title: A novel design for a dose finding, safety, and drug interaction study of an antiepileptic drug (retigabine) in early clinical development.
abstract: OBJECTIVE
  To obtain information on the acceptable doses of the antiepileptic drug (AED) retigabine (RTG), the maximum tolerated dose (MTD), drug interactions, safety and tolerability, and preliminary evidence of efficacy when administered as adjunctive therapy and as monotherapy.
  
  
  METHODS
  Study 202 was an open-label, add-on study in patients with partial or generalized epilepsy treated with valproic acid (VPA), carbamazepine (CBZ), phenytoin (PHT), or topiramate (TPM) as monotherapy. Following baseline assessments, patients entered a dose titration phase of 28 â 56 days. The initial daily RTG dose was 100 or 200 mg (2 or 3 Ã daily). The RTG dose was increased every 1 - 2 weeks by 50 - 200 mg to a maximum of 1,600 mg/day. Once the RTG MTD had been attained, patients entered a 14-day maintenance period. Following this, the patient's background AED dose could be reduced, with the possibility of achieving RTG monotherapy. The final dosing regimen attained was maintained for an additional 14 days. Patients who completed study 202 could choose to continue treatment with RTG (with or without other AEDs) in study 208, the long-term extension of study 202. Safety assessments included adverse event (AE) monitoring, clinical laboratory evaluations, electrocardiograms, and physical and neurologic examinations. Patients' seizure diaries to assess the frequency and type of seizures, the percentage change in seizure rate, and the responder rate (>= 50% reduction in seizure rate from baseline) were evaluated.
  
  
  RESULTS
  60 patients (mean age 37.2, range 16 - 64 years) were enrolled in study 202, and 47 (78%) continued treatment with RTG in the extension study (208). In study 202, the most commonly reported AEs were: dizziness (53%), asthenia (42%), somnolence (33%), nausea (27%), speech disorder (27%), and tremor (27%). In the extension study, AEs were similar and included dizziness, somnolence, diplopia, feeling "drunk", confusion, fatigue, and dysarthria. The median percent reductions in 28-day seizure rate, relative to baseline in Studies 202 and 208, were ~ 20% and 47%, respectively. RTG did not alter the pharmacokinetics of the four monotherapy AEDs investigated. CBZ and PHT increased RTG clearance by 27% and 36%, respectively, whereas TPM and VPA had no effect on RTG clearance.
  
  
  CONCLUSIONS
  Studies 202 and 208 provided critical information on RTG safety and tolerability, and reductions in seizure rates towards the design and conduct of subsequent pivotal clinical trials. Likewise, information regarding the appropriate dosage of RTG with VPA, CBZ, PHT, or TPM was obtained, which permitted the subsequent pivotal trials to be performed appropriately. *Currently at Shire Pharmaceuticals, Behavioral Health Business Unit, Wayne, PA, USA **Currently at University of Pennsylvania, Department of Neurology, Philadelphia, PA, USA.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Sachdeo
authors.forename: Arnaud
authors.initials: A
authors.lastname: Partiot
authors.forename: Victor
authors.initials: V
authors.lastname: Biton
authors.forename: William E
authors.initials: WE
authors.lastname: Rosenfeld
authors.forename: Virinder
authors.initials: V
authors.lastname: Nohria
authors.forename: Debra
authors.initials: D
authors.lastname: Tompson
authors.forename: Sarah
authors.initials: S
authors.lastname: DeRossett
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Porter
mesh_terms: D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D002219:Carbamates / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D054796:Drug Dosage Calculations; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D004828:Epilepsies, Partial / Q000175:diagnosis / Q000517:prevention & control*; D004829:Epilepsy, Generalized / Q000175:diagnosis / Q000517:prevention & control*; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D061214:Patient Safety; D010655:Phenylenediamines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D012107:Research Design; D018570:Risk Assessment; D013997:Time Factors; D016896:Treatment Outcome; D014481:United States; D055815:Young Adult
chemical_list: D000927:Anticonvulsants; D002219:Carbamates; D010655:Phenylenediamines; C101866:ezogabine