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- Title
Time-to-Seizure Modeling of Lacosamide Used in Monotherapy in Patients with Newly Diagnosed Epilepsy.
- Authors
Lindauer, Andreas; Laveille, Christian; Stockis, Armel
- Abstract
<bold>Objectives: </bold>To quantify the relationship between exposure to lacosamide monotherapy and seizure probability, and to simulate the effect of changing the dose regimen.<bold>Methods: </bold>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.<bold>Results: </bold>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.<bold>Conclusion: </bold>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.
- Subjects
VIMPAT; TREATMENT of epilepsy; ANTICONVULSANTS; PEOPLE with epilepsy; WEIBULL distribution; DRUG therapy for convulsions; ACETIC acid; BIOLOGICAL models; COMPARATIVE studies; COMPUTER simulation; EPILEPSY; RESEARCH methodology; MEDICAL cooperation; RESEARCH; SPASMS; TIME; EVALUATION research; RANDOMIZED controlled trials; BLIND experiment; SEVERITY of illness index; PATIENT dropouts; THERAPEUTICS
- Publication
Clinical Pharmacokinetics, 2017, Vol 56, Issue 11, p1403
- ISSN
0312-5963
- Publication type
journal article
- DOI
10.1007/s40262-017-0530-8