title: Efficacy and tolerability exposure-response relationship of retigabine (ezogabine) immediate-release tablets in patients with partial-onset seizures.
abstract: BACKGROUND
  Retigabine (international nonproprietary name)/ezogabine (United States adopted name) is an antiepileptic drug (AED) that enhances KCNQ (Kv7) potassium channel activity.
  
  
  OBJECTIVE
  The aim of this study was to explore the relationship between retigabine/ezogabine systemic exposure and efficacy and adverse events (AEs) of retigabine/ezogabine from Phase III clinical trials.
  
  
  METHODS
  Data were combined from Studies 301 and 302, which were both randomized, double-blind, placebo-controlled, multicenter, parallel-group studies with similar inclusion and exclusion criteria. All patients had partial-onset seizures and were receiving 1 to 3 concomitant AEDs. Systemic exposure was predicted for each patient as the average steady-state AUC0-τ during the 12-week maintenance phase, based on a population pharmacokinetic model developed for retigabine/ezogabine. Efficacy end points included reduction in total partial-seizure frequency from baseline and probability of ≥50% reduction from baseline in seizure frequency. The probabilities of occurrence of 6 AEs were also evaluated.
  
  
  RESULTS
  AUC0-τ values increased linearly over the 600- to 1200-mg/d dose range. Over the entire AUC0-τ range, the probability of efficacy was greater than that for any AE. The slopes of the exposure-response relationship for probability of dizziness and abnormal coordination were similar to that for efficacy, whereas the slopes for dysarthria, somnolence, tremor, and blurred vision were shallower, indicating that the probability of these events occurring was less affected than the probability of efficacy by increases in retigabine/ezogabine AUC0-τ.
  
  
  CONCLUSIONS
  Based on the summary statistics of pharmacokinetic parameters, systemic exposure to retigabine/ezogabine increased linearly with dose (600-1200 mg/d). Population pharmacokinetics and pharmacodynamics showed that the probability of efficacy and AEs increased with increasing systemic retigabine/ezogabine exposure, and the probability of efficacy was higher than the probability of any of the AEs. The 35%-50% between-patient variability and overlap between retigabine/ezogabine dose levels in AUC0-τ values indicate that, as with other AEDs, doses should be individually titrated based on a balance between efficacy and tolerability.
authors.affiliation: GlaxoSmithKline, Stevenage, Hertfordshire, United Kingdom. debra.j.tompson@gsk.com
authors.forename: Debra J
authors.initials: DJ
authors.lastname: Tompson
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Crean
authors.forename: Russell
authors.initials: R
authors.lastname: Reeve
authors.forename: N Seth
authors.initials: NS
authors.lastname: Berry
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000927:Anticonvulsants / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use*; D002219:Carbamates / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use*; D006970:Disorders of Excessive Somnolence / Q000139:chemically induced; D004244:Dizziness / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004828:Epilepsies, Partial / Q000188:drug therapy*; D005260:Female; D020233:Gait Disorders, Neurologic / Q000139:chemically induced; D006801:Humans; D008297:Male; D008875:Middle Aged; D010655:Phenylenediamines / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use*; D013607:Tablets; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000927:Anticonvulsants; D002219:Carbamates; D010655:Phenylenediamines; D013607:Tablets; C101866:ezogabine
keywords: ezogabine; partial-onset seizures; pharmacodynamics; pharmacokinetics; retigabine