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 central nervous system (CNS) effects such as headache and dizziness. Lacosamide IR has a rapid rate of rise in plasma concentration (tmax ~1 h), and we hypothesize that reducing the initial rate of rise in plasma concentration may reduce CNS adverse events. The objective of these studies was to correlate the rate of rise in lacosamide plasma concentrations with CNS side effects, measured as an impairment of motor coordination in rodents using the rotarod. Methods: The pharmacokinetic (PK) profile of lacosamide was determined following single oral doses in mice, and following single intraperitoneal (IP) doses or continuous, ramped IP infusion in rats. The ramped infusion protocol was designed to give a slow rate of rise by delaying the tmax from 1 h to 15-18 h. The effect of oral lacosamide on rotarod performance was determined in mice and these effects were correlated with brain and plasma concentrations from the PK studies. The effect of different rates of rise to achieve the same Cmax on rotarod performance was determined in rats. Results: Oral lacosamide produced a dose-dependent impairment of rotarod performance in mice with an ED50 of 61 mg/kg, and with 90 mg/kg producing maximal impairment. Mean plasma and brain levels at 90 mg/kg were 38 µg/mL and 16 µg/g, respectively. Tmax in both compartments was 0.25 h post dose, with maximal rotarod impairment observed at 0.5 h post dose. In rats, a single IP bolus injection of lacosamide (tmax = 0.5 h) resulted in significant rotarod impairment compared to vehicle (-61% decrease in time on the rotarod relative to vehicle, p 0.05); Cmax was similar for both the IP bolus and the slow IP infusion (19 µg/mL). Importantly, the total administered dose and exposure over 15 h by the slow IP infusion were 6.4-fold and 12-fold higher, respectively, than those achieved with the IP bolus. Conclusions: These results indicate that, while CNS impairment as determined by rotarod performance was dose-dependent, the rate of rise of lacosamide plasma concentration was a major contributor to the expression of CNS adverse events. Slowing the rate of rise in lacosamide plasma levels by > 10-fold without a reduction in Cmax resulted in significantly reduced rotarod impairment. These data provide proof of concept that slowing the rate of rise of lacosamide plasma concentrations improves tolerability in rats. A formulation of lacosamide resulting in a slower rate of rise of plasma concentrations may enable a higher dose and offer improved efficacy. Funding: This study was supported by Adamas Pharmaceuticals, Inc.