Abstracts

Rationale: Lacosamide immediate release (IR), Vimpat®, is approved for the treatment of partial onset seizures. EEG monitoring studies in epilepsy suggest seizures are not randomly distributed, with the highest frequency occurring during wakeful hours (Hofstra, 2009). Dose limiting adverse events associated with lacosamide IR include headache and dizziness, which may be related to the rapid rise in plasma concentrations. ADS-4101 (lacosamide) modified release (MR) formulations have been developed 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 study was to evaluate the pharmacokinetics and tolerability of four ADS-4101 MR formulations for further development. Methods: This is a randomized, open label, cross-over PK study in 24 healthy volunteers comparing the PK profile, safety, and tolerability of four ADS-4101 (lacosamide) MR formulations to lacosamide IR. A single 400 mg dose (2 x 200 mg) was administered for each of the 5 formulations. This study was divided into 2 separate cross-over groups, where each group had 3 periods. Group 1 consisted of Formulations 1, 2, and IR, and Group 2 consisted of Formulations 3, 4, and IR. Results: 12 subjects were randomized to each group, with 22 (91.7%) completing the study and 2 (8.3%) discontinued early due to non-study drug related adverse events (AE). The geometric least squared mean ratios (ADS-4101 MR formulation/lacosamide IR) for AUC0-inf were all approximately 100%, with 90% confidence intervals within the range of 96% to 107%. The 4 MR formulations each had lower mean Cmax and longer median tmax values than those of lacosamide IR (Table 1, Figure 1). Adverse events were reported for a greater proportion of subjects administered lacosamide IR (62.5%) than any of the ADS-4101 MR formulations (10 – 50%). Following administration of lacosamide IR, the most frequently reported AEs were oral hypoesthesia (11 subjects [45.8%]) and dizziness (8 subjects [33.3%]). For each ADS-4101 MR formulation, no AE was reported for more than 1 subject. The incidence of oral hypoesthesia and dizziness was greatly reduced in the ADS-4101 MR formulation (=10%). Conclusions: All 4 ADS-4101 MR formulations were well tolerated and exhibited comparable exposure (as measured by AUC0-inf), lower mean Cmax values, and longer median tmax values compared with lacosamide IR. ADS-4101 MR Formulation 2 was chosen for further evaluation in a multi-dose PK study due to the longer tmax and suitable Cmax. The improved tolerability profile of ADS-4101 warrants exploration of higher doses. Funding: This study was supported by Adamas Pharmaceuticals, Inc.