Abstracts

Rationale: Lacosamide (LCM) is a newer antiepileptic drug indicated as adjunctive therapy for partial-onset seizures (POS) in adults. The objective of this analysis was to assess the effect of age and gender on the pharmacokinetic (PK) parameters of LCM through normalization processes and to evaluate if PK of LCM is different over age or influenced by gender and enforces considerations about therapeutic regimes. Methods: Data were extracted from two Phase I clinical pharmacology studies in healthy subjects. First study included healthy Caucasian women (18-40 years, oral LCM 400mg/day) whereas the second study included healthy male and female subjects (≥65 years, 200mg/day) and healthy male subjects (18-45 years, 200mg/day). The PK parameters, area under the concentration time curve over a dosing interval at steady state (AUC_tau,ss) and maximum measured concentration in a dosing interval at steady state (C_max,ss) were determined by non-compartmental methods. AUC_tau,ss and C_max,ss values were normalized by body weight, height, fat free mass (FFM), lean body weight (LBW), and by volume of distribution (Vd). FFM, LBW and Vd were approximated through empiric equations. For AUC_tau,ss and C_max,ss statistical comparison of different groups were performed after log-transformation based on an analysis of variance (ANOVA). Results were compared to results of a population pharmacokinetic (POP PK) study of LCM in patients with POS. Results: A total of 66 healthy subjects were included and stratified by age group and gender. AUC_tau,ss and C_max,ss tended to show higher values in females compared to males and also in elderly vs. young subjects. Differences between groups were smaller when data were normalized by the above mentioned parameters. Before normalization higher AUC_tau,ss and C_max,ss values in females compared with males in both age groups (older and younger) were found. The relative bioavailability for AUC_tau,ss and C_max,ss concerning age and gender effects showed that normalization by Vd led the 90% confidence intervals of the ratio for AUC_tau,ss and C_max,ss for age and gender comparisons to fall within the range 80-125%. Same was true for C_max,ss normalized by LBW or FFM. The POP PK study in adults with POS confirmed these results and concluded that inter-individual variability of Vd can be explained to a large extent by differences in gender and body composition. Conclusions: Pharmacokinetic evaluations in healthy subjects and in patients with POS revealed that almost all differences in LCM PK parameters observed between young and elderly or between male and female subjects can be explained by body weight or differences in Vd. Results are confirmed by the results of the POP PK study. Disclosure: Work was funded by UCB. All authors are employees of UCB Pharma.