Lacosamide: a review of preclinical properties

Abstract

Lacosamide (LCM), (SPM 927, (R)-2-acetamido-N-benzyl-3-methoxypropionamide, previously referred to as harkoseride or ADD 234037) is a member of a series of functionalized amino acids that were specifically synthesized as anticonvulsive drug candidates. LCM has demonstrated antiepileptic effectiveness in different rodent seizure models and antinociceptive potential in experimental animal models that reflect distinct types and symptoms of neuropathic as well as chronic inflammatory pain. Recent results suggest that LCM has a dual mode of action underlying its anticonvulsant and analgesic activity. It was found that LCM selectively enhances slow inactivation of voltage-gated sodium channels without affecting fast inactivation. Furthermore, employing proteomic affinity-labeling techniques, collapsin-response mediator protein 2 (CRMP-2 alias DRP-2) was identified as a binding partner. Follow-up experiments confirmed a functional interaction of LCM with CRMP-2 in vitro. LCM did not inhibit or induce a wide variety of cytochrome P450 enzymes at therapeutic concentrations. In safety pharmacology and toxicology studies conducted in mice, rats, rabbits, and dogs, LCM was well tolerated. Either none or only minor side effects were observed in safety studies involving the central nervous, respiratory, gastrointestinal, and renal systems and there is no indication of abuse liability. Repeated dose toxicity studies demonstrated that after either intravenous or oral administration of LCM the adverse events were reversible and consisted mostly of exaggerated pharmacodynamic effects on the CNS. No genotoxic or carcinogenic effects were observed in vivo, and LCM showed a favorable profile in reproductive and developmental animal studies. Currently, LCM is in a late stage of clinical development as an adjunctive treatment for patients with uncontrolled partial-onset seizures, and it is being assessed as monotherapy in patients with painful diabetic neuropathy. Further trials to identify LCM's potential in pain and for other indications have been initiated.

Figure 1

Chemical structure of lacosamide (C₁₃H₁₈N₂O₃).

Figure 2

Physiology of voltage‐gated sodium channels. Depending on the membrane potential and the neuronal activity voltage‐gated sodium channels are in different states. At the resting potential sodium channels are closed and can be opened by depolarization of the membrane potential allowing the flux of sodium ions into the cell. Within a few milliseconds the channels close from the inside of the neuron and go into the fast inactivated state from which they cannot be activated. When the membrane potential returns to its baseline the sodium channel goes back to its resting state. Under conditions of slight prolonged depolarization and repetitive neuronal activity the sodium channel can go into the slow inactivated state by closing the pore from the inside. This process happens on a second‐to‐minute time scale. Drugs can either block the open channel (e.g., local anaesthetics), or enhance fast inactivation (classical anticonvulsants) or enhance slow inactivation (lacosamide).

Figure 3

Schema showing CRMP‐2‐mediated transduction of neurotrophic signals to neuronal response and the possible interaction of lacosamide. Neurotrophins like NT‐3 and BDNF activate their receptors in the plasma membrane, triggering a transduction cascade, which regulates the activity of intracellular protein kinases (e.g., PI3 kinase or GSK‐3β) finally resulting in increased levels of active CRMP‐2. Active, nonphosphorylated CRMP‐2 has been shown to enhance axonal outgrowth and might also be involved in the induction of other cellular responses. Interaction site of lacosamide is indicated.

Figure 4

Pathophysiological mechanisms inducing central sensitization in neuropathic pain. Under conditions of neuropathic pain a cascade of pathophysiological processes is induced: Neuronal loss including neurite retraction (1), neurodegeneration (2) and demyelination (3), neuronal rearrangements including ephapse (4) and sprouting (5) as well as changes in gene expression, for example, of sodium channels (6) or glutamate receptors (7), finally resulting in ectopic firing (8) and enhanced transmission of pain signals (9).

Figure 5

Lacosamide displays anticonvulsant activity in hippocampal‐kindled rats. Male rats were implanted with a bipolar electrode into the ventral hippocampus. After recovery, animals were kindled to a stage 5 behavioral seizure using a stimulus of 50 Hz, 10‐sec train of 1‐msec biphasic 200 μA pulses delivered every 30 min for 6 h on alternating days for a total of 60 stimulations. Drug testing was initiated after a 1‐week stimulus‐free period. Fifteen minutes after drug administration each rat was stimulated every 30 min for 3–4 h with suprathreshold stimulations. After each stimulation individual seizure scores and afterdischarge duration (ADD) were noted. Lacosamide dose dependently reduced ADDs with an ED₅₀ of 13.5 mg/kg.

Figure 6

Lacosamide and amitriptyline reversed thermal allodynia in the STZ model. (Modified from Beyreuther et al. 2006). Diabetic neuropathic pain was induced by acute administration of streptozotocin (55 mg/kg, i.v.) in rats. Animals were placed in a glass cylinder on a warm plate adjusted to 38°C on day 10 after treatment with STZ. The latency of the first reaction (licking, moving the paws, little leaps, or a jump to escape the heat) was recorded with a cut‐off time of 30 sec. The activity of different anticonvulsants and antidepressants on allodynia and hyperalgesia was investigated starting 30–45 min after drug treatment and expressed as percentage of pain threshold of nondiabetic control rats.

Figure 7

Lacosamide and amitriptyline reversed mechanical hyperalgesia in the STZ model. (Modified from Beyreuther et al. 2006). Diabetic neuropathic pain was induced by acute administration of streptozotocin (55 mg/kg, i.v.) in rats. The nociceptive flexion reflex was quantified using the Randall–Selitto paw pressure device (Bioseb, France), which applies a linearly increasing mechanical force to the dorsum of the rat's hind paw at day 21 after treatment with STZ. The mechanical nociceptive threshold was defined as the force in grams at which the rat withdrew its paw. The cut‐off pressure was set to 250 g. The activity of different anticonvulsants and antidepressants on allodynia and hyperalgesia was investigated starting 30–45 min after drug treatment and expressed as a percentage of pain threshold of nondiabetic control rats.