Time-to-Seizure Modeling of Lacosamide Used in Monotherapy in Patients with Newly Diagnosed Epilepsy

Abstract

Objectives: To quantify the relationship between exposure to lacosamide monotherapy and seizure probability, and to simulate the effect of changing the dose regimen.

Methods: Structural time-to-event models for dropouts (not because of a lack of efficacy) and seizures were developed using data from 883 adult patients newly diagnosed with epilepsy and experiencing focal or generalized tonic-clonic seizures, participating in a trial (SP0993; ClinicalTrials.gov identifier: NCT01243177) comparing the efficacy of lacosamide and carbamazepine controlled-release monotherapy. Lacosamide dropout and seizure models were used for simulating the effect of changing the initial target dose on seizure freedom.

Results: Repeated time-to-seizure data were described by a Weibull distribution with parameters estimated separately for the first and subsequent seizures. Daily area under the plasma concentration-time curve was related linearly to the log-hazard. Disease severity, expressed as the number of seizures during the 3 months before the trial (baseline), was a strong predictor of seizure probability: patients with 7-50 seizures at baseline had a 2.6-fold (90% confidence interval 2.01-3.31) higher risk of seizures compared with the reference two to six seizures. Simulations suggested that a 400-mg/day, rather than a 200-mg/day initial target dose for patients with seven or more seizures at baseline could potentially result in an additional 8% of seizure-free patients for 6 months at the last evaluated dose level. Patients receiving lacosamide had a slightly lower dropout risk compared with those receiving carbamazepine.

Conclusion: Baseline disease severity was the most important predictor of seizure probability. Simulations suggest that an initial target dose >200 mg/day could potentially benefit patients with greater disease severity.

Conflict of interest statement

Funding

This study was funded by UCB Pharma (Brussels, Belgium).

Conflict of interest

Andreas Lindauer is an employee of SGS Exprimo. Christian Laveille was an employee of SGS Exprimo when the study was performed. Armel Stockis is an employee of UCB Pharma.

Figures

Fig. 1

Design of lacosamide (LCM) SP0993 clinical trial. The randomization starting dose was LCM 100 mg/day or carbamazepine controlled release (CBZ-CR) 200 mg/day

Fig. 2

Visual predictive check of dropout probability. Blue line observed Kaplan–Meier curve of dropout not because of a lack of efficacy in SP0993; shaded area represents the 95% prediction interval based on 500 simulations with the updated dropout model using SP0993 data. The drop of the curve after 400 days is owing to most patients (the responders) exiting the trial as planned after 385 days (21 days up-titration/stabilization + 364 days on treatment without escalation). After this point, only a few patients remained in the trial such that the Kaplan–Meier curve declined appreciably on any subsequent event. CBZ carbamazepine, LCM lacosamide

Fig. 3

Visual predictive check of time to first seizure in the evaluation period. Blue line observed Kaplan–Meier curve; shaded area represents the 95% PI based on 500 simulations. The vertical ticks indicate dropouts in the observed data (right censoring). CBZ carbamazepine, LCM lacosamide

Fig. 4

Posterior predictive check for the cumulative percentage of patients seizure free for 6 months. Gray histograms outcome of 500 replicate simulations; solid green line median of the 500 simulations; dotted blue line observed percentages in SP0993; green area encompasses the 95% prediction interval. CBZ carbamazepine, LCM lacosamide