[P3.257] Impact of Delayed-Dose Administration of USL255, an Extended-Release Topiramate Formulation

Bob Anders,1Qiang Lu,2Elizabeth Ludwig,2Annie M. Clark1
1Maple Grove, MN, USA, 2Buffalo, NY, USA

OBJECTIVE: Gain an understanding of pharmacokinetic effects associated with delayed administration of USL255.
BACKGROUND: USL255, a once-daily, extended-release formulation of topiramate, was developed for the treatment of epilepsy. While once-daily formulations may improve patient compliance, delayed dosing may cause steady-state plasma concentrations to decrease below minimum therapeutic concentrations.
DESIGN/METHODS: Nonparametric superpositioning was used to simulate steady-state pharmacokinetic profiles from single-dose USL255 200 mg data. A 14-day dose administration (200 mg/day) to achieve steady-state conditions was simulated (full compliance), followed by a 6, 12, 18, and 24 hr (double dose) simulated delay in dosing, with once-daily dosing resuming after the late dose. Mean-predicted topiramate concentrations were calculated for each delayed-dose scenario and compared with full compliance. Simulated minimum (Cmin) and maximum concentrations (Cmax)were evaluated for 96 hr following the late dose.
RESULTS: Mean-predicted plasma concentrations prior to the next scheduled dose decreased incrementally as the time delay increased. However, within 24 hr after late-dose administration (followed by compliant dosing), topiramate concentrations for all delayed-dose scenarios were similar by visual comparison to simulated full-compliance concentrations. Concentrations were generally highest 2 days after a USL255 dose was administered 6, 12, 18, or 24 hr late; mean Cmax values were 2.09%, 4.25%, 6.79%, and 11.85% higher than steady-state concentrations, and corresponding Cmin values increased by 2.55%, 5.12%, 7.67%, and 10.23%. Three days after delayed-dose administration, Cmax and Cmin values were 1.14-7.03% and 1.33-5.31% higher, respectively, as compared with compliant dosing.
CONCLUSIONS: After a USL255 dose was administered up to 24 hr late, simulated topiramate concentrations returned to near steady state within one 24-hr interval. These data demonstrate dosing USL255, up to 18 hr after a missed dose (ie, 6 hr before the next scheduled dose), minimizes the time that topiramate concentrations may be below minimum therapeutic concentrations without significant risk of increased (>10%) Cmax.
Study Supported by: Upsher-Smith Laboratories, Inc.
Category - Epilepsy and Clinical Neurophysiology (EEG): Therapeutics: Medical

Tuesday, April 29, 2014 3:00 PM

P3: Poster Session III: Epilepsy and Clinical Neurophysiology: AED (3:00 PM-6:30 PM)


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