Abstracts

Rationale: The clinical usefulness of TPM-IR as a broad-spectrum AED, with a safety profile based on more than 4 million exposures, is well established. Tolerability issues, especially distinctive neurocognitive effects, and b.i.d. dosing may adversely affect patient adherence. SPN-538 (Trokendi XR, Supernus Pharmaceuticals, Inc.) is a novel extended-release, once-daily capsule formulation of TPM that may improve tolerability and enhance adherence. This study compared relative bioavailability of once-daily SPN-538 and b.i.d. TPM-IR to assess steady-state bioequivalence.Methods: In a single-blind, randomized-sequence, crossover study, healthy adults received b.i.d. TPM-IR (Topamax, Janssen Pharmaceuticals) and once-daily SPN-538 (active drug in AM; matching placebo capsule in PM). Study drug was force-titrated in 50-mg weekly increments over 4 wks to 200 mg/day, which was maintained for 10 days. A 32-day washout separated treatment periods. Pre-dose (trough) plasma TPM concentrations were determined at each titration step and at steady-state; post-dose concentrations on the last dosing day were determined at multiple time points over 168 hrs. Bioequivalence was established by conventional criteria (AUC_0-24, C_max, C_min) if the 90% CIs for SPN-538/TPM-IR ratios fell within 80%-125% limits. A post-hoc analysis calculated partial AUCs from time 0 to time t to compare TPM absorption throughout a 24-hr post-dose period. In addition to safety, assessments included periodic neurocognitive testing.Results: 33/39 (85%) subjects completed both treatment periods and comprised the PK Population. At steady-state, 90% CIs for ratios of AUC_0-24 (94.0, 100.2), C_max (85.1, 91.0), and C_min (95.9, 104.1) fell within 80%-125% limits. Steady-state SPN-538/TPM-IR partial AUC ratios at paired time points ranged from 83.9 (2 hrs) to 99.8 (12 hrs); 90% CIs fell within 80%-125% limits at all (n=11) time points. Peak-to-trough fluctuation was significantly less (-14.1%; 90% CI: -16.7, -11.5) with SPN-538 vs. TPM-IR. Most (92%) treatment-related AEs were mild. AE incidences were generally similar across treatments although certain CNS/cognitive AEs (dizziness, speech disorder, aphasia, attention disorder) were reported by more subjects during TPM-IR period. Cognitive testing favored SPN-538 over TPM-IR.Conclusions: At steady state, once-daily SPN-538 is bioequivalent to b.i.d. TPM-IR based on conventional criteria and on the more rigorous measure of partial AUCs throughout the 24-hr dosing period. Slower absorption with once-daily SPN-538 is associated with less peak-trough fluctuation for more consistent TPM plasma concentrations over the dosing interval. In the secondary endpoint, the concentration-time profile of SPN-538 was associated with significantly less adverse cognitive effects on objective measures. Once-daily SPN-538 may improve tolerability and adherence for potentially greater retention and effectiveness in epilepsy patients. Study funded by Supernus Pharmaceuticals, Inc.