PMID- 24861853
OWN - NLM
STAT- MEDLINE
DCOM- 20140922
LR  - 20211021
IS  - 1528-1167 (Electronic)
IS  - 0013-9580 (Print)
IS  - 0013-9580 (Linking)
VI  - 55
IP  - 7
DP  - 2014 Jul
TI  - USL255 extended-release topiramate: dose-proportional pharmacokinetics and 
      tolerability in healthy volunteers.
PG  - 1069-76
LID - 10.1111/epi.12654 [doi]
AB  - OBJECTIVE: Evaluate the pharmacokinetics (PK), safety, and tolerability of single 
      doses of once-daily USL255, Qudexy XR (topiramate) extended-release capsules, 
      over a wide dosing range. METHODS: Two single-dose, phase I studies in healthy 
      adults were used to evaluate the PK profile and maximum tolerated dose (MTD) of 
      USL255 from 25-1,400 mg. Standard PK parameters assessed included area under the 
      plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax ). 
      Dose proportionality, linearity, and intersubject and intrasubject variability 
      (coefficient of variation [%CV]) of AUC and Cmax were evaluated. 
      Investigator-reported adverse events (AEs) were obtained throughout the studies. 
      RESULTS: After the initial increase in plasma concentration levels immediately 
      following administration of USL255 25-1,400 mg, plasma topiramate 
      concentration-time profiles were flat up to 24 h after dosing. AUC was dose 
      proportional from 25-1,400 mg, and Cmax was dose proportional from 50-1,400 mg; 
      both AUC and Cmax were linear across the entire dose range. Low intersubject and 
      intrasubject %CV values were observed for AUC0-t , AUC0-infinity , and Cmax 
      (intersubject %CV: 20.2, 19.6, and 22.4%, respectively; intrasubject %CV of 
      dose-normalized mean values: 10.8, 8.2, and 13.2%, respectively). USL255 was 
      generally safe and well tolerated with MTD established at 1,200 mg. SIGNIFICANCE: 
      These results demonstrate that USL255 provides consistent plasma topiramate 
      exposure across an extended-dosing interval and predictable plasma topiramate 
      concentrations over a wide dosing range. Overall, the favorable safety profile 
      and consistency of exposure suggest once-daily USL255 can be a useful treatment 
      option for patients with epilepsy.
CI  - (c) 2014 The Authors. Epilepsia published by Wiley Periodicals, Inc. on behalf of 
      International League Against Epilepsy.
FAU - Clark, Annie M
AU  - Clark AM
AD  - Upsher-Smith Laboratories, Inc., Maple Grove, Minnesota, U.S.A.
FAU - Halvorsen, Mark B
AU  - Halvorsen MB
FAU - Braun, Tricia L
AU  - Braun TL
FAU - Johnson, Krista M
AU  - Johnson KM
FAU - Cloyd, James C
AU  - Cloyd JC
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20140523
PL  - United States
TA  - Epilepsia
JT  - Epilepsia
JID - 2983306R
RN  - 0 (Anticonvulsants)
RN  - 0 (Delayed-Action Preparations)
RN  - 0H73WJJ391 (Topiramate)
RN  - 30237-26-4 (Fructose)
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Anticonvulsants/*administration & dosage/*adverse effects/*pharmacokinetics
MH  - Area Under Curve
MH  - Cohort Studies
MH  - Cross-Over Studies
MH  - Delayed-Action Preparations
MH  - Dose-Response Relationship, Drug
MH  - Double-Blind Method
MH  - Female
MH  - Fructose/administration & dosage/adverse effects/*analogs & 
      derivatives/pharmacokinetics
MH  - *Healthy Volunteers
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Topiramate
MH  - Young Adult
PMC - PMC4283972
OTO - NOTNLM
OT  - Antiepileptic
OT  - Antiepileptic drug
OT  - Epilepsy
OT  - Once-daily
OT  - Seizures
EDAT- 2014/05/28 06:00
MHDA- 2014/09/23 06:00
CRDT- 2014/05/28 06:00
PHST- 2014/04/09 00:00 [accepted]
PHST- 2014/05/28 06:00 [entrez]
PHST- 2014/05/28 06:00 [pubmed]
PHST- 2014/09/23 06:00 [medline]
AID - 10.1111/epi.12654 [doi]
PST - ppublish
SO  - Epilepsia. 2014 Jul;55(7):1069-76. doi: 10.1111/epi.12654. Epub 2014 May 23.