Absorption, disposition, metabolic fate and elimination of the anti-epileptic drug lacosamide in humans: mass balance following intravenous and oral administration

Abstract

The absorption, distribution, metabolism and elimination of the anti-epileptic drug lacosamide were determined in 10 healthy male volunteers following intravenous or oral administration in a single-center, open-label, single-dose trial. Volunteers were randomized to receive either a continuous intravenous infusion of 100 mg (40 μCi) [¹⁴C]-lacosamide administered over 60 min, or a 100 mg (40 μCi) [¹⁴C]-lacosamide dose given as an oral solution. During the infusion, total radioactivity concentrations reached peak levels at 1 h post dose followed by a decline of 71 % within 24 h. More than 97 % of radioactivity was excreted within 168 h; 96.8 % in urine and 0.3 % in feces. Following oral administration, total radioactivity concentrations increased to peak levels within 0.5 h followed by a decline of 65 % within 24 h. Approximately 94.6 % of radioactivity was excreted within 168 h after oral administration, 94.2 % by the kidneys and 0.4% in feces. A comparison of AUC values (po/iv) of unchanged lacosamide indicates a high absolute bioavailability. The metabolic profile was analyzed using pooled urine samples, and following intravenous and oral administration, respectively, a total of 38 and 34 % unchanged lacosamide, 28 and 28 % of the desmethyl metabolite and 19 and 17 % of a polar fraction were measured. Additional metabolites were identified only in small amounts (<3 %). In plasma at maximum concentration, most of the total radioactivity was found as unchanged drug after intravenous and oral dose. The plasma concentration curves of total radioactivity following intravenous and oral administration were similar.

Acute or chronic use of lacosamide does not alter its distribution between serum and cerebrospinal fluid

“…As expected, with intravenous administration, there was no correlation between the time between dose delivery and blood/CSF sampling and the LCM concentration in the CSF and serum given that the average time interval for sample collection ranged from 16 to 140 min and the terminal half‐life of LCM is ~13 h . However, in the LCM‐naive group, the time interval between LCM infusion and sample collection did positively correlate with the CSF/serum ratio, consistent with the known linear pharmacokinetic properties of LCM .…”

“…Of vital importance is that the CSF/serum ratios in our patient populations are congruent with a recent study of epilepsy patients chronically treated with LCM, in which the CSF concentration was reported to be~85% of the serum concentration. 10 As expected, with intravenous administration, there was no correlation between the time between dose delivery and blood/CSF sampling and the LCM concentration in the CSF and serum given that the average time interval for sample collection ranged from 16 to 140 min and the terminal half-life of LCM is 13 h. 5,11 However, in the LCM-naive group, the time interval between LCM infusion and sample collection did positively correlate with the CSF/serum ratio, consistent with the known linear pharmacokinetic properties of LCM. 5 Not surprisingly, a single additional dose of LCM in the chronically treated group did not impact the CSF/serum ratio, as LCM concentration was presumably already at steady state.…”

“…LCM readily crosses the BBB, as demonstrated by consistent CSF/serum drug ratios in both study groups: naive to LCM and chronic treatment with LCM. With the minimum 2‐week dosing period for the chronic treatment group, steady‐state drug levels would have been achieved and contributed to the higher CSF and serum levels found in our chronically treated patients. Although the chronic LCM dosing was administered as the oral formulation and the acute presurgical dose was intravenous, the different formulations have been previously shown to produce equivalent free drug in serum .…”

Preparation of Lacosamide Sustained-release Tablets and Their Pharmacokinetics in Beagles and Mini-pigs

“…[1][2][3] This compound is thought to work by selective enhancement of sodium channel slow inactivation, was effective and well-tolerated in clinical trials and is currently available for clinical use as immediate release tablets, oral solutions and intravenous injectable solutions. 4 The pharmacokinetic profile of lacosamide exhibits low intra-and inter-patient variability.…”

Pharmacodynamic and pharmacokinetic evaluation of coadministration of lacosamide and an oral contraceptive (levonorgestrel plus ethinylestradiol) in healthy female volunteers

“…Lacosamide and its major metabolite (an O ‐desmethyl metabolite) are eliminated primarily by the kidneys (Doty et al., ). The metabolism of lacosamide has not been fully characterized, but CYP2C19 and possibly CYP3A4 and CYP2C9 are involved in the formation of the O ‐desmethyl‐metabolite (Cawello et al., , ). Lacosamide did not induce or inhibit the activity of CYP isoenzymes at therapeutic concentrations, with the exception of potential inhibition of CYP2C19; however, an in vivo study with the CYP2C19 substrate omeprazole did not show an inhibitory effect on omeprazole pharmacokinetics (UCB, ).…”