Supervisors info:
Μαρκαντώνη - Κυρούδη Σοφία, Καθηγήτρια, Τμήμα Φαρμακευτικής, ΕΚΠΑ
Βαλσαμή Γεωργία, Καθηγήτρια, Τμήμα Φαρμακευτικής, ΕΚΠΑ
Καραλής Ευάγγελος, Επίκουρος Καθηγητής, Τμήμα Φαρμακευτικής, ΕΚΠΑ
Summary:
Background: Epilepsy is one of the few nosological entities that have been described extensively since ancient times, however, clarification of the pathophysiological mechanisms of the disorder occurred during the 19th and 20th century AD, with the discovery of the first antiepileptic drugs. Nowadays, the contribution of global leagues, such as the ILAE, to the systematic classification and clarification of the disease profile, as well as the discovery of newer generation drugs with comparative advantages over their predecessors, have significantly improved the therapeutic management of epilepsy. Levetiracetam is a newer generation antiepileptic drug with an optimal pharmacokinetic and pharmacodynamic profile resulting in its widespread use for the prevention of seizures in modern therapy. Its pharmacokinetics have been extensively studied in many clinical trials and in a multitude of subgroups of the general population, with the exception of adult critically ill ICU patients, for whom only a few studies have been reported in the literature. Objective: The aim of the present study was to investigate the population pharmacokinetics of levetiracetam in adult ICU patients. Methods: The study involved 14 adult patients to whom levetiracetam doses of 1000 - 1500 mg were administered, by IV infusion for 15 minutes, once or twice daily. The collection of whole blood samples was performed at specific time points. Levetiracetam blood concentrations were quantified using High Performance Liquid Chromatography with a UV detector, following sample preparation by solid phase extraction using a kit. Concentration - time data were analysed by nonlinear mixed effects modelling using the program Monolix Suite v2019R2 (Lixoft, Orsay, France). The statistical analysis of the patients’ clinical data was performed using the IBM SPSS Statistics, Version 25 (IBM Corporation, Armonk, New York, USA). Results: A single-compartment pharmacokinetic model with first-order kinetic clearance and a proportional residual variability error model optimally described the data. The covariates incorporated in the final model for which statistically significant correlations with Cl were found, were the APACHE II score (p = 0.00 <0.05) which was significantly negatively correlated and the Cockroft - Gault eGFR (p = 0.028 <0.05) which was significantly positively correlated, while the values of the population parameters of the final model were: Vd = 48.7 L and Cl = 6.87 L/h. The evaluation of the final model was performed with goodness-of-fit plots and visual predictive checks (VPCs) using 1000 dataset Monte Carlo simulations, which confirmed the robustness and good prediction power of the model. No significant difference was found between prophylaxis with levetiracetam and induction of epileptic activity (p = 0.442 >0.05), as well as between loading dose of levetiracetam and induction of epileptic activity (p = 0.506 >0.05) (Chi-square test). In contrast, a statistically significant difference was found between the APACHE II score and the induction of epileptic activity (p = 0.034 <0.05), as well as between Cockroft - Gault eGFR and induction of epileptic activity (p = 0.031 <0.05) (One-Way ANOVA). Discussion and Conclusions: The final population model found to best describe the pharmacokinetics of levetiracetam in the present study was consistent with that reported in the literature based on the findings of a variety of clinical studies in other populations. Out of all the covariates included in the analysis, the accumulation of levetiracetam in ICU patients with increasing severity of illness score and decreasing renal function was found to be clinically significant. Also, a statistically significant relationship was noted between the induction of epileptic activity and the APACHE II score and between the induction of epileptic activity and the Cockroft - Gault eGFR.
Keywords:
Epilepsy, levetiracetam, pharmacokinetics, population pharmacokinetic modeling, critically ill patients
