Chemical formula: C₁₃H₁₈N₂O₃ Molecular mass: 250.294 g/mol PubChem compound: 219078
The active substance, lacosamide (R-2-acetamido-N-benzyl-3-methoxypropionamide) is a functionalised 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.
Lacosamide protected against seizures in a broad range of animal models of partial and primary generalised 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.
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. Lacosamide tablets and oral syrup are bioequivalent. Food does not affect the rate and extent of absorption.
After intravenous administration, Cmax is reached at the end of infusion. The plasma concentration increases proportionally with dose after oral (100-800 mg) and intravenous (50-300 mg) administration.
The volume of distribution is approximately 0.6 L/kg. Lacosamide is less than 15% bound to plasma proteins.
95% of the dose is excreted in the urine as lacosamide and metabolites. The metabolism of lacosamide has not been completely characterised.
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.
In vitro data show that CYP2C9, CYP2C19 and CYP3A4 are capable of catalysing the formation of the O-desmethyl metabolite but the main contributing isoenzyme has not been confirmed in vivo. No clinically relevant difference in lacosamide exposure was observed comparing its pharmacokinetics in extensive metabolisers (EMs, with a functional CYP2C19) and poor metabolisers (PMs, lacking a functional CYP2C19). Furthermore an interaction study with omeprazole (CYP2C19-inhibitor) demonstrated no clinically relevant changes in lacosamide plasma concentrations indicating that the importance of this pathway is minor. 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.
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 faeces. The elimination half-life of lacosamide 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.
Clinical studies indicate that gender does not have a clinically significant influence on the plasma concentrations of lacosamide.
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 haemodialysis compared to healthy subjects, whereas Cmax was unaffected. Lacosamide is effectively removed from plasma by haemodialysis. Following a 4-hour haemodialysis treatment, AUC of lacosamide is reduced by approximately 50%. Therefore, dosage supplementation following haemodialysis is recommended. The exposure of the O-desmethyl metabolite was several-fold increased in patients with moderate and severe renal impairment. In absence of haemodialysis 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.
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.
In a study in elderly men and women including 4 patients >75 years of age, AUC was about 30 and 50% increased 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.
The paediatric pharmacokinetic profile of lacosamide was determined in a population pharmacokinetic analysis using sparse plasma concentration data obtained in six placebo-controlled randomised clinical studies and five open-label studies in 1655 adult and paediatric patients with epilepsy aged 1 month to 17 years. Three of these studies were performed in adults, 7 in pediatric patients, and 1 in a mixed population. The administered lacosamide doses ranged from 2 to 17.8 mg/kg/day in twice daily intake, not to exceed 600 mg/day.
The typical plasma clearance was estimated to be 0.46 L/h, 0.81 L/h, 1.03 L/h and 1.34 L/h for paediatric patients weighing 10 kg, 20 kg, 30 kg and 50 kg respectively. In comparison, plasma clearance was estimated at 1.74 L/h in adults (70 kg body weight).
Population pharmacokinetic analysis using sparse pharmacokinetic samples from PGTCS study showed a similar exposure in patients with PGTCS and in patients with partial-onset seizures.
In the toxicity studies, the plasma concentrations of lacosamide obtained were similar or only marginally higher than those observed in patients, which leaves low or non-existing margins to human exposure.
A safety pharmacology study with intravenous administration of lacosamide in anesthetised dogs showed transient increases in PR interval and QRS complex duration and decreases in blood pressure most likely due to a cardiodepressant action. These transient changes started in the same concentration range as after maximum recommended clinical dosing. In anesthetised dogs and Cynomolgus monkeys, at intravenous doses of 15-60 mg/kg, slowing of atrial and ventricular conductivity, atrioventricular block and atrioventricular dissociation were seen.
In the repeated dose toxicity studies, mild reversible liver changes were observed in rats starting at about 3 times the clinical exposure. These changes included an increased organ weight, hypertrophy of hepatocytes, increases in serum concentrations of liver enzymes and increases in total cholesterol and triglycerides. Apart from the hypertrophy of hepatocytes, no other histopathologic changes were observed.
In reproductive and developmental toxicity studies in rodents and rabbits, no teratogenic effects but an increase in numbers of stillborn pups and pup deaths in the peripartum period, and slightly reduced live litter sizes and pup body weights were observed at maternal toxic doses in rats corresponding to systemic exposure levels similar to the expected clinical exposure. Since higher exposure levels could not be tested in animals due to maternal toxicity, data are insufficient to fully characterise the embryofetotoxic and teratogenic potential of lacosamide. Studies in rats revealed that lacosamide and/or its metabolites readily crossed the placental barrier.
In juvenile rats and dogs, the types of toxicity do not differ qualitatively from those observed in adult animals. In juvenile rats, a reduced body weight was observed at systemic exposure levels similar to the expected clinical exposure. In juvenile dogs, transient and dose-related CNS clinical signs started to be observed at systemic exposure levels below the expected clinical exposure.
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