The unique mechanism of action of lacosamide, as well as a lack of significant drug interactions, a relatively mild adverse effect profile, and the availability of both oral and intravenous dosage forms have made it a useful addition to the antiseizure drug armamentarium. Lacosamide was approved by the U.S. Food and Drug Administration (FDA) in 2008 and is currently indicated for use as monotherapy or adjunctive therapy in patients 17 years of age and older with focal onset seizures. While not yet approved for use in the pediatric population, preliminary studies support its role in children with refractory seizures.

CHEMISTRY, ANIMAL PHARMACOLOGY, AND MECHANISM OF ACTION

Chemistry

Lacosamide, (R)-2-acetamido-N-benzyl-3-methoxypropionamide, is a functionalized amino acid synthesized as an antiseizure medication (Figure 56.1). It is a white to light yellow powder that is sparingly soluble in water and only slightly soluble in ethanol or acetonitrile (1,2).

Preclinical Studies

Efficacy

The antiseizure effect of lacosamide was first demonstrated in screening tests, including the maximal electroshock (MES) test in mice and rats (3–7). Results from the MES test suggested an antiseizure potency comparable to that of phenytoin. The effective dose (ED₅₀) of lacosamide given intraperitoneally in mice was 4.5 mg/kg in the MES test. With a dose needed to cause neurologic toxicity (TD₅₀) of 27 mg/kg on the rotorod test, the protective index of lacosamide has been determined to be 6, similar to other antiseizure medications in clinical use. In the 6 Hz electrical stimulation test, lacosamide (20 mg/kg injected intraperitoneally 30 minutes prior to stimulation) was shown to completely antagonize seizure-induced brain metabolic activation without suppressing normal brain metabolic activity. When given in combination, lacosamide has been shown to act synergistically with carbamazepine, gabapentin, lamotrigine, levetiracetam, or topiramate in preventing 6 Hz–induced seizures and to produce an additive effect with phenytoin or valproic acid (8).

Differentiation tests have been conducted that demonstrate the protective effects of lacosamide in the genetically susceptible Frings mouse and n-methyl-d-aspartate (NMDA)–induced seizures in mice (6). Lacosamide has been shown to have no significant effect against clonic seizures induced by pentylenetetrazol, bicuculline, and picrotoxin. In animal models of epilepsy, including both rat hippocampal and amygdala kindling models, lacosamide has led to a dose-dependent reduction in seizure scores and after discharge duration, with an ED₅₀ of 13.5 mg/kg in the hippocampal kindling model (9).

Toxicity

There has been no evidence of carcinogenicity in mice or rats when exposed to oral lacosamide for up to 104 weeks at plasma exposures from one to three times the exposure from the maximum recommended human dose (400 mg/day) (2). There have also been no adverse effects on male or female fertility or reproductive function in rats exposed to lacosamide at doses producing plasma exposures approximately twice that of humans receiving the maximum recommended dose.

Mechanism of Action

In vitro and preclinical studies have demonstrated the unique mechanism of action of lacosamide, related to its effects on voltage-gated sodium channels (3–10). Lacosamide selectively enhances slow inactivation of voltage-gated sodium channels, increasing the proportion of sodium channels unavailable for depolarization. This enhancement of the slow inactivation of the voltage-gated sodium channels produces stabilization of neuronal membranes and inhibition of sustained repetitive neuronal firing. Unlike other antiepileptic drugs (AEDs) that target the voltage-gated sodium channels, including carbamazepine, felbamate, lamotrigine, oxcarbazepine, phenytoin, and topiramate, lacosamide does not alter fast inactivation of voltage-gated sodium channels.

FIGURE 56.1 Lacosamide; (R)-2-acetamido-N-benzyl-3-methoxypropionamide.

A role of a secondary mechanism, interaction with collapsing-response mediator protein 2 (CRMP-2), remains controversial (11–13). CRMP-2 is part of a signal transduction cascade of neurotrophic factors involved in neuronal differentiation, regulation of gene expression, polarization, and axonal outgrowth. It has been proposed that binding at CRMP-2 could produce a neuroprotective effect, reducing glutamate-induced excitotoxicity and enhancing the clinical efficacy of lacosamide.

BIOTRANSFORMATION, PHARMACOKINETICS, AND INTERACTIONS IN HUMANS

The pharmacokinetic profile of lacosamide has been evaluated in several studies of adults, including those with renal and hepatic impairment. A multicenter, open-label safety and pharmacokinetic study in children between 1 month and 17 years of age has been completed, but has not yet been published (as of May 1, 2016).

Absorption and Distribution

Lacosamide is completely absorbed after oral administration, with a bioavailability of approximately 100% in studies of adults. Bioequivalence has been demonstrated between intravenous administrations over 30 or 60 minutes, tablet, and oral solution formulations (14–16). Food does not alter the rate or extent of absorption. Maximum serum concentrations (C_max) occur 30 minutes to 1 hour after an oral dose, with a mean C_max of 5 to 6 mcg/mL. There is a linear relationship between dose and plasma lacosamide concentrations over the recommended dosing range. The volume of distribution of lacosamide is approximately 0.6 L/kg, approximating the volume of total body water. Lacosamide is only minimally bound to plasma proteins, with most studies reporting less than 15% protein binding. The mean plasma area under the concentration–time curve (AUC) for the tablet and oral solution in adults are 84.5 and 83.3 mcg/mL/hr, respectively, similar to that achieved with intravenous administration.

Metabolism and Elimination

The elimination half-life of lacosamide in adults is approximately 13 hours (15,16). Approximately 30% to 40% of a lacosamide dose is excreted in the urine as unchanged drug. Conversion to inactive O-desmethyl-lacosamide, the major metabolite, by cytochrome P450 (CYP) isoforms CYP2C19, CYP2C9, and CYP3A4 accounts for another 20% to 30%. Genetic polymorphism does not appear to produce clinically significant changes in lacosamide pharmacokinetics. A study of extensive metabolizers and poor metabolizers of CYP2C19 resulted in similar plasma concentrations in both groups. The only difference between the two groups was a 70% reduction in the amount of the O-desmethyl metabolite in the poor metabolizers.

Renal or hepatic impairment impairs the elimination of lacosamide and its metabolites, resulting in greater drug exposure. AUC is increased by 25% in patients with mild to moderate renal impairment (defined as a creatinine clearance of 30–80 mL/min) and 60% in those with severe renal impairment (creatinine clearance ≤ 30 mL/min), compared to adults with normal renal function (2,17). In patients with moderate hepatic impairment (Child–Pugh class B), the AUC of lacosamide is increased by approximately 50% to 60%. Lacosamide has not been studied in patients with severe hepatic impairment and its use is not recommended in these patients.

Drug Interactions

Lacosamide is a substrate for CYP2C9, CYP2C19, and CYP3A4, but does not appear to produce significant induction or inhibition of cytochrome P450 enzymes. It is neither an inhibitor nor substrate for P-glycoprotein. While no definitively significant drug interactions with lacosamide have been documented, there is the potential for alterations in plasma concentrations with several drugs. In healthy adults, administration of lacosamide with valproic acid, a substrate for CYP2C9 and CYP2C19, had no effect on the C_max or AUC of either drug (18). Likewise, administration of lacosamide with omeprazole, a substrate for CYP2C19, produced no changes in the pharmacokinetics of either drug (19).

Studies of the coadministration of lacosamide with carbamazepine, phenobarbital, or phenytoin, strong CYP enzyme inducers, however, have produced mixed results. In premarketing studies, coadministration resulted in reductions in lacosamide C_max and AUC values of less than 20%, suggesting that no dosage adjustment was necessary (2,20). In contrast, a recent “real world” trial of 33 patients who were taking lacosamide and a strong inducer for at least 3 weeks documented an approximately 30% decrease in lacosamide plasma concentrations, leading the investigators to conclude that dose adjustment may be required for these patients (21).

The effects of coadministration of lacosamide with strong inhibitors of CYP3A4, such as clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, and telithromycin, or grapefruit juice have not been studied, but could potentially result in a reduction in lacosamide clearance (2).

The coadministration of lacosamide with a combination oral contraceptive was recently studied to identify any risk for contraceptive failure or loss of seizure control. A total of 37 women taking a combination of 0.03 mg ethinylestradiol and 0.15 mg were placed on lacosamide at a dose of 400 mg/day for up to three cycles. Comparing C_max and AUC values at baseline and after the addition of lacosamide revealed no significant changes, suggesting that coadministration did not result in a clinically significant interaction. Lacosamide use was associated with a slight, but clinically insignificant, increased serum progesterone concentrations (22).

An increase in neurologic adverse effects has been noted when lacosamide was added to a regimen containing other AEDs that block voltage-gated sodium channels (23). There was no evidence of a pharmacokinetic drug interaction or elevated serum drug concentrations in the seven patients that might have explained the increased incidence of diplopia, dizziness, and drowsiness. Reduction in the patient’s original AEDs produced symptomatic improvement in all of the patients. It has been proposed that adverse effects noted during lacosamide titration may represent a pharmacodynamic drug interaction resulting from synergistic voltage-gated sodium channels blockade, similar to that noted with other combinations of AEDs affecting these channels, such as carbamazepine and lamotrigine (23–25).

CLINICAL EFFICACY

Refractory Focal Onset, Generalized Seizures, or Mixed Seizure Types

In randomized controlled trials conducted in adults, lacosamide has demonstrated significant benefit in treating refractory focal onset seizures, with 30% to 40% of patients achieving a 50% or more reduction in seizure frequency at doses of 400 to 600 mg/day (1,26,27). Two recent studies have demonstrated long-term safety and efficacy in these patient populations out to 8 years (28,29).

Several retrospective studies reported response rates (≥ 50% reduction in seizure frequency) ranging from approximately 35% to 70% in pediatric cohorts (30–32). The two largest retrospective studies to date have included 40 children and adolescents treated with lacosamide for refractory focal onset or generalized seizures. In the first, lacosamide was used as adjunctive therapy in 36 patients and monotherapy in four (33). Forty-two percent of patients had a 50% or more reduction in seizure frequency, and six became seizure-free. The patients who responded to treatment had a mean decrease in seizures of 76.5%. The mean effective dose was 7 mg/kg/day. Average follow-up was at 9.2 months. Fifteen children had adverse effects, with one patient discontinuing lacosamide for development of a tremor and one for behavioral changes. In the second study, 40 children between 2 and 19 years of age with refractory seizures were treated with lacosamide as adjunctive therapy (34). A reduction of 50% or more was seen in 20% of patients, with continued efficacy at 9-month follow-up in eight children. The mean effective dose was 5.7 mg/kg/day. Two children became seizure free. Sixty-five percent of children remained on lacosamide at 9 months. Therapy was well tolerated by this patient sample, with minor adverse effects in seven patients and no discontinuations because of adverse effects.

In the first prospective case series in children, 14 patients between 3 and 18 years of age with focal onset seizures were treated with oral lacosamide for a period of at least 3 months (35). All of the children had been treated with multiple AEDs; the average number of previously failed therapies was seven drugs, with a range from 3 to 16. Lacosamide was initiated at 1 mg/kg/day and increased in 1-mg/kg/day increments on a weekly basis. Final doses ranged from 2 to 10 mg/kg/day. Five of the children (36%) experienced a 50% or more reduction in seizure frequency at the time of initial assessment that ranged from 3 to 8 months (mean 5 months). Two children maintained this level of seizure control for an additional 8 to 13 months. One year after enrollment, only four children were still on therapy. Lacosamide was discontinued in most patients owing to lack of efficacy or loss of efficacy at follow-up. Mild adverse effects were common, with 39% of children experiencing symptoms of somnolence or irritability. Only one patient discontinued therapy because of an adverse effect. The patient developed normochromic anemia with thrombocytopenia and granulocytopenia while on therapy, but had a similar history of pancytopenia prior to initiation of lacosamide. After a period of worsening seizure frequency, lacosamide was restarted without any adverse effect on blood counts.

A second prospective study described the use of lacosamide in 21 children (ages 1 to 16 years) with both focal onset and generalized onset seizures (36). Sixteen patients were included in the final analysis, with a mean age of 8.6 years. Of the eight children with generalized onset seizures, four were diagnosed with Lennox–Gastaut syndrome (LGS). The average length of follow-up was 9.8 months. The patients had failed an average of 6.6 previous treatments, as well as the ketogenic diet and vagal nerve stimulation. The mean dose at initiation was 5.8 mg/kg/day, with an average lacosamide dose at the end of titration of 9.4 mg/kg/day (range of 2.4–19.4 mg/kg/day). Eight patients (50%) had a 50% or more reduction in seizure frequency. Three patients had a 90% or more reduction. Children with focal onset seizures were the most likely to respond, while patients with generalized tonic–clonic and tonic seizures were the least likely to benefit from lacosamide. Of the four patients with LGS, two had significant improvement (≥ 90% reduction in frequency) and two had no response. Adverse effects included nausea, vomiting, dizziness, headache, somnolence, and facial edema.

There have been four other prospective studies investigating the use of lacosamide in the pediatric population. A single-center open-label observational study evaluated the efficacy and tolerability of lacosamide in children with refractory focal onset seizures (37). Seventy-nine children were enrolled, ranging in age from 5 to 15 years. Lacosamide was initiated at 25 mg once daily for 1 week, with an increase to 50 mg twice daily (mean dose 4.1 mg/kg/day) for the 3-month maintenance period. Thirty-five patients (44.3%) became seizure free in this study, while another 32 patients (40.6%) achieved a reduction in seizure frequency of 50% or more. Three patients discontinued treatment because of vomiting, aggressive behavior, or lack of benefit.

A multicenter prospective, open-label, observational study from Spain enrolled 130 children with refractory epilepsy to evaluate the efficacy and tolerability of lacosamide as adjunctive therapy (38). The patients, between 6 months and 16 years of age, were started on lacosamide at a dose of 1 to 2 mg/kg/day divided and given every 12 hours. After 3 months of therapy, 62.3% of patients had a 50% or more reduction in seizure frequency, with 13.8% of patients becoming seizure free. The mean effective dose was 6.8 ± 2.4 mg/kg/day. Adverse effects were reported in 39 (30%) patients, with the most common being nausea and vomiting (10%), instability (8%), dizziness (4%), nystagmus (2%), and somnolence (2%). Thirteen patients discontinued therapy because of adverse effects.

Another multicenter prospective study evaluated lacosamide as adjunctive therapy in both children and adults with refractory seizures (39). A total of 118 patients were enrolled: 59 children and 59 adults. The children received an initial lacosamide dose of 2 mg/kg/day, while the adults received 100 mg/day. Following dose titration, patients entered a 12-month maintenance phase. At 3 months, 47.4% of patients in each group had achieved a 50% or more reduction in seizure frequency. At 12 months, 47.4% of children and 39% of adults had achieved the 50% or more reduction. Approximately 30% of patients in each age group experienced an adverse effect, with dyspepsia occurring most often in children and dizziness in adults. Among the children evaluated at 12 months, those with focal onset seizures had the highest response rate (57.9%), compared to those with focal onset evolving to generalized seizures (28.6%) and those with mixed seizure types (52.4%).

The last of these prospective studies was a multicenter study that enrolled 24 children aged less than 4 years old (mean age 2.7 years) who presented with refractory focal seizures (40). Dosing was initiated at 1 to 2 mg/kg/day and titrated to final doses ranging from 7 to 15.5 mg/kg/day. At these doses, a good initial response was observed in 10 patients who had more than a 50% decrease in seizure frequency at 3 months, and 4 of these patients were seizure free. Over time, a loss of efficacy was observed in four of these patients. Adverse events included drowsiness (21%), nervousness (12.5%), vomiting (8%), and ataxic gait (4%). No life-threatening side effects were observed.

Myoclonic Seizures

A recent case series demonstrated benefit from lacosamide in three young adults (19–23 years of age) with juvenile myoclonic epilepsy (41). One of the patients received lacosamide as single-agent therapy, while the other two had lacosamide added to their current regimens for breakthrough seizures. All three patients became seizure free on a lacosamide dose of 200 mg given twice daily. Two patients remained on therapy at the time of publication (12 and 18 months), while one discontinued therapy after 4 months because of fatigue, depression, and anxiety. In the latter case, symptoms continued after lacosamide was stopped but later abated when levetiracetam was discontinued.

Lennox–Gastaut Syndrome

In addition to the patients with LGS included in the prospective study previously described (36) and a retrospective study that included two children with LGS who experienced an increase in seizure frequency during treatment with lacosamide (31), a recent multicenter retrospective study evaluated the efficacy and tolerability of lacosamide in 18 children with LGS (42). At a mean follow-up of 9 months, 33% of the patients were responders, although none were seizure free. The overall reduction in seizure frequency was 29%. The percentage reduction from baseline in tonic seizures was 31% and for drop attacks was 20%. Adverse effects were reported in 44% of patients. Three patients discontinued lacosamide because of increased seizures and one for walking instability.

Despite the positive response in some patients with LGS, the role of lacosamide in treating children and young adults with this syndrome remains unclear. A case series of three young adult patients from 24 to 27 years of age with LGS described worsening of seizure frequency after initiation of lacosamide (24). All three patients had been initiated on the recommended adult dose of 50 mg/day, increased at increments of 50 mg/day each week. Two of the patients reached a final dose of 200 mg/day; one of these patients experienced increased seizures at 15 days and the other at 30 days from the time of the last dose increase. The third patient developed an increase in seizure frequency 4 days after reaching a dose of 100 mg/day. All patients returned to their baseline seizure frequency after lacosamide was discontinued. The authors hypothesized that this worsening of seizure frequency may reflect a pharmacodynamic interaction resulting from an additive or synergistic effect of lacosamide with the patient’s other antiseizure drugs that block voltage-gated sodium channels. In a similar case report, a 20-year-old man with LGS who had failed multiple AEDs was given a trial of intravenous lacosamide at a dose of 200 mg/day (43). Within days of starting therapy, the patient began to experience an increase in tonic seizures, from an average of 4 per day to 10 per day, coinciding with a worsening of electroencephalographic (EEG) findings. The patient returned to baseline within 48 hours of lacosamide discontinuation.

Refractory Status Epilepticus

Lacosamide has also been used in the management of refractory status epilepticus. Several papers describe a beneficial effect in adult patients (44–46), but to date there have been only limited reports of its use in children. In an early case report, an 8-year-old child with prolonged status epilepticus in spite of receiving multiple AEDs responded to oral lacosamide at a dose of 25 mg twice daily (47). Within 3 days, seizure frequency had significantly declined and at 5 days, there was complete resolution of seizure activity. At follow-up 3 months later, the patient remained seizure free.

A retrospective multicenter study evaluated the efficacy of intravenous lacosamide as adjunctive therapy for refractory status epilepticus (48). Lacosamide was used after failure of a benzodiazepine, phenytoin, valproic acid, phenobarbital, and levetiracetam. Eleven children (ages 3–16 years) were included in the study, six with convulsive status epilepticus (CSE) and five with nonconvulsive status epilepticus (NCSE). Eighty percent had a prior history of epilepsy. The mean loading dose of lacosamide was 8.8 mg/kg (range 6.9–9.9 mg/kg) in the CSE group and 8.3 mg/kg (range 6.7–9.5 mg/kg) in the NCSE group. Mean maintenance doses were 12.9 mg/kg and 11.9 mg/kg, respectively. Seizure cessation occurred in three children in the CSE group (50%) and two children in the NCSE group (40%).

ADVERSE EFFECTS

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