Pharmacokinetic Evaluations of ADS-4101 (Lacosamide) Modified Release Capsules versus Lacosamide IR in Two Phase 1 Studies up to 600 mg (P1.263)

Objective: ADS-4101 (lacosamide) modified-release (MR) formulation was designed to reduce the rate of initial rise in plasma concentrations and delay the t max . ADS-4101 is intended to be administered at bedtime and to provide high plasma concentrations in the morning and throughout the day when the burden of seizures is highest (Hofstra, 2009). Background: Dose limiting adverse events associated with lacosamide immediate release (IR), VIMPAT ® , include dizziness and nausea, which may be related to the rapid initial rise in plasma concentrations. Design/Methods: In the single-dose study (Study 1), a single 400 mg dose was administered for each of the 4 formulations of ADS-4101 and lacosamide IR. In the multi-dose study (Study 2), ADS-4101 was dosed once-nightly at up to 600 mg, starting at 200 mg in Week 1 and increasing by 200 mg each week for 3 weeks; lacosamide IR was dosed BID in equal divided doses at up to 400 mg a day, starting at 200 mg in Week 1 increasing by 100 mg each week. Results: In Study 1, the 4 MR formulations each had lower C max and prolonged t max compared to lacosamide IR, with equivalent bioavailability. The incidence of adverse events was greater in subjects administered lacosamide IR (62.5%) than any of the ADS-4101 MR formulations (10 – 33%). In Study 2, at the 600 mg dose, ADS-4101 provided a 1.4- to 2.4-fold greater daytime (8 am to 8 pm) lacosamide concentration and a 1.0- to 2.0-fold greater nighttime (8 pm to 8 am) concentration compared to 400 mg of lacosamide IR. For known lacosamide AEs (oral hypoesthesia, dizziness, abnormal dreams, and euphoria), incidences were comparable for 600 mg ADS-4101 versus 400 mg lacosamide IR. 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. Study Supported by: Adamas Pharmaceuticals, Inc. Disclosure: Dr. Patni has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Adamas Pharmaceuticals, Inc. Dr. Ghosh has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Adamas Pharmaceuticals, Inc. Dr. Wargin has nothing to disclose. Dr. Ruby has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Adamas Pharmaceuticals, Inc. Dr. Lewallen has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Adamas Pharmaceuticals, Inc. Dr. Llorens has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Adamas Pharmaceuticals, Inc. Dr. Nguyen has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Adamas Pharmaceuticals, Inc.