Vimpat Mechanism of Action

Pharmacotherapeutic Group: Antiepileptics, other antiepileptics. ATC Code: N03AX18.
Pharmacology: Pharmacodynamics: Mechanism of action: 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.
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.
Clinical efficacy and safety: Conversion to monotherapy: The efficacy of VIMPAT in conversion to monotherapy was established in a historical-controlled, multicenter, double-blind, randomized trial with a 16-week maintenance period (i.e. a 6-week withdrawal period for background antiepileptic drugs, followed by a 10-week monotherapy period) involving 425 patients aged 16 to 70 years with partial-onset seizures. In this study, patients were taking stable doses of 1 or 2 marketed antiepileptic drugs during the 8 weeks baseline period. Patients taking 2 antiepileptic drugs must have been taking ≤50% of the minimum recommended maintenance dose for 1 of the 2 antiepileptic drugs. Patients were randomized 3 to 1 to ultimately receive either lacosamide 400 mg/day (200 mg twice a day) or 300 mg/day (150 mg twice a day), and their responses were compared to those of a historical control group. The historical control consisted of a pooled analysis of the control groups from 8 studies of similar design, which utilized a sub-therapeutic dose of an antiepileptic drug as a control. Statistical superiority to the historical control was considered to be demonstrated if the upper limit from a 2 sided 95% confidence interval for the percentage of patients meeting exit criteria in patients receiving lacosamide remained below the lower 95% prediction limit of 65.3% derived from the historical control data.
The exit criteria were one or more of the following: (1) doubling of average monthly seizure frequency during any 28 consecutive days, (2) doubling of highest consecutive 2-day seizure frequency, (3) occurrence of a single generalized tonic-clonic seizure, (4) clinically significant prolongation or worsening of overall seizure duration, frequency, type or pattern considered by the investigator to require trial discontinuation, (5) status epilepticus or new onset of serial/cluster seizures.
The study population was comparable to the historical controlled population.
For the lacosamide 400 mg/day group, the estimate of the percentage of patients meeting at least 1 exit criterion was 30.0% (95% CI: 24.6%, 35.5%). The upper limit of the 2-sided 95% CI (35.5%) was below the threshold of 65.3% derived from the historical control data and superiority of lacosamide 400 mg/day over historical control was demonstrated. The primary efficacy result was supported by sensitivity analyses.
For the lacosamide 300 mg/day group, the estimate of the percentage of patients meeting at least 1 exit criterion was 27.3% (95% CI: 18.4%, 36.3%). The upper limit of the 2-sided 95% CI (36.3%) was below the threshold of 65.3% derived from the historical control data although the study was not powered for the evaluation of lacosamide 300 mg/day versus the historical control group.
In both the Clinical (CGIC) and Patient (PGIC) Global Impression of Change assessments, the majority of patients in both lacosamide treatment groups were reported to have an improved status (CGIC: 75.4% and 72.7% of subjects in the 400 mg/day and 300 mg/day groups, respectively. PGIC: 74.3% and 72.7% of subjects in the 400 mg/day and 300 mg/day groups, respectively).
Adjunctive therapy: The efficacy of VIMPAT as adjunctive therapy at recommended doses (200 mg/day, 400 mg/day) was established in 3 multicenter, randomized, placebo-controlled clinical trials with a 12-week maintenance period. VIMPAT 600 mg/day was also shown to be effective in controlled adjunctive therapy trials, although the efficacy was similar to 400 mg/day and patients were less likely to tolerate this dose because of CNS- and gastrointestinal-related adverse reactions. Thus, the 600 mg/day dose is not recommended. The maximum recommended dose is 400 mg/day. These trials, involving 1308 patients with a history of an average of 23 years of partial-onset seizures, were designed to evaluate the efficacy and safety of lacosamide when administered concomitantly with 1-3 antiepileptics in patients with uncontrolled partial-onset seizures with or without secondary generalisation. Overall the proportion of subjects with a 50% reduction in seizure frequency was 23%, 34%, and 40% for placebo, lacosamide 200 mg/day and lacosamide 400 mg/day.
There are insufficient data regarding the withdrawal of concomitant antiepileptic medicinal products to achieve monotherapy with lacosamide.
The pharmacokinetics and safety of a single loading dose of iv lacosamide were determined in a multicenter, open-label study designed to assess the safety and tolerability of rapid initiation of lacosamide using a single iv loading dose (including 200 mg) followed by twice daily oral dosing (equivalent to the iv dose) as adjunctive therapy in adult subjects 16 to 60 years of age with partial-onset seizures.
Pharmacokinetics: Absorption: FC tab: 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 C_max about 0.5 to 4 hours post-dose. Food does not affect the rate and extent of absorption.
Soln for infusion: After intravenous administration, C_max 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.
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 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 trial 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.
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 patient groups: Gender: Clinical trials indicate that gender does not have a clinically significant influence on the plasma concentrations of lacosamide.
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 endstage renal disease requiring hemodialysis compared to healthy subjects, whereas C_max 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 (see Dosage & Administration). 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 endstage renal disease, the levels were increased and continuously rising during the 24-hour sampling. It is unknown whether the increased metabolite exposure in endstage 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 AUC_norm). 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 (see Dosage & Administration).
Older people (over 65 years of age): 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 (see Dosage & Administration).
Toxicology: Preclinical safety data: 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 anesthetized 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 anesthetized 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.