(Abst. 2.157 ), 2013
IMPACT OF DELAYED-DOSE ADMINISTRATION OF USL255, AN EXTENDED-RELEASE TOPIRAMATE FORMULATION
Authors: B. Anders, Q. Lu, E. Ludwig, A. M. Clark, M. B. Halvorsen
When antiepileptic drug (AED) administration is delayed, the risk of seizures may be increased. While extended-release (XR) formulations are likely to improve patient compliance compared with immediate-release AEDs, a delay in dose administration can cause steady-state (SS) plasma concentrations to drop below minimum therapeutic concentrations. USL255 is a once-daily (QD), XR formulation of topiramate (TPM) developed for the treatment of epilepsy. Simulations were performed to gain an understanding of the effects associated with delayed administration of USL255. The magnitude of change in maximum plasma concentrations (Cmax) and minimum plasma concentrations (Cmin) after administration of the delayed dose was also assessed.
Data used for these analyses were obtained from a phase 1, single-dose study (N=36) that evaluated the pharmacokinetic (PK) profile of 200 mg USL255 administered in the fasted state to healthy volunteers. Nonparametric superpositioning was used to predict SS PK profiles from the single-dose data. Dose administration for 14 days was simulated to assure SS conditions were reached, followed by a simulated delay in dosing (6, 12, 18, and 24 hr later than scheduled), with QD dosing resuming after the late dose. For the 24 hr delay, two doses were assumed to be taken together. Mean-predicted concentrations were calculated for each delayed-dose scenario and were compared with SS concentrations without a delayed dose (full compliance). Simulated Cmin and Cmax were evaluated for up to 96 hr following the late dose.
As expected, the mean-predicted plasma concentrations prior to the next scheduled dose decreased incrementally as the time delay increased. However, within one 24 hr dosing interval after the late dose was administered, the TPM concentration-time profiles for all 4 scenarios were similar by visual comparison to simulated SS concentrations with full compliance. Topiramate plasma 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 compliant dosing concentrations, and corresponding Cmin values increased by 2.55%, 5.12%, 7.67%, and 10.23%, respectively. Three days after delayed-dose administration, Cmax values were 1.14 – 7.03% higher than concentrations without a delayed dose, and Cmin values were 1.33 – 5.31% higher.
When a single dose of USL255 was simulated to be taken 6, 12, 18, or 24 hr later than scheduled, TPM plasma concentrations returned to near SS within one 24-hr dosing interval after the delayed dose was administered. These data demonstrate that administration of USL255, up to 18 hr after a missed dose, will minimize the duration of decreased TPM concentrations without significant risk of increased (>10%) maximal plasma concentrations. Supported by Upsher-Smith Laboratories, Inc.
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