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.

Transdermal estradiol gel 0.1% for the treatment of vasomotor symptoms in postmenopausal women.

OBJECTIVE: The objective of this study was to evaluate the efficacy and safety of three doses of estradiol gel 0.1% (Divigel, a novel formulation consisting of 1 mg estradiol per 1 g transdermal gel) to reduce the frequency and severity of vasomotor symptoms and signs of vulvar and vaginal atrophy associated with menopause. DESIGN: A total of 488 postmenopausal women were evaluated in a 12-week study comparing placebo with estradiol gel 0.1% at doses of 1.0, 0.5, and 0.25 mg/day, with estimated daily deliveries of 0.027, 0.009, and 0.003 mg of estradiol, respectively. Primary endpoints were the change from baseline in daily frequency and severity of moderate to severe vasomotor symptoms. Change from baseline in the signs of vulvar and vaginal atrophy (vaginal pH and percentage of superficial cells) was also assessed. RESULTS: Treatment with estradiol gel 0.1% showed statistically significant reductions in frequency and severity of vasomotor symptoms from baseline compared with placebo as early as Week 2 that were maintained throughout treatment. Signs of vulvar and vaginal atrophy were also significantly improved from baseline with all three doses of estradiol gel 0.1% compared with placebo. CONCLUSIONS: Low-dose transdermal estradiol gel 0.1% is an effective treatment for relief of vasomotor symptoms, as well as signs of vulvar and vaginal atrophy, associated with menopause. Estradiol gel 0.1% offers multiple dosing options to individualize patient therapy, including the lowest available effective dose (0.25 mg estradiol, delivering 0.003 mg/d estradiol) to treat the vasomotor symptoms of menopause.