Abstract Details

Title Single, High Doses of USL255, an Extended-Release Topiramate Formulation, Are Well Tolerated and Demonstrate a Dose-Proportional Pharmacokinetic Profile in Healthy Subjects

Topic Epilepsy

Presentation(s) P04 - (-)

Poster/Presentation
Number 212

Objective

Background BACKGROUND: USL255, extended-release topiramate (TPM), is being evaluated as a once-daily treatment for seizures (NCT01142193). Previously, administration of USL255 from 25-400mg resulted in consistent, dose proportional total exposure (AUC) with maximum exposure (Cmax) approaching proportionality over 100-400mg.

Design/Methods DESIGN/METHODS: In this Phase 1, randomized, placebo-controlled, double-blind, MTD study, 60 healthy subjects were planned for enrollment into 6 cohorts and randomly assigned 8:2 to a single USL255 dose (600, 800, 1000, 1200, 1400, 1600mg) or matching placebo. For 14 days post-dose, blood samples were collected and tolerability (eg, vital signs, ECG, adverse events [AEs]) was evaluated. If USL255 demonstrated tolerability 4 days post-dose, the study would proceed to the next cohort until all cohorts were completed. However, if a priori tolerability criteria were not met, dose escalation would cease and the previous dose would be declared the MTD. Dose proportionality of TPM exposure was determined using a power model approach, where AUC and Cmax were considered dose proportional if the 90% confidence interval for the ratio of dose-normalized geometric mean values was contained between 0.80-1.25. Linearity was assessed using the Type I F test.

Results RESULTS: Single-ascending USL255 doses from 600 to 1200mg (MTD) were generally well tolerated, with no serious or severe AEs. AUC0-t, AUC0-[infin], and Cmax were dose proportional and linear from 600-1400mg; the 1600mg cohort was not dosed due to AEs in a subject administered 1400mg. Additionally, USL255 provided consistent plasma TPM exposure over 24 hours with low inter-subject variability across cohorts.

Conclusions CONCLUSIONS: Single doses of USL255 were well tolerated up to 1200mg, and exhibited dose proportionality and a relatively flat concentration-time profile with low variability across subjects. These data further support the favorable tolerability and the predictable, consistent pharmacokinetic profile of USL255.

Authors/Disclosures
PRESENTER	No disclosure on file
	No disclosure on file
James C. Cloyd, PharmD	No disclosure on file
Mark Halvorsen, PharmD (Upsher-Smith Laboratories, LLC)	Dr. Halvorsen has received personal compensation for serving as an employee of Upsher-Smith Laboratories, LLC. Dr. Halvorsen has stock in Pfizer. Dr. Halvorsen has stock in Amgen. Dr. Halvorsen has stock in Stryker.
	No disclosure on file

��ɫ��

��ɫ��