Extended-Release Topiramate (USL255) Exhibits Linear Dose-Proportional Pharmacokinetic Characteristics (P06.128)

Abstract

Objective: Evaluate dose proportionality, linearity, and tolerability of USL255 at 25, 50, 100, 200, and 400 mg. Background Upsher-Smith Laboratories, Inc. has developed USL255, a novel, once-daily, extended-release topiramate (TPM) formulation. USL255 provides equivalent TPM exposure as compared with immediate-release TPM (TMP-IR) administered twice-daily, yet exhibits an improved pharmacokinetic (PK) profile (eg, lower C max , higher C min , decreased fluctuation index [FI]). Design/Methods: This Phase I, single-dose, open-label, 5-way crossover study evaluated the PK profile of USL255 in healthy subjects. Dose proportionality was determined using a power model approach, where PK parameters were considered proportional if the confidence interval (CI) for the ratios of dose-normalized geometric mean values (R dnm ) or geometric least-squares means (GLSM) were completely contained between 0.8 – 1.25. Linearity was assessed by modeling, and deviation from linearity was tested using the type I F test (α=.05). Tolerability was evaluated through adverse event (AE) monitoring, vital sign measurements, and clinical laboratory evaluations. Results: Total TPM exposure for USL255 was dose proportional and linear from 25 mg – 400 mg. Maximum TPM plasma concentration neared dose-proportionality for the 100 mg – 400 mg doses (R dnm 90%;CI, 1.10 – 1.27). Subsequent analyses compared the dose-normalized C max values of USL255 400 mg to 200 mg, and 200 mg to 100 mg; 90% CIs for these analyses were completely contained between 0.80 – 1.25, indicating that C max changed proportionally with dose. All USL255 doses were well tolerated, and the percentage of subjects who experienced a treatment-emergent AE generally increased with ascending doses. Conclusions: Single-dose USL255 TPM exposure was dose proportional and linear from 25 mg to 400 mg, and C max appeared dose proportional over the higher doses (100 mg – 400 mg), suggesting that USL255 may provide a once-daily alternative to TPM-IR with flexible dosing (25 mg – 400 mg), predictable plasma concentrations, and a favorable tolerability profile. Supported by: Upsher-Smith Laboratories, Inc. Disclosure: Dr. Halvorsen has received personal compensation for activities with Upsher-Smith Laboratories, Inc. as an employee.Dr. Halvorsen holds stock and/or stock options in Medtronic, Stryker, Elan, Teva, Gilead, and Pfizer. Dr. Lambrecht has received personal compensation for activities with Upsher-Smith Laboratories, Inc. as an employee.Dr. Lambrecht holds stock and/or stock options in Medtronic, Inc. Dr. Todd has received personal compensation for activities with Upsher-Smith Laboratories, Inc., as an employee. Dr. Todd holds stock and/or stock options in Pfizer Inc.