PMID- 23916044
OWN - NLM
STAT- MEDLINE
DCOM- 20140318
LR  - 20130826
IS  - 1879-114X (Electronic)
IS  - 0149-2918 (Linking)
VI  - 35
IP  - 8
DP  - 2013 Aug
TI  - Efficacy and tolerability exposure-response relationship of retigabine 
      (ezogabine) immediate-release tablets in patients with partial-onset seizures.
PG  - 1174-1185.e4
LID - S0149-2918(13)00340-8 [pii]
LID - 10.1016/j.clinthera.2013.06.012 [doi]
AB  - BACKGROUND: Retigabine (international nonproprietary name)/ezogabine (United 
      States adopted name) is an antiepileptic drug (AED) that enhances KCNQ (Kv7) 
      potassium channel activity. OBJECTIVES: 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-tau 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-tau values increased linearly over the 600- to 1200-mg/d 
      dose range. Over the entire AUC0-tau 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-tau. 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-tau values indicate that, as with other AEDs, doses should be individually 
      titrated based on a balance between efficacy and tolerability.
CI  - (c) 2013 Elsevier HS Journals, Inc. All rights reserved.
FAU - Tompson, Debra J
AU  - Tompson DJ
AD  - GlaxoSmithKline, Stevenage, Hertfordshire, United Kingdom. 
      debra.j.tompson@gsk.com
FAU - Crean, Christopher S
AU  - Crean CS
FAU - Reeve, Russell
AU  - Reeve R
FAU - Berry, N Seth
AU  - Berry NS
LA  - eng
PT  - Clinical Trial, Phase III
PT  - Journal Article
PT  - Multicenter Study
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20130801
PL  - United States
TA  - Clin Ther
JT  - Clinical therapeutics
JID - 7706726
RN  - 0 (Anticonvulsants)
RN  - 0 (Carbamates)
RN  - 0 (Phenylenediamines)
RN  - 0 (Tablets)
RN  - 12G01I6BBU (ezogabine)
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Aged
MH  - Anticonvulsants/administration & dosage/*adverse effects/*therapeutic use
MH  - Carbamates/administration & dosage/*adverse effects/*therapeutic use
MH  - Disorders of Excessive Somnolence/chemically induced
MH  - Dizziness/chemically induced
MH  - Dose-Response Relationship, Drug
MH  - Double-Blind Method
MH  - Drug Administration Schedule
MH  - Epilepsies, Partial/*drug therapy
MH  - Female
MH  - Gait Disorders, Neurologic/chemically induced
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Phenylenediamines/administration & dosage/*adverse effects/*therapeutic use
MH  - Tablets
MH  - Treatment Outcome
MH  - Young Adult
OTO - NOTNLM
OT  - ezogabine
OT  - partial-onset seizures
OT  - pharmacodynamics
OT  - pharmacokinetics
OT  - retigabine
EDAT- 2013/08/07 06:00
MHDA- 2014/03/19 06:00
CRDT- 2013/08/07 06:00
PHST- 2012/05/30 00:00 [received]
PHST- 2013/06/14 00:00 [revised]
PHST- 2013/06/15 00:00 [accepted]
PHST- 2013/08/07 06:00 [entrez]
PHST- 2013/08/07 06:00 [pubmed]
PHST- 2014/03/19 06:00 [medline]
AID - S0149-2918(13)00340-8 [pii]
AID - 10.1016/j.clinthera.2013.06.012 [doi]
PST - ppublish
SO  - Clin Ther. 2013 Aug;35(8):1174-1185.e4. doi: 10.1016/j.clinthera.2013.06.012. 
      Epub 2013 Aug 1.