Pharmacokinetics, brain distribution, and plasma protein binding of the antiepileptic drug lacosamide in rats

Abstract

The study aimed to characterize the pharmacokinetics of lacosamide, a new antiepileptic drug, in rats after intravenous and oral administration at doses of 1, 3, 10, and 30 mg/kg. Moreover, brain distribution and plasma protein binding were estimated. After intravenous injection, terminal half-life, systemic clearance, and steady state volumes of distribution remained unaltered as a function of dose with values in the range 3.01-3.53 h, 221-241 mL/h/kg and 702-732 mL/kg, respectively. Following oral administration, absolute oral bioavailability was not dose dependent and was at 93.3-106%. However, the time to peak concentration and the dose-normalized peak concentration for 30 mg/kg were significantly different with those for other doses. The extent of urinary excretion of lacosamide was 17.1% and 16.5% for intravenous and oral doses, respectively, whereas fecal excretion was negligible. The brain to plasma ratio of lacosamide was consistent regardless of post-dosing time and the brain to plasma partition coefficient was 0.553. Further, the plasma protein binding of lacosamide was concentration independent with free fraction at 95.9%. Lacosamide showed linear pharmacokinetics at an intravenous dose of 1-30 mg/kg and an oral dose of 1-10 mg/kg but non-linear pharmacokinetics at a 30 mg/kg oral dose.