title: Comparative pharmacokinetic analysis of USL255, a new once-daily extended-release formulation of topiramate.
abstract: OBJECTIVE
  To compare the pharmacokinetics of USL255, a once-daily extended-release (ER) formulation of topiramate (TPM), with Topamax (immediate-release TPM) in healthy subjects after oral dosing and evaluate the effect of food on USL255 bioavailability and pharmacokinetics.
  
  
  METHODS
  This randomized, single-center, open-label, cross-over design study had three dosing periods separated by 21 days of washout between treatments. Thirty-six volunteers received single doses of USL255 (200 mg) in fasted and fed conditions and two doses of Topamax (100 mg) administered 12 h apart. TPM plasma samples were analyzed by liquid chromatography-mass spectroscopy. Pharmacokinetic parameters were calculated by noncompartmental methods.
  
  
  RESULTS
  USL255 fasted pharmacokinetic parameters [point estimate (90% confidence interval, CI) compared to Topamax] were: relative bioavailability (F) 91.2% (84-99%), peak plasma concentration (C(max)) USL255/Topamax-ratio 59% (53-65%), time to reach C(max) (t(max)) 19.5 ± 7.2 h, accumulation ratio (R(ac)) 3.9 ± 1.2, effective half-life (t(1/2,eff)) 55.7 ± 19.9 h, terminal half-life (t(1/2,z)) 80.2 ± 14.2 h, and peak-occupancy-time (POT) 12.1 ± 4.0 h. Although the F and C(max) were unaffected by food, R(ac) and t(1/2,eff) increased to 4.9 ± 0.9, and 72.5 ± 15.4 h, respectively. In contrast to t(1/2,z,) t(1/2,eff) reflects absorption rate; therefore, USL255's t(1/2,eff) was significantly longer than Topamax's t(1/2,eff) (37.1 ± 6.5 h).
  
  
  CONCLUSIONS
  Although bioequivalent to Topamax in extent of absorption, USL255 had a slower absorption rate as reflected in its lower C(max) and longer t(max), larger POT and longer t(1/2,eff), and similar R(ac) values to that of Topamax (q12 h). This relative flat plasma profile allows for once-daily dosing with diminished fluctuations in TPM plasma levels. In addition, neither USL255's peak nor extent of plasma exposure of TPM was affected by food.
authors.affiliation: Upsher-Smith Laboratories, Inc, Minneapolis, Minnesota, USA.
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Lambrecht
authors.forename: Tawfeeq
authors.initials: T
authors.lastname: Shekh-Ahmad
authors.forename: Wesley M
authors.initials: WM
authors.lastname: Todd
authors.forename: Mark B
authors.initials: MB
authors.lastname: Halvorsen
authors.forename: Meir
authors.initials: M
authors.lastname: Bialer
mesh_terms: D000328:Adult; D000927:Anticonvulsants / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D001682:Biological Availability; D018592:Cross-Over Studies; D003692:Delayed-Action Preparations; D005260:Female; D005632:Fructose / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077236:Topiramate; D055815:Young Adult
chemical_list: D000927:Anticonvulsants; D003692:Delayed-Action Preparations; D000077236:Topiramate; D005632:Fructose