title: USL255 extended-release topiramate: dose-proportional pharmacokinetics and tolerability in healthy volunteers.
abstract: 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-∞ , 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Upsher-Smith Laboratories, Inc., Maple Grove, Minnesota, U.S.A.
authors.forename: Annie M
authors.initials: AM
authors.lastname: Clark
authors.forename: Mark B
authors.initials: MB
authors.lastname: Halvorsen
authors.forename: Tricia L
authors.initials: TL
authors.lastname: Braun
authors.forename: Krista M
authors.initials: KM
authors.lastname: Johnson
authors.forename: James C
authors.initials: JC
authors.lastname: Cloyd
mesh_terms: D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics*; D019540:Area Under Curve; D015331:Cohort Studies; D018592:Cross-Over Studies; D003692:Delayed-Action Preparations; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005632:Fructose / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077236:Topiramate; D055815:Young Adult
chemical_list: D000927:Anticonvulsants; D003692:Delayed-Action Preparations; D000077236:Topiramate; D005632:Fructose
keywords: Antiepileptic; Antiepileptic drug; Epilepsy; Once-daily; Seizures