Christian Laveille (1), Rik Schoemaker (1), Armel Stockis (2)
(1) Exprimo NV, (2) UCB Pharma
Objectives: To analyze preliminary data obtained from children aged 3−17 years with partial-onset seizures (POS) to support the design of phase III trials.
Methods: A retrospective exposure-response model was built for lacosamide based on daily seizure counts (N=210,234) of 1308 adult patients who participated in three double-blind, placebo-controlled clinical trials in adjunctive treatment of POS (SP667, SP754, SP755). A negative binomial distribution with zero-inflation and Markovian element associated with a mixture model, stratifying patients according to reduced or increased seizure frequency (SF), provided the best fit. Preliminary SF data from a multicenter, open-label trial designed to investigate the safety and pharmacokinetics of lacosamide as adjunctive therapy in children with POS (SP847) were analyzed using the exposure-response model developed in adults. In addition to an empirical Bayesian feedback estimation, simulations (VPC-like with 1000 replicates) were performed in order to evaluate the performance of the exposure-response model of lacosamide developed in adults to predict the median percentage reduction from baseline in SF and the responder rate (≥50% reduction in SF from baseline). Model development and simulations were performed using non-linear mixed-effects modeling implemented in NONMEM V7.1.0 with the Laplacian method.
Results: At the preliminary cut-off date, 28 pediatric patients aged 3−17 years had completed the dose-finding study. Their daily seizure count data (N=1,360) were satisfactorily described by the model developed in adults. Furthermore, the simulation results showed the ability of the adult exposure-response model to correctly predict the median percentage reduction from baseline and the responder rate in the study sample.
Conclusions: Based on the preliminary results, and on the limited information from the SP847 trial, no signal was seen in the present pediatric study suggesting a possible alteration of the exposure-response relationship established in adults. Therefore, the lacosamide dosing strategy in the pediatric population will probably be driven only by lacosamide pharmacokinetics.
Reference: PAGE 21 () Abstr 2381 [www.page-meeting.org/?abstract=2381]
Poster: Paediatrics