SUMMARYPurpose: 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. Thirtysix 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. Key Findings: 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). Significance: 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.