Abstracts

Rationale: To examine the safety and tolerability of a single IV loading dose of lacosamide, given as a 15 minute infusion, followed by oral lacosamide maintenance treatment in subjects with partial-onset seizures currently taking 1-2 antiepileptic drugs. Methods: Consecutive 25-subject cohorts are given three progressively increasing doses of lacosamide (200, 300 or 400 mg) administered IV over 15 minutes. Each cohort receives the loading dose followed by the equivalent daily dose administered orally twice daily for 6.5 days. The last cohort repeats the highest well tolerated dose to achieve 50 subjects at this dosage. Safety and tolerability data for each cohort are assessed by an independent data monitoring committee (DMC) prior to enrollment of subsequent cohorts. Thus, up to four cohorts are possible. Safety evaluations include adverse events, 12-lead ECGs, vital signs and laboratory parameters. Lacosamide plasma concentrations are measured. Interim results for completed cohorts (1 - 3) are reported. Results: The first three cohorts (200 mg, 300 mg and 400 mg loading dose) have completed. All subjects in cohort 1 (200 mg loading dose) completed the trial. One subject (4%) from the second cohort (300 mg loading dose) and 4 subjects (16%) from the third cohort (400 mg loading dose) withdrew due to adverse events. Lacosamide mean peak plasma concentrations, measured immediately following the 200, 300 and 400 mg loading doses, were 6.33 ± 2.30 μg/mL, 7.19 ± 2.97 μg/mL and 12.23 ± 3.97 μg/mL. Initial trough concentrations measured 12 hours post-infusion and prior to initial oral dosing (3.11 ± 1.39 μg/mL [200 mg load], 3.18 ± 1.48 μg/mL [300 mg load] and 4.41 ± 1.46 μg/mL [400 mg load]) were similar to those measured on Day 2 (3.44 ± 1.53 μg/mL, 3.87 ± 1.77 μg/mL and 4.77 ± 1.46 μg/mL) and Day 8 with b.i.d. oral dosing (3.80 ± 1.50 μg/mL, 4.74 ± 2.61 μg/mL and 5.06 ± 3.04 μg/mL). The dose for the final cohort will be decided based on DMC recommendations. Conclusions: This interim evaluation supports the feasibility of lacosamide loading doses in patients with partial-onset seizures, and shows that these doses provided plasma concentrations similar to steady-state plasma concentrations achieved with 100 mg b.i.d., 150 mg b.i.d. and 200 mg b.i.d. oral doses, respectively. Based on results of these cohorts, enrollment of the fourth, repeat cohort will proceed with the highest well-tolerated loading dose.