Acode 50 Mechanism of Action

Antiepileptic.
Pharmacology: Pharmacodynamics: Mechanism of action:The active substance, lacosamide (R-2-acetamido-N-benzyl-3-methoxypropionamide) is a functionalized amino acid.
The precise mechanism by which lacosamide exerts its antiepileptic effect in humans remains to be fully elucidated. In vitro electrophysiological studies have shown that lacosamide selectively enhances slow inactivation of voltage-gated sodium channels, resulting in stabilization of hyperexcitable neuronal membranes.
Pharmacodynamic Effects: Lacosamide protected against seizures in a broad range of animal models of partial and primary generalized seizures and delayed kindling development.
In non-clinical experiments lacosamide in combination with levetiracetam, carbamazepine, phenytoin, valproate, lamotrigine, topiramate or gabapentin showed synergistic or additive anticonvulsant effects.
Pharmacokinetics: Absorption: Lacosamide is rapidly and completely absorbed after oral administration. The oral bioavailability of lacosamide tablets is approximately 100%. Following oral administration, the plasma concentration of unchanged lacosamide increases rapidly and reaches Cmax about 0.5 to 4 hours post-dose. Food does not affect the rate and extent of absorption.
Distribution: The volume of distribution is approximately 0.6 L/kg. Lacosamide is less than 15% bound to plasma proteins.
Metabolism: 95% of the dose is excreted in the urine as drug and metabolites. The metabolism of lacosamide has not been completely characterized. The major compounds excreted in urine are unchanged lacosamide (approximately 40% of the dose) and its O-desmethyl metabolite less than 30%. A polar fraction proposed to be serine derivatives accounted for approximately 20% in urine, but was detected only in small amounts (0-2%) in human plasma of some subjects. Small amounts (0.5-2%) of additional metabolites were found in the urine.
CYP2C19, 2C9 and 3A4 are mainly responsible for the formation of the O-desmethyl metabolite. No clinically relevant difference in lacosamide exposure was observed comparing its pharmacokinetics in extensive metabolizers (EMs, with a functional CYP2C19) and poor metabolizers (PMs, lacking a functional CYP2C19). No other enzymes have been identified to be involved in the metabolism of lacosamide.
The plasma concentration of O-desmethyl-lacosamide is approximately 15% of the concentration of lacosamide in plasma. This major metabolite has no known pharmacological activity.
Elimination: Lacosamide is primarily eliminated from the systemic circulation by renal excretion and biotransformation. After oral and intravenous administration of radiolabeled lacosamide, approximately 95% of radioactivity administered was recovered in the urine and less than 0.5% in the feces. The elimination half-life of the unchanged drug is approximately 13 hours.
The pharmacokinetics is dose-proportional and constant over time, with low intra- and inter-subject variability. Following twice daily dosing, steady state plasma concentrations are achieved after a 3-day period. The plasma concentration increases with an accumulation factor of approximately 2.
A single loading dose of 200 mg approximates steady-state concentrations comparable to 100 mg twice daily oral administration.
Pharmacokinetics in special population: Elderly: In a study in elderly men and women including 4 patients >75 years of age, AUC was about 30 and 50% increase compared to young men, respectively. This is partly related to lower body weight. The body weight normalized difference is 26 and 23%, respectively. An increased variability in exposure was also observed. The renal clearance of lacosamide was only slightly reduced in elderly subjects in this study.
A general dose reduction is not considered to be necessary unless indicated due to reduced renal function.
Renal impairment: The AUC of lacosamide was increased by approximately 30% in mildly and moderately and 60% in severely renal impaired patients and patients with end stage renal disease requiring hemodialysis compared to healthy subjects, whereas Cmax was unaffected. Lacosamide is effectively removed from plasma by hemodialysis. Following a 4-hour hemodialysis treatment, AUC of lacosamide is reduced by approximately 50%. Therefore, dosage supplementation following hemodialysis is recommended. The exposure of the O- desmethyl metabolite was several-fold increase in patients with moderate and severe renal impairment. In absence of hemodialysis in patients with end stage renal disease, the levels were increased and continuously rising during the 24-hour sampling. It is unknown whether the increased metabolite exposure in end stage renal disease subjects could give rise to adverse effects but no pharmacological activity of the metabolite has been identified.
Hepatic impairment: Subjects with moderate hepatic impairment (Child-Pugh B) showed higher plasma concentrations of lacosamide (approximately 50% higher AUCnorm). The higher exposure was partly due to a reduced renal function in the studied subjects. The decrease in non-renal clearance in the patients of the study was estimated to give a 20% increase in the AUC of lacosamide. The pharmacokinetics of lacosamide has not been evaluated in severe hepatic impairment.
Gender: Clinical trials indicate that gender does not have a clinically significant influence on the plasma concentrations of lacosamide.
Race: There are no clinically relevant differences in the pharmacokinetics of Lacosamide between Asian, Black, and Caucasian subjects.