Lacosamide

Lacosamide (INN, formerly known as erlosamide, harkeroside, SPM 927, or ADD 234037), is a medication for the adjunctive treatment of partial-onset seizures and diabetic neuropathic pain. It is marketed under the trade name Vimpat. Lacosamide (INN, formerly known as erlosamide, harkeroside, SPM 927, or ADD 234037), is a medication for the adjunctive treatment of partial-onset seizures and diabetic neuropathic pain. It is marketed under the trade name Vimpat. Lacosamide is an anticonvulsant compound approved for the adjunctive treatment, as well as, conversion to monotherapy and monotherapy treatment of partial-onset seizures and neuropathic pain (not FDA approved). The U.S. Food and Drug Administration (FDA) accepted UCB's New Drug Application for lacosamide as of November 29, 2007, beginning the approval process for the drug. UCB also filed for marketing approval in the European Union (EU); the European Medicines Agency accepted the marketing application for review in May 2007. The drug was approved in the EU on September 3, 2008. It was approved in the US on October 29, 2008. Lacosamide release was delayed owing to an objection about its placement into schedule V of the Controlled Substances Act. The FDA issued their final rule of placement into Schedule V on June 22, 2009. Lacosamide was discovered by Dr. Harold Kohn, Dr. Shridhar Andurkar, and colleagues at the University of Houston in 1996. They hypothesized that modified amino acids may be therapeutically useful in the treatment of epilepsy. A few hundred such molecules were synthesized over several years and these were tested phenotypically in an epilepsy disease model performed in rats. N-benzyl-2-acetamido-3-methoxypropionamide was found to be highly efficacious in this model, with the biological activity traced specifically to its R enantiomer. This compound was to become Lacosamide after being licensed by Schwarz Pharma, which completed its pre-clinical and early clinical development. After its purchase of Schwarz Pharma in 2006, Union Chimique Belge (UCB) completed the clinical development program and obtained marketing approval for Lacosamide. Its precise mechanism of action was unknown at the time of approval, and the exact amino acid targets involved remain uncertain to this day. Lacosamide is a functionalized amino acid that produces activity in the maximal electroshock seizure (MES) test, that, like some other antiepileptic drugs (AEDs), are believed to act through voltage-gated sodium channels. Lacosamide enhances the slow inactivation of voltage-gated sodium channels without affecting the fast inactivation of voltage-gated sodium channels. This inactivation prevents the channel from opening, helping end the action potential. Many antiepileptic drugs, like carbamazepine or lamotrigine, slow the recovery from inactivation and hence reduce the ability of neurons to fire action potentials. Inactivation only occurs in neurons firing action potentials; this means that drugs that modulate fast inactivation selectively reduce the firing in active cells. Slow inactivation is similar but does not produce complete blockade of voltage gated sodium channels, with both activation and inactivation occurring over hundreds of milliseconds or more. Lacosamide makes this inactivation happen at less depolarized membrane potentials. This means that lacosamide only affects neurons which are depolarized or active for long periods of time, typical of neurons at the focus of epilepsy. Lacosamide administration results in the inhibition of repetitive neuronal firing, the stabilization of hyperexcitable neuronal membranes, and the reduction of long-term channel availability, but does not affect physiological function. Lacosamide has a dual mechanism of action. It also modulates collapsin response mediator protein 2 (CRMP-2), preventing the formation of abnormal neuronal connections in the brain. Lacosamide does not affect AMPA, kainate, NMDA, GABAA, GABAB or a variety of dopaminergic, serotonergic, adrenergic, muscarinic or cannabinoid receptors and does not block potassium or calcium currents. Lacosamide does not modulate the reuptake of neurotransmitters including norepinephrine, dopamine, and serotonin. In addition, it does not inhibit GABA transaminase. When administered orally in healthy individuals, lacosamide is rapidly absorbed from the gastrointestinal tract. Little of the drug is lost via the first pass effect, and thus has an oral bioavailability of nearly 100%.   In adults, lacosamide demonstrates a low plasma protein binding of <15%, which reduces the potential for interaction with other drugs. Lacosamide is at its highest concentration in blood plasma approximately 1 to 4 hours after oral administration. Lacosamide has a half life of about 12–16 hours, which remains unchanged if the patients is also taking enzyme inducers. Consequently, the drug is administered twice per day at 12-hour intervals. Lacosamide is excreted renally, with 95% of the drug eliminated in the urine. 40% of the compound remains unchanged from its original structure, while the rest of the elimination product consists of metabolites of lacosamide. Just 0.5% of the drug is eliminated in the feces. The major metabolic pathway of lacosamide is CYP2C9, CY2C19, and CYP3A4-mediated demethylation. The dose-response curve for lacosamide is linear and proportional for oral doses of up to 800 mg and intravenous doses of up to 300 mg. Lacosamide has low potential for drug-drug interactions, and no pharmacokinetic interactions have been found to occur with other (AEDs) that act on sodium channels. A study on the binding of lacosamide to CRMP-2 in Xenopus oocytes showed both competitive and specific binding. Lacosamide has a Kd value just under 5μM and a Bmax of about 200 pM/mg. The volume of distribution (Vd) of lacosamide in plasma is 0.6 L/kg, which is close to the total volume of water. Lacosamide is ampiphilic and is thus hydrophilic while also lipophilic enough to cross the blood-brain barrier.