Mechanism of Action

The precise mechanism by which VIMPAT exerts its antiepileptic effects in humans remains to be fully elucidated. In vitroelectrophysiological studies have shown that lacosamide selectively enhances slow inactivation of voltage-gated sodium channels, resulting in stabilization of hyperexcitable neuronal membranes and inhibition of repetitive neuronal firing.

Lacosamide binds to collapsin response mediator protein-2 (CRMP-2), a phosphoprotein whic h is mainly expressed in the nervous system and is involved in neuronal differentiation and control of axonal outgrowth. The role of CRMP-2 binding in seizure control is unknown.

Pharmacodynamics

A pharmacokinetic-pharmacodynamic (efficacy) analysis w as performed based on the pooled data from the 3 efficacy trials for partial-onset seizures. Lacosamide exposure is correlated with the reduction in seizure frequency. However, doses above 400 mg/day do not appear to confer additional benefit in group analyses.

Cardiac Electrophysiology

Electrocardiographic effects of VIMPAT were determined in a double-blind, randomized clinical pharmacology trial of 247 healthy subjects. Chronic oral doses of 400 and 800 mg/day were compared with placebo and a positive control (400 mg moxifloxacin). VIMPAT did not prolong QTc interval and did not have a dose-related or clinically important effect on QRS duration. VIMPAT produced a small, dose-related increase in mean PR interval. At steady-state, the time of the maximum observed mean PR interval corresponded with tmax. The placebo-subtracted maximum increase in PR interval (at tmax) was 7.3 ms for the 400 mg/day group and 11.9 ms for the 800 mg/day group. For patients who participated in the controlled trials, the placebo-subtracted mean maximu m increase in PR interval for a 40 0 mg/day VIMPAT dose was 3.1 ms in patients with partial-onset seizures and 9.4 ms for patients with diabetic neuropathy.

Pharmacokinetics

The pharmacokinetics of VIMPAT have been studied in healthy adult subjects (age range 18 to 87), adults with partial-onset seizures, adults with diabetic neuropathy, and subjects with renal and hepatic impairment.

VIMPAT is completely absorbed after oral administration with negligible first-pass effect with a high absolute bioavailability of approximately 100%. The maximum lacosamide plasma concentrations occur approximately 1 to 4 hour post-dose after oral dosing, and elimination half-life is approximately 13 hours. Steady state plasma concentrations are achieved after 3 days of twice daily repeated administration. Pharmacokinetics of VIMPAT are dose proportional (100-800 mg) and time invariant, with low inter- and intra-subject variability. Compared to lacosamide the major metabolite, O­desmethyl metabolite, has a longer Tmax (0.5 to 12 hours) and elimination half-life (15-23 hour s).

Absorption and Bioavailability

VIMPAT is completely absorbed after oral administration. The oral bioavailability of VIMPAT tablets is approximately 100%. Food does not affect the rate and extent of absorption.

After intravenous administration, Cmax is reached at the end of infusion . The 30- and 60-minute intravenous infusions are bioequivalent to the oral tablet.

In a trial comparing the oral tablet with and an oral solution containing 10 mg/mL lacosamide, bioequivalence between both formulations was shown.

Distribution

The volume of distribution is approximately 0.6 L/kg and thus close to the volume of total body water. VIMPAT is less than 15% bound to plasma proteins.

Metabolism and Elimination

VIMPAT is primarily eliminated from the systemic circulation by renal excretion and biotransformation.

After oral and intravenous administration of 100 mg [14C]-lacosamide approximately 95% of radioactivity administered was recovered in the urine and less than 0.5% in the feces. The major compounds excreted were unchanged lacosamide (approximately 40% of the dose), its O-de smethyl metabolite (approximately 30%), and a structurally unknown polar fraction (~20%). The plasma exposure of the major human metabolite, O-desmethyl-lacosamide, is approximately 10% of that of lacosamide. This metabolite has no known pharmacological activity.

Lacosamide is a CYP2C19 substrate. The relative contribution of other CYP isoforms or non-CYP enzymes in the metabolism of lacosamide is not clear. The elimination half-life of the unchanged drug is approximately 13 hours and is not altered by different doses, multiple dosing or intravenous administration.

There is no enantiomeric interconv ersion of lacosamide.

Special Populations

Renal impairment

Lacosamide and its major metabolite are eliminated from the systemic circulation primarily by renal excretion.

The AUC of VIMPAT was increased approximately 25% in mildly (CLCR 50-80 mL/min) and moderately (CLCR 30-50 mL/min) and 60% in severely (CLCR ≤ 30mL/min) renally impaired patients compared to subjects with normal renal function (CLCR > 80mL/min), whereas Cmax was unaffected. No dose adjustment is considered necessary in mildly and moderately renal impaired subjects. A maximum dose of 300 mg/day is recommended for patients with severe renal impairment (CLCR ≤ 30mL/min) and in patients with endstage renal disease. VIMPAT is effectively removed from plasma by hemodialysis. Following a 4-hour hemodialysis treatment, AUC of VIMPAT is reduced by approximately 50%. Therefore dosage s upplementation of up to 50% following hemodialysis should be considered. In all renal impaired patients, the dose titration should be performed with caution. [see DOSAGE AND ADMINISTRATION]

Hepatic impairment

Lacosamide undergoes metabolism. Subjects with moderate hepatic impairment (Child-Pugh B) showed higher plasma concentrations of lacosamide (approximately 50-60% higher AUC compared to healthy subjects). The dose titration should be performed with caution in patients with hepatic impairment. A maximum dose of 300 mg/day is recommended for patients with mild or moderate hepatic impairment .

Patients with mild to moderate hepatic impairment should be observed closely during dose titration. A maximum dose of 300 mg/day is recommended for patients with mild to moderate hepatic impairment. The pharmacokinetics of lacosamide have not been evaluated in severe hepatic impairment. VIMPAT use is not recommended in patients with severe hepatic impairment. [see DOSAGE AND ADMINISTRATION] Patients with co-existing hepatic and renal impairment should be monitored closely during dose titration.

Geriatric

In the elderly ( > 65 years), dose and body-weight normalized AUC and Cmax is about 20% increased compared to young subjects (18-64 years). This may be related to body weight and decreased renal function in elderly subjects. Dose reduction is not considered to be necessary.

Pediatric Patients

Pharmacokinetics of VIMPAT have not been studied in pediatric patients.

Gender

VIMPAT clinical trials indicate that gender does not have a clinically relevant influence on the pharmacokinetics of VIMPAT.

Race

There are no clinically relevant differences in the pharmacokinetics of VIMPAT between Asian, Black, and Caucasian subjects.

CYP2C19 Polymorphism

There are no clinically relevant differences in the pharmacokinetics of VIMPAT between CYP2C19 poor metabolizers and extensive metabolizers. Results from a trial in poor metabolizers (PM) (N=4) and extensive metabolizers (EM) (N=8) of cytochrome P450 (CYP) 2C19 showed that lacosamide plasma concentrations were similar in PM s and EMs, but plasma concentrations and the amount excreted into urine of the O-desmethyl metabolite were about 70% reduced in PMs compared to EMs.

Drug interactions

In Vitro Assessment of Drug Interactions

In vitro metabolism studies indicate that lacosamide does not induce the enzyme activity of drug metabolizing cytochrome P450 isoforms CYP1A2, 2B6, 2C9, 2C19 and 3A4. Lacosamide did not inhibit CYP 1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2D6, 2E1, 3A4/5 at plasma concentrations observed in clinical studies.

In vitro data suggest that lacosamide has the potential to inhibit CYP2C19 at therapeutic concentrations. However, an in vivo study with omeprazole did not show an inhibitory effect on omeprazole pharmacokinetics.

Lacosamide was not a substrate or inhibitor for P-glycoprotein.

Lacosamide is a CYP2C19 substrate. The relative contribution of other CYP isoforms or non-CYP enzymes in the metabolism of lacosamide is not clear.

Since < 15% of lacosamide is bound to plasma proteins, a clinically relevant interaction with other drugs through competition for protein binding sites is unlikely.

In Vivo Assessment of Drug Interactions

Drug interaction studies with AEDs

Effect of VIMPAT on concomitant AEDs: VIMPAT 400 mg/day had no influence on the pharmacokinetics of 600 mg/day valproic acid and 400 mg/day carbamazepine in healthy subjects.

The placebo-controlled clinical studies in patients with partial-onset seizures showed that steady-state plasma concentrations of levetiracetam, carbamazepine, carbamazepine epoxide, lamotrigine, topiramate, oxcarbazepine monohydroxy derivative (MHD), phenytoin, valproic acid, phenobarbital, gabapentin, clonazepam, and zonisamide were not affected by concomitant intake of VIMPAT at any dose.

Effect of concomitant AEDs on VIMPAT: Drug-drug interaction studies in healthy subjects showed that 600 mg/day valproic acid had no influence on the pharmacokinetics of 400 mg/day VIMPAT. Likewise, 400 mg/day carbamazepine had no influence on the pharmacokinetics of VIMPAT in a healthy subject study. Population pharmacokinetics results in patients with partial-onset seizures showed small reductions (15% to 20% lower) in lacosamide plasma concentrations when VIMPAT was coadministered with carbamazepine, phenobarbital or phenytoin.

Drug-drug interaction studies with other drugs

Digoxin

There was no effect of VIMPAT (400 mg/day) on the pharmacokinetics of digoxin (0.5 mg once daily) in a study in healthy subjects.

Metformin

There were no clinically relevant changes in metformin levels following coadministration of VIMPAT (400 mg/day).

Metformin (500 mg three times a day) had no effect on the pharmacokinetics of VIMPAT (400 mg/day).

Omeprazole

Omeprazole is a CYP2C19 substrate and inhibitor.

There was no effect of VIMPAT (600 mg/day) on the pharmacokinetics of omeprazole (40 mg single dose) in healthy subjects. The data indicated that lacosamide had little in vivo inhibitory or inducing effect on CYP2C19.

Omeprazole at a dose of 40 mg once daily had no effect on the pharmacokinetics of VIMPAT (300 mg single dose). However, plasma levels of the O-desmethyl metabolite were reduced about 60% in the presence of omeprazole.

Oral Contraceptives

There was no influence of VIMPAT (400 mg/day) on the pharmacody namics and pharmacokinetics of an oral contraceptive containing 0.03 mg ethinylestradiol and 0.15 mg levonorgestrel in healthy subjects, except that a 20% increase in ethinylestradiol Cmax was observed.

Clinical Studies

Effectiveness in Partial-Onset Seizures

The efficacy of VIMPAT as adjunctive therapy in partial-onset seizures was established in three 12­week, randomized, double-blind, placebo-controlled, multicenter trials in adult patients. Patients enrolled had partial-onset seizures with or without secondary generalization and were not ad equately controlled with 1 to 3 concomitant AEDs. During an 8-week baseline period, patients were required to have an average of ≥ 4 partial-onset seizures per 28 days with no seizure-free period exceeding 21 days. In these 3 trials, patients had a mean duration of epilepsy of 24 years and a median baseline seizure frequency ranging from 10 to 17 per 28 days. 84% of patients were taking 2 to 3 concomitant AEDs with or without concurrent vagal nerve stimulation.

Study 1 compared doses of VIMPAT 200, 400, and 600 mg/day with placebo. Study 2 compared doses of VIMPAT 400 and 600 mg/day with placebo. Study 3 compared doses of VIMPAT 200 and 400 mg/day with placebo. In all three trials, following an 8-week Baseline Phase to establish baseline seizure frequency prior to randomization, subjects were randomized and titrated to the randomized dose (a 1-step back-titration of VIMPAT 100 mg/day or placebo was allowed in the case of intolerable adverse events at the end of the Titration Phase). During the Titration Phase in all 3 trials, treatment was initiated at 100 mg/day (50 mg given twice daily) and increased in weekly increments of 100 mg/day to the target dose. The Titration Phase lasted 6 weeks in Study 1 and Study 2 and 4 weeks in Study 3. In all three trials, the Titration Phase was followed by a Maintenance Phase that lasted 12 weeks, during which patients were to remain on a stable dose of VIMPAT.

A reduction in 28 day seizure frequency (Baseline to Maintenance Phase) as compared to the placebo group was the primary variable in all three trials. The criteria for statistical significance was p < 0.05. A statistically significant effect was observed with VIMPAT treatment (Figure 1) at doses of 200 mg/day (Study 3), 400 mg/day (Studies 1, 2, and 3), and 600 mg/day (Studies 1 and 2).

Subset evaluations of VIMPAT demonstrate no important differences in seizure control as a function of gender or race, although data on race was limited (about 10% of patients were non-Caucasian).

Figure 1: Median Percent Reduction in Seizure Frequency per 28 days from Baseline to the Maintenance Phase by Dose

Figure 2 presents the percentage of patients (X-axis) with a percent reduction in partial seizure frequency (responder rate) from Baseline to the Maintenance phase at least as great as that represented on the Y-axis. A positive value on the Y-axis indicates an improvement from Baseline (i.e., a decrease in seizure frequency), while a negative value indicates a worsening from Baseline (i.e., an increase in seizure frequency). Thus, in a display of this type, a curve for an effective treatment is shifted to the left of the curve for placebo. The proportion of patients achieving any particular level of reduction in seizure frequency was consistently higher for the VIMPAT groups compared to the placebo group. For example, 40% of patients randomized to VIMPAT (400 mg/day) experienced a 50% or greater reduction in seizure frequency, compared to 23% of patients randomized to placebo. Patients with an increase in seizure frequency > 100% are represented on the Y-axis as equal to or greater than -100%.

Figure 2: Proportion of Patients by Responder Rate for VIMPAT and Placebo Groups in Studies 1, 2, and 3

Last reviewed on RxList: 4/29/2013
This monograph has been modified to include the generic and brand name in many instances.