Comparative pharmacokinetic analysis of USL255, a new once-daily extended-release formulation of topiramate.

PURPOSE

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.

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.