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

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

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.

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.

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.