title: Time-to-Seizure Modeling of Lacosamide Used in Monotherapy in Patients with Newly Diagnosed Epilepsy.
abstract: 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.
authors.affiliation: SGS Exprimo NV, Generaal De Wittelaan 19A Bus 5, B-2800, Mechelen, Belgium. andreas.lindauer@sgs.com.
authors.forename: Andreas
authors.initials: A
authors.lastname: Lindauer
authors.affiliation: SGS Exprimo NV, Generaal De Wittelaan 19A Bus 5, B-2800, Mechelen, Belgium.|Calvagone, Liergues, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Laveille
authors.affiliation: UCB Pharma, Braine-l'Alleud, Belgium.
authors.forename: Armel
authors.initials: A
authors.lastname: Stockis
mesh_terms: D000081:Acetamides / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000927:Anticonvulsants / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D003198:Computer Simulation; D004311:Double-Blind Method; D004827:Epilepsy / Q000097:blood / Q000188:drug therapy*; D005260:Female; D006801:Humans; D000078334:Lacosamide; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D010352:Patient Dropouts; D012640:Seizures / Q000188:drug therapy*; D012720:Severity of Illness Index; D013997:Time Factors; D055815:Young Adult
chemical_list: D000081:Acetamides; D000927:Anticonvulsants; D000078334:Lacosamide