[P3.265] USL255, Extended-Release Topiramate, Displays an Improved Pharmacokinetic Profile With Reduced Adverse Events Compared With Immediate-Release Topiramate
Annie M. Clark,1Robert Hogan,2Bob Anders1
1Maple Grove, MN, USA, 2Saint Louis, MO, USA
OBJECTIVE: Compare the PK and TEAE profiles of USL255 with immediate-release topiramate (TPM-IR [Topamax®]) after multiple-dose administration.
BACKGROUND: Extended-release antiepileptic drugs aim to reduce drug plasma fluctuations compared with IR formulations. This reduction may increase efficacy and decrease peak-related TEAEs, including cognitive-related AEs.
DESIGN/METHODS: Three pooled phase 1, multiple-dose studies in healthy adults were used to evaluate TEAEs with USL255 (n=105) and TPM-IR (n=109) at 200 - 400 mg/day maintenance doses for up to 14 days. PK data from 1 of these studies (N=38; crossover design) was used to determine equivalence between USL255 and TPM-IR.
RESULTS: In the PK study, USL255 was pharmacokinetically equivalent to TPM-IR, as the 90% CIs for the USL255/TPM-IR ratios of AUC0‑24 (1.02-1.05), Cmin (1.03-1.09), and Cmax (0.90-0.97) were contained within the 0.8 to 1.25 equivalence limits. USL255 demonstrated significantly lower Cmax (P<.001), higher Cmin (P<.001), and a 26% lower mean fluctuation index compared with TPM-IR. When pooling AEs across the 3 studies, TEAEs rates were similar in both groups (USL255, 75%; TPM-IR, 79%). TEAEs were lower with USL255 vs TPM-IR treatment during up titration (67% vs 78%; 14% relative reduction). The most common TEAEs were nervous systems disorders, and occurrence was lower with USL255 than TPM-IR (49% vs 56%; 12.5% relative reduction). Individual topiramate-associated nervous system TEAEs were reduced with USL255, including cognitive disorder (1.9% vs 4.6%), headache (18% vs 25%), memory impairment (2.9% vs 9.2%), dizziness (9.5% vs 11%) and paresthesia (25% vs 29%); similar reductions were observed with psychiatric AEs overall and individually (eg, agitation, anxiety). Somnolence was slightly greater in USL255-treated participants (13%) vs TPM-IR (10%).
CONCLUSIONS: Once-daily, extended-release USL255 provides equivalent topiramate exposure to twice-daily TPM-IR, with reduced Cmax, lower fluctuation index, and fewer overall and cognitive TEAEs. These data suggest the improved pharmacokinetic profile of USL255 vs TPM-IR may be associated with reduced side effects.
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)