Abstracts

Rationale: Lacosamide immediate release (IR), VIMPAT®, is approved for the treatment of partial onset seizures. Dose limiting adverse events associated with lacosamide IR include headache and dizziness, which may be related to the rapid rise in plasma concentrations. In addition, EEG monitoring studies in epilepsy suggest seizures occur with the highest frequency during wakeful hours (Hofstra, 2009). ADS-4101 (lacosamide) modified release (MR) formulation was designed to reduce the rate of rise in plasma concentrations and delay the tmax. ADS-4101 is intended to be administered at bedtime and to provide high and sustained plasma concentrations during the day when the burden of seizures is highest. The objective of this Phase 1b study was to evaluate the steady state pharmacokinetic (PK) profiles of three ascending doses of ADS-4101 compared to three ascending doses of lacosamide IR in 24 healthy volunteers as well as compare overall safety and tolerability of ADS-4101 vs. lacosamide IR. Methods: This was an open-label, single-center, 2-treament (administered at three dose levels), 2-period, 2-sequence, crossover study in 24 healthy volunteers comparing the PK profile, safety, and tolerability of ADS-4101 (lacosamide) MR formulation to lacosamide IR. ADS-4101 was dosed once-nightly starting at 200 mg in Week 1, increasing to 400 mg in Week 2 and 600 mg in Week 3, compared to lacosamide IR dosed per the approved label at daily doses of 200 mg in Week 1, 300 mg in Week 2 and 400 mg in Week 3, all taken BID in equal divided doses. Results: ADS-4101 exhibited a plasma concentration-time profile characterized by an apparent lag-time followed by a slow initial rise in plasma concentrations overnight that peaked the following morning and were sustained throughout the day. At the 600 mg dose, ADS-4101 provided a 1.7-fold increase in average daytime lacosamide concentration and a 1.4-fold increase in average nighttime concentration compared to 400 mg daily, taken as 200 mg BID, of lacosamide IR. The types of central nervous system/psychiatric adverse events (AEs) reported during the ADS-4101 treatment were mild and consistent with the known lacosamide safety profile in healthy volunteers. For known lacosamide IR AEs (oral hypoesthesia, dizziness, abnormal dreams, and euphoria), incidences were comparable or lower for 600 mg ADS-4101 versus 400 mg lacosamide IR, despite the higher dose, and the number of subjects with these AEs were small (<10%). Conclusions: ADS-4101 600 mg achieved higher lacosamide plasma concentration throughout the 24-hour day and had comparable tolerability relative to the approved maximum dose (400 mg) of lacosamide IR tablets, in healthy volunteers. ADS-4101 was safe and well-tolerated across all three doses. Funding: This study was supported by Adamas Pharmaceuticals, Inc. VIMPAT® is a registered trademark used under license from Harris FRC Corporation.