Abstracts

Rationale: The site of therapeutic effectiveness for all antiepileptic drugs (AEDs) is the brain. However, pharmacokinetic properties of most AEDs are studied by measuring serum concentration and actual cerebrospinal fluid (CSF) penetration of such compounds is variable and often have not been studied in detail. Lacosamide (LCM) is a new AED approved for treatment of partial epilepsy and available in intravenous formulation. It has high oral bioavailability and linear pharmacokinetic properties. Its penetration across blood-brain barrier is not well known.Methods: Adults receiving LCM and undergoing craniotomy procedures were recruited and informed consent was obtained. The Wayne State University IRB approved the study. There were two groups of patients; one group received LCM as part of their ongoing AED regimen while the second group received LCM for the first time as prophylaxis for higher perioperative risk of seizures. A single IV dose of LCM was administered over 15 min at the time of skin incision and time was recorded. The patients received either their scheduled maintenance dose of LCM or 200 mg if they were drug na ve. After craniotomy and dural opening, pooled CSF was collected non-invasively from the Sylvian or interhemispheric fissure. Simultaneously, an arterial blood sample was collected and time of collection of both samples was recorded. The samples were placed on ice and plasma was separated via centrifuge. The serum and CSF samples were stored at -20 C until assayed. The analysis was performed by the NMS Labs (Willow Grove, PA) using a quantitative analysis developed by and validated for LCM by the lab using LC tandem MS. The serum and CSF samples were analyzed using a Waters HPLC and TQD Mass Spectrometer with a Waters Acquity Ultra Performance LC instrumentation, and a Waters Acquity BEH C18 2.1 mm x 50 mm, particle size 1.7 micron analytical column. The serum and CSF concentration of LCM were recorded and CSF/serum ratio was calculated.Results: Preliminary data from 6 patients was analyzed, three of which were LCM treatment naive. Of the 6 patients 2 were female, mean age = 53 years (range 42-60 years), mean weight = 89 kg (range 61-154 kg). LCM dose received was 100 mg for one patient and 200 mg for the rest, and ranged from 1.01 3.28 mg/kg (mean=2.32 mg/kg). Time between end of LCM infusion and specimen collection varied 16 to 122 min (mean=54 min). Serum concentration ranged from 4.8-12.0 mcg/mL (mean=7.33, SD=2.94 mcg/mL). The CSF concentration ranged from 1.6-9.5 mcg/mL (mean=3.82, SD=3.06 mcg/mL). The CSF/Serum concentration ratio ranged from 0.27 to 0.79 (mean=0.47, SD=0.19).Conclusions: Lacosamide concentration can be reliably determined in CSF. Serum concentration reported here is similar to the concentrations reported in the serum of patients that received the single IV dose. Lacosamide CSF concentration varies individually but in this single time point study, it was about half of the serum concentration. We continue to recruit and expect to recruit total of 30 subjects for the study.