safety and pharmacokinetics of intravenous levetiracetam infusion as add-on in status epilepticus. Epilepsia. 2009;50(3):415-21. 3. Pigeolet E, Jacqmin P, Sargentini-Maier M-L, Stockis A. Population Pharmacokinetics of Levetiracetam in Japanese and Western Adults. Clinical Pharmacokinetics. 2012;46(6):503-12. 4. Patsalos PN. Clinical Pharmacokinetics of Levetiracetam. Clinical Pharmacokinetics. 2004;43(11):707-24. 5. Toublanc N, Okagaki T, Boyce M, Chan R, Mugitani A, Watanabe S, et al. Pharmacokinetics of the antiepileptic drug levetiracetam in healthy Japanese and Caucasian volunteers following intravenous administration. European Journal of Drug Metabolism and Pharmacokinetics. 2014;40(4):461-9. 6. Strolin Benedetti M, Whomsley R, Nicolas J-M, Young C, Baltes E. Pharmacokinetics and metabolism of 14C-levetiracetam, a new antiepileptic agent, in healthy volunteers. European Journal of Clinical Pharmacology. 2003;59(8):621-30.