Andreas Lindauer (1), Christian Laveille (1), Armel Stockis (2)
(1) SGS Exprimo NV, Mechelen, Belgium; (2) UCB, Braine-l’Alleud, Belgium
Objectives: To quantify the relationship between exposure to lacosamide (LCM) and seizure probability in monotherapy and to explore the relationship with other covariates, including age and disease severity. To perform simulations exploring the effect of changes to the dosing regimen of LCM on the clinical endpoint.
Methods: A structural time-to-event model for dropouts and seizures was developed using data from a study (N01061) testing levetiracetam and carbamazepine controlled-release (CBZ-CR). Subsequently, the model was updated with data from a recently completed trial (SP0993) comparing LCM to CBZ-CR. Trough plasma concentrations of LCM were analyzed with a previously developed population PK model. Individual PK parameter estimates were used to derive the daily AUC. Final PK, dropout/seizure models for LCM were used for simulations assessing the impact of changes to the dosing regimen.
Results: Data from 883 patients in SP0993 were used for modeling. A time-to-event model was developed describing the time-varying hazard of dropout using step-functions. Patients in the LCM group had a slightly lower risk of dropping out compared to those receiving CBZ-CR.
The repeated time-to-seizure data were best described by a Weibull distribution with parameters estimated independently for the first and for subsequent events [1]. Daily AUC was linearly related to the log-hazard. Disease severity, expressed as the number of seizures a patient experienced in the 3 months prior to the study (NSP3M), was found to be a strong predictor of seizure-probability with about 2.6-fold (90% CI: 2.01 – 3.31) higher risk of seizures for patients with 7 to 50 NSP3M compared to the reference category (NSP3M: 2-6). In the LCM group the hazard ratio of a first seizure for a patient aged 65 compared to 41 years (median) was 0.74 (90% CI: 0.59 – 0.88).
Simulations suggest that an individualized dosing regimen for LCM, with an initial target dose of 400 mg/day for patients with NSP3M>7, could potentially result in about 8% more patients seizure-free for 6 months at the last evaluated dose level compared with an initial target dose of 200 mg/day.
Conclusions: Baseline disease severity (NSP3M) was the most important predictor of the seizure probability in the study. Simulations suggest that dose individualization based on NSP3M could potentially be beneficial for patients with more than 7 seizures in the past 3 months. Clinical data are needed to confirm these simulation findings.
UCB-sponsored
References:
[1] Abrantes J, Almeida A, Sales F, Falcao A, Jönsson S. A repeated time-to-event model for epileptic seizures in patients undergoing antiepileptic drug withdrawal during Video-EEG monitoring. PAGE-meeting 2014, Alicante. http://www.page-meeting.org/?abstract=3180
Reference: PAGE 25 (2016) Abstr 5955 [www.page-meeting.org/?abstract=5955]
Poster: Drug/Disease modeling - CNS