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Single, High Doses of USL255, an Extended-Release Topiramate Formulation, Are Well Tolerated and Demonstrate a Dose-Proportional Pharmacokinetic Profile in Healthy Subjects (P04.212)

OBJECTIVE: Characterize the pharmacokinetics and determine maximum tolerated dose (MTD) of USL255 at single-ascending doses from 600 – 1600mg. 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 (C max ) approaching proportionality over 100–400mg. 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 C max 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: Single-ascending USL255 doses from 600 to 1200mg (MTD) were generally well tolerated, with no serious or severe AEs. AUC 0-t , AUC 0-∞ , and C max 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: 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. Supported by: Upsher-Smith Laboratories, Inc. Disclosure: Dr. Braunhas received personal compensation for activities with Upsher-Smith Laboratories, Inc., as an employee. Dr. Clark has received personal compensation for activities with Upsher-Smith Laboratories, Inc. Dr. Cloyd has received personal compensation for activities with Sepracor, Special Products, and Upsher-Smith Laboratories, Inc. Dr. Cloyd has received license fee payments from CyDex. Dr. Cloyd has received research support from Medtronic, Inc., CyDex, and Valeant Pharmaeuticals International. Dr. Halvorsen has received personal compensation for activities with Upsher-Smith Laboratories, Inc as an employee. Dr. Halvorsen holds stock in Medtronic, Stryker, Elan, Teva, Gilead, and Pfizer.