CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`APPLICATION NUMBER:
` 022255Orig1s000
`PHARMACOLOGY REVIEW(S)
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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
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`PHARMACOLOGY/TOXICOLOGY REVIEW AND EVALUATION
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`NDA NUMBER:
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`SERIAL NUMBER:
`DATE RECEIVED BY CENTER:
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`INTENDED CLINICAL POPULATION:
`SPONSOR:
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`REVIEW DIVISION:
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`DIVISION DIRECTOR:
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`PROJECT MANAGER:
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`22-253, 22-254, 22-255
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`9/28/07
`Lacosamide (SPM927) Tablet, Injection, Oral Syrup
`epilepsy
`Schwarz Biosciences
`Division of Neurology Products (HFD-120)
`Ed Fisher
`Lois Freed
`Russell Katz
`Jackie Ware
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`TABLE OF CONTENTS
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`I. INTRODUCTION AND DRUG HISTORY................................................................................................3
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`II. PHARMACOLOGY..................................................................................................................................4
` A. Brief summary.................................................................................................................... 4
` B. Mechanism of action.......................................................................................................... 4
` C. Animal models……………………………………………………………………………………..6
` D. Safety pharmacology...........................................................................................................7
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`III. PHARMACOKINETICS/TOXICOKINETICS…………………………………………………………………12
` A. Brief summary……………………………………………………………………………………12
` B. Plasma drug levels………………………………………………………………………………12
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`IV. TOXICOLOGY…………………………………………………………………………………………………..14
` A. Repeat-dose oral toxicity………………………………………………………………………..14
` B. Repeat-dose iv toxicity…………………………………………………………………………..14
` C. Genetic toxicity…………………………………………………………………………………...18
` D. Carcinogenicity…………………………………………………………………………………...27
` E. Reproductive and developmental toxicology………………………………………………….35
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`V. SUMMARY AND EVALUATION ...........................................................................................................64
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`VI. RECOMMENDATIONS ........................................................................................................................74
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`INTRODUCTION AND DRUG HISTORY
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`Trade name:
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`Generic name: lacosamide
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`Code names: ADD 234037; harkoseride; SPM 927
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`Chemical name: (R)-2-acetamido-N-benzyl-3-methoxypropionamide
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`CAS registry number: 175481-36-4
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`Molecular formula: C13H18N2O3
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`Molecular weight: 250.3
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`Structure:
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` I.
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`NDA number: 22-253 (oral tablet), 22-254 (injection), 22-255 (oral syrup)
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`Date of submission: 9/28/07
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`Sponsor: Schwarz Biosciences
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`Drug:
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`Relevant IND: 57,939
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`Drug class: sodium channel modulator
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`Indication: epilepsy
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`Route of administration: oral (tablets, solution), injection
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`Previous reviews: Original IND review dated 3/22/99
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` CAC-EC reviews dated 7/13/00, 3/1/01, and 6/5/02
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` CAC-EC minutes dated 8/8/00, 4/24/01, and 7/9/02
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`Tables and figures are taken directly from the sponsor’s submission unless noted otherwise.
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`PHARMACOLOGY
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`BRIEF SUMMARY
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`II.
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`A.
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`Lacosamide (LCM) is a member of a series of functionalized amino acids that were specifically
`synthesized as anticonvulsant drug candidates. In standard in vitro radioligand binding assays,
`LCM showed no significant affinity for any of the typical binding sites, including a variety of
`neurotransmitter, neuropeptide, and growth factor receptors, ion channels, transporters, and
`intracellular signaling enzymes. However, weak displacement of binding (25% at 10 uM) was
`observed for the sodium channel site 2. Electrophysiological studies indicated that LCM
`selectively enhances the slow inactivation of sodium channels without affecting fast inactivation.
`This was shown to be in contrast to other sodium channel modulators such as lamotrigine,
`phenytoin, and carbamazepine which enhance fast inactivation. No significant modulation of
`voltage-gated potassium (KCNQ2/3) or calcium channels (L-, N-, P- and T-type) was detected.
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`In studies using proteomic affinity-labeling techniques, collapsin-response mediator protein 2
`(CRMP-2; also called DRP-2, dihydropyrimidinase-related protein) was subsequently identified as
`a potential binding target of LCM. In radioligand binding experiments using a cloned human
`analogue of CRMP-2 expressed in Xenopus oocytes, LCM exhibited a binding affinity of 5 µM.
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`Due its structural relationship to the endogenous amino acid D-serine, which acts as an NMDA
`receptor antagonist, LCM was assessed for binding at glutamate receptors. In an initial
`experiment, 50% displacement of a glycine site antagonist was observed with an IC50 of 5.2
`µmol/L. However, in a follow-up study using more specific ligands, LCM (10 µmol/L) did not
`produce significant (>50%) displacement of specific binding at AMPA, kainate, NMDA (agonist,
`glycine and phencyclidine binding sites) or glycine receptors isolated from rat brain. But in a
`functional experiment using recombinant NMDA receptor subtypes, LCM inhibited NMDA- and
`glycine-induced currents at NR1/2B receptors, albeit with an IC50 of 1.89 mmol/L.
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`LCM showed anticonvulsant activity in various rodent seizure models, ie, maximal electroshock
`seizures (MES), 6 Hz seizures, hippocampal kindling, audiogenic seizures (AGS), and self
`sustaining status epilepticus (SSSE). Lacosamide was inactive against clonic convulsions
`induced by sc pentylenetetrazol (PTZ), bicuculline, and picrotoxin, but it did inhibit NMDA-induced
`convulsions in mice. Although inactive against sc PTZ-induced threshold clonic convulsions, LCM
`elevated the seizure threshold somewhat in the iv PTZ test at the MES ED50. The O-desmethyl
`metabolite, SPM 12809, and the S-entantiomer of LCM, SPM 6953, were inactive in the MES test
`at relevant doses.
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`In vitro investigations of the cardiovascular effects of LCM showed that LCM reduced the action
`potential duration in cardiac tissue and inhibited sodium current in isolated cells. Effects on
`sodium current were dependent on membrane potential, with higher inhibition at more
`depolarized potentials. In vivo studies showed that LCM decreased cardiac conduction. In
`anesthetized instrumented dogs, LCM induced hypotensive effects characterized mainly by
`reduced contractility, as indicated by decreases in systolic left ventricular pressure and left
`ventricular pressure over time (dP/dt) and reduced cardiac output. These effects were
`accompanied by increases in PR interval and QRS complex duration and by AV block. Similar
`EEG effects were seen in monkeys, ie, QRS prolongation and AV and ventricular block.
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`B.
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`LCM (10–100 µM) showed no significant affinity (>50% inhibition) for any of the typical receptors,
`channels, or enzymes screened, but did bind weakly (25–50% inhibition) to the sodium channel at
`the batrachotoxin site 2. LCM did not modulate the uptake of NE, DA, or 5HT into synaptosomes,
`and did not bind to GABA transporters or influence the activity of GABA transaminases. The
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`major desmethyl metabolite (SPM 12809) also showed no significant binding to the receptors
`tested.
`In early mechanistic studies, sustained repetitive firing (SRF) of current clamped rat cortical
`neurons evoked by applying current pulses (750 ms, every 12–14 s) was weakly (78 vs 96% in
`control) but significantly reduced in frequency by LCM (100 uM) without apparent changes in
`individual spike properties. This effect was different from that produced by the known sodium
`channel-blocker phenytoin (100 uM), which produced a large (28 vs 96%) attenuation of spiking
`during the evoked period of SRF and progressively reduced the amplitude and eventually
`terminated the AP, but the results suggested that LCM could be acting in part via inhibition of
`voltage gated sodium channels (VGSCs). When SRF duration was prolonged (10 s) LCM
`produced significant (EC50: 48 µM) inhibition, but not within the first second of the burst (EC50:
`640 µM).
`In a study conducted in patch-clamped mouse neuroblastoma cells, which was designed to
`recruit only fast inactivation (without significant development of slowly inactivated conformations)
`of the VGSC, significant hyperpolarizing shifts in the fast inactivation voltage curves were
`produced by the classical anticonvulsants LTG, CBZ, and DPH (all 100 uM). In contrast, LCM
`(100 µM) did not produce a hyperpolarizing shift in the V50 for inactivation of sodium currents in
`these cells, ie, the voltage for half maximal inactivation after equilibration with LCM was not
`significantly different from V50 in control solutions. However, LCM (100 µM) did produce a
`hyperpolarizing shift in the voltage dependence of slow sodium channel inactivation and
`promoted channel entry into the slow inactivated state, but did not alter the rate of recovery. The
`effect of the other drugs on slow inactivation was not tested. (Table IIB.1; adapted from
`Beyreuther et al, CNS Drug Reviews, 13:21-42,2007).
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`Table IIB.1. Effect of anticonvulsants on the voltage dependence of Na+ channel inactivation
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`inactivation,
`indicated a selective effect of LCM on slow
`that
`In another experiment
`neuroblastoma cells were maintained at a holding potential of -60 mV and depolarized by a 10 ms
`test pulse to 0 mV at 0.5 Hz. The protocol was then repeated in each cell with a 500 ms
`hyperpolarizing pulse to -100 mV applied prior to the depolarizing test pulse in order to remove
`fast inactivation. In all cells tested all four of the anticonvulsants (LCM, LTG, CMZ, DPH; all 100
`µM) produced a reduction in Na+ current when the holding potential was -60 mV. For LTG, CBZ,
`and DPH application of the hyperpolarizing prepulse to -100 mV markedly reduced the blocking
`action on the channel. In contrast, the inhibition produced by LCM was not significantly altered by
`the hyperpolarizing prepulse. (Table IIB.2; adapted from Beyreuther et al, CNS Drug Reviews,
`13:21-42,2007).
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`Table IIB.2. Inhibition of Na+ current with and without removal of fast inactivation
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`In affinity-labeling studies, LCM was modified chemically in order to allow covalent crosslinking to
`potential targets. A set of four LCM-related affinity reagents applied to rat brain fractions led to
`enrichment of an overlapping set of proteins, including a dihydropyrimidinase-related protein and
`some additional proteins related to the vesicle release machinery. Although the results suggested
`that dihydropyrimidinase-related protein may be a target of LCM, they were considered
`inconclusive, since this type of chemical crosslinking experiment is susceptible to nonspecific side
`reactions.
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`Based on the results of this study, a follow-up study was performed in which the human analogue
`of DRP-2 (CRMP-2) was cloned, expressed in Xenopus oocytes, and the binding of radiolabeled
`SPM 927 was examined. The results indicated a membrane-associated binding site in oocytes
`transfected with DRP-2; competitive and specific binding could be observed with a KD value of
`about 5 uM. It was pointed out, however, that the expression of DRP-2 could not be monitored
`directly in this system due to the lack of a functional assay. In cultured rat hippocampal neurons,
`NT3 and BDNF-stimulated axon growth was inhibited by 1, 10, 100 and 200µM LCM. The
`positive reference compound wortmannin had a similar inhibitory effect on both neurotrophin-
`induced effects. These results were thought to provide evidence that LCM may exert some of its
`pharmacological action via inhibition of CRMP-2.
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`When LCM (10uM) was evaluated for displacement of various radioligands from glutamate
`subtype and glycine binding sites (glutamate, AMPA; glutamate, kainate; glutamate, NMDA,
`agonist; glutamate, NMDA, glycine; glutamate, NMDA, phencyclidine; glutamate, non- selective;
`and glycine, strychnine-sensitive), no significant responses (≥50% stimulation or inhibition) were
`seen. In a functional experiment using recombinant NR1/2A and NR1/2B NMDA receptor
`subtypes expressed in Xenopus oocytes, LCM inhibited NMDA- and glycine-induced currents at
`NR1/2B but not at NR1/2A receptors with an IC50 of 1.89 mmol/L. Binding was observed to be
`independent of glycine concentration, indicating noncompetitive antagonism.
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`C.
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`In initial screening, LCM blocked sound-induced seizures in mice with an ED50 of 0.63 mg/kg, ip
`and protected mice (ED50 = 4.5 mg/kg, ip) and rats (ED50 = 3.9 mg/kg, po) against maximal
`electroshock (MES)-induced tonic-extension seizures, indicating that LCM is effective in
`preventing seizure spread (Table IIC.1; from Stöhr et al, Epilepsy Res 74:147-54,2007). LCM
`showed efficacy in the 6-Hz psychomotor seizure test, which is considered a model for treatment-
`resistant seizures, with an ED50 of 9.99 mg/kg ip. In this model, LCM exhibited additive to
`synergistic effects with a variety of AEDs (pronounced synergism observed with levetiracetam
`and CBZ). LCM did not block GTCSs induced by the GABAA-receptor antagonist bicuculline or
`the chloride channel blocker picrotoxin. LCM was also ineffective against clonic seizures induced
`by sc bolus injection of pentylenetetrazole (PTZ) in rats and mice. However, LCM significantly
`increased the threshold for minimal seizures induced by timed iv infusion of PTZ in mice. In the
`rat hippocampal kindling model, which is thought to predict activity against complex partial
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`ANIMAL MODELS OF EPILEPSY
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`seizures, the ED50 of LCM for reduction of the seizure score from 5 to ≤3 in fully kindled rats was
`13.5 mg/kg. LCM (≥10 mg/kg ip) also significantly inhibited kindling development in this model.
`LCM was also active in a model of status epilepticus, blocking limbic seizures induced by self
`sustaining status epilepticus (SSSE)
`in rats. LCM also
`increased survival and was
`neuroprotective in this model.
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`Table IIC.1
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`SAFETY PHARMACOLOGY
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`D.
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`In Purkinje fibers isolated from male Beagle dog hearts, LCM (1.5, 5, 15, 50, 150 µmol/L) induced
`concentration-dependent decreases (SS) in action potential duration at 50%, 70% and 90% of
`repolarization (APD50, APD70, APD90, respectively), both at normal (1 Hz) and low (0.2 Hz)
`stimulation frequencies (Table IID.1). At the high concentration, decreases in APD50, APD70 and
`APD90 ranged from 30 to 47% at normal frequencies and from 32 to 54% at low stimulation
`frequencies, respectively. This shortening in action potential duration was associated with
`reductions in the maximal rate of depolarization (Vmax). At 150 µmol/L, Vmax was reduced by
`32% and 36% at 1 Hz and 0.2 Hz, respectively.
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`Table IID.1
`Effect of lacosamide on cardiac action potential in isolated Purkinje fibers
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`Change in % versus pretreatment values
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`Stimulation frequency 1 Hz
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` Stimulation frequency 0.2 Hz
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`* = p ≤ 0.05, ** = p ≤ 0.01 compared to the vehicle group
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`In human embryonic kidney cells (HEK293) stably expressing the cardiac SCN5A Na+ channel (=
`hHNa), LCM (10, 100, 200, 500, 1000 µM) produced a concentration-dependent inhibition of
`sodium currents (IC50 of 293 µmol/L). The block was incomplete, plateauing at about 70%. When
`the use-dependence of the block was tested by applying a train of test pulses (10 ms, to -15 mV)
`from a holding potential of -80 mV until a steady state was reached, the additional block was
`1.5% at 0.3 Hz (n=2) and 26% at 3 Hz (n=2) at a LCM concentration of 200 µmol/L. The
`reference compound lidocaine produced a complete block at 2 mmol/L (n=2).
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`In CHO cells transiently expressing the human SCN5A channel, LCM (10, 50, 500, 5000 µmol/L;
`cells clamped to a holding potential of -100 mV) produced a concentration-dependent inhibition of
`Na+ current (IC50: 112 µmol/L). The maximum block at 5000 µmol/L was 53% for the first and
`67% for the average of the last five pulses (use-dependence). In a washout experiment channels
`were reactivated 150s after drug removal, demonstrating reversibility of the LCM effect. The
`reference compound lidocaine elicited almost complete block of sodium current at a concentration
`of 500 µmol/L. The desmethyl-metabolite SPM 12809 did not inhibit the SCN5A mediated current
`significantly compared to vehicle under similar condition, but when a less negative holding
`potential of -80 mV was used, a concentration of 100 umol/L SPM 12809 produced a 20%
`inhibition of the Na+ current.
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`In isolated human atrial myocytes obtained from human right atrial appendage tissue which had
`been removed during cardiac surgery, LCM (0.1, 0.3, 1, 3, 10, 100, 5000 µmol/L) produced only
`minimal Na+ current inhibition (1.4% at 5000 µmol/L) at a hyperpolarized membrane potential (-
`140 mV). However at a depolarized holding potential (-70 mV), LCM dose-dependently blocked
`the Na+ current with an IC50 of 67.5 µmol/L and elicited complete block at 5000 µmol/L. Using
`the same test system, LCM (10, 100, 5000 µmol/L) produced minimal inhibition of Ca2+ currents
`(9.9%). In ventricular myocytes from female guinea-pigs, LCM (15, 50, 150, 500 µmol/L) also
`failed to affect the current amplitude or current-voltage relationship of the calcium channel.
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`In voltage clamped human embryonic kidney (HEK293) cells stably expressing the human-ether-
`a-go-go-related gene (hERG), LCM (10, 100, 300, 3000 µmol/L) produced only a weak inhibition
`(7%) at the highest concentration.
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`In an early anesthetized dog study (Study No. 0247DH15.001), dose-related decreases in arterial
`blood pressure (SAP, DAP, MAP), LVP, and +dP/dt were observed following iv administration of
`LCM (consecutive 1-min bolus doses of 2.5, 5, 10, and 15 mg/kg; 30 min between doses) to a
`single male Beagle. MAP was decreased by up to 10, 15, and 27% and LVP by up to 10, 11 and
`21%, respectively. Maximum reductions of +dP/dt were 21, 29 and 38%, respectively. The
`duration of the effect increased with dose. No effects on HR, CO, LVEDP, or ECG parameters
`were noted in this study.
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`Another study (#0247DH15.002) in anesthetized dogs (1 male, 1 female), LCM (consecutive
`doses of 2.5, 5, 10, and 15 mg/kg by iv infusion over 10 minutes; 25 min between doses), D-R
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`changes in BP (SAP, DAP, MAP), CO, +dP/dt, and LVP were observed. Maximal reductions were
`29 and 59% for MAP, 22 and 81% for CO, 33 and 78% for +dP/dt, and 24 and 45% for LVP at 10
`and 15 mg/kg, respectively. At the HD, HR was markedly decreased (up to 76%) in both dogs,
`and the female dog died after about 10 min.. The marked decreases in MAP, CO, and HR
`appeared at the same time as AV dissociation was observed in the ECG. The ECG evaluation (by
`Detweiler) stated that LCM “produces hemodynamic changes, including bradycardia, negative
`inotropy, and lowered arterial blood pressure that can be expected to decrease coronary arterial
`blood flow. The latter was probably the cause of the one death that occurred. The single lead II
`electrocardiograms monitored showed that [LCM] causes depression of P wave amplitude and
`various degrees of AV block. This single lead was insufficient to allow description of the changes
`in the atrial complexes when the P waves flattened. It appears that atrial conductivity may have
`been markedly depressed, although this is an uncertain diagnosis.”
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`In a follow-up study (#0247DH15.003) in a single male dog, 3 consecutive doses of 15 mg/kg
`LCM were administered iv over ten minutes (30 min between doses). After the initial dose, there
`was a 23, 22 and 24% decrease in SAP, DAP and MAP, respectively, with no HR change (Table
`IID.2). The 3rd dose produced a 47%, 54%, and 53% reduction in SAP, DAP, and MAP and HR
`decreased from 129 to 57 bpm (-53%). The ECG evaluation (by Detweiler) stated that LCM
`“slows intra-atrial conductivity, causes atrioventricular block and dissociation, abolishes surface
`lead P waves and may cause minor QT prolongation, although the latter is uncertain. The effect
`on atrial conductivity is like that seen with hyperkalemia or certain drugs that affect potassium ion
`channels in some way causing hypekalemia-like ECG changes.” Regarding the QT effect:
`“Throughout there was a gradual increase in QT interval duration and STT complex form changes
`with some ST segment depression. The latter did not exceed normal limits except at the end.
`These changes also may occur during anesthesia so that the test article cannot be implicated
`with certainty.”
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`Table IID.2
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`In the final study (20000376 P) in Beagle dogs (5/sex), LCM (2, 4, 8, and 12 mg/kg iv over 30
`sec; 30 min between doses) produced a D-D hypotensive effect due to a cardiodepressant action
`as suggested by decreases in systolic LVP, -dP/dt, +dLVP/dt, and CO (Table IID.3). Increases in
`PR and PQ interval and QRS complex duration were seen indicating a slowing in both atrio-
`ventricular and ventricular conductivity at ≥2 mg/kg in females and ≥8 mg/kg in males. One
`female dog died immediately after receiving the 12 mg/kg dosage due to a marked drop in arterial
`blood pressure followed by a cardiac arrest. One male dog displayed disturbances of the
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`electrocardiogram manifesting as junctional rhythm (loss of P wave) at the 12 mg/kg. One female
`displayed disturbances of the electrocardiogram manifesting as junctional rhythm and junctional
`premature contractions at 8 mg/kg. There was no effect on QTc in this study. In male dogs
`plasma LCM concentrations ranged from 11.3 to 22.6 µg/mL, 29.2 to 46 µg/mL, and from 59.2 to
`85.6 µg/mL at 4, 8 and 12 mg/kg iv, respectively. In female dogs plasma levels ranged from 5.8 to
`8.5 µg/mL, 15.8 to 19.5 µg/mL, 29 to 44.7 µg/mL, and from 56.5 to 80.2 µg/mL at 2, 4, 8 and 12
`mg/kg iv, respectively.
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`Table IID.3
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`Finally, in a study (0247XH15.004) in cynomolgus monkeys (3 males), LCM (10 min iv infusion of
`1, 5, 10, and 15 mg/kg [1 monkey] or 30 mg/kg [2 monkeys]; 20 minutes between doses)
`decreased MAP by up to 50% at 30 mg/kg (Table IID.4). HR was decreased by about 30%. ECG
`changes in the 2 monkeys receiving 30 mg/kg included prolonged P wave duration and
`decreased P wave amplitude (total loss of P wave), prolongation and increased amplitude of QRS
`complex, deviation of ST segment, and first and second degree AV block. The ECG evaluation
`(by Detweiler) stated that LCM “can slow intra-atrial conduction, cause atrioventricular block,
`abolish surface P waves, prolong the QRS markedly, and cause intraventricular block. QT interval
`prolongation associated with the QRS prolongation was present. The QT interval itself was
`lengthened somewhat beyond the QRS effect, but it is uncertain whether this is a [LCM] effect
`because of the presence of anesthesia.”
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`Table IID.4
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` 6958-103).
`Possible neurotoxic effects of LCM were assessed in two rat studies (Olney
`Since early radioligand binding studies indicated a potential interaction with NMDA receptors, the
`potential for LCM to produce neuronal vacuolization in rat brains was examined. In a study by
`John Olney, LCM was administered at a single ip dose of 50 mg/kg (10-fold anticonvulsant dose
`in rats), and brains was processed for the determination of vacuolization (6 h after LCM) or cell
`death (48 h after LCM). Brain tissue from treated rats did not show any signs of vacuolization or
`neuronal necrosis, while MK-801 produced the expected neuronal vacuolization in the
`retrosplenial cortex and cell death in different regions of the brain. These results were confirmed
`in a second study (6958-103). No neuronal vacuolization or cell death were observed at 4 h or 72
`h, respectively, following single ip doses of 10 or 50 mg/kg LCM. MK-801 treatment resulted in
`the expected neuronal vacuolization and necrosis.
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`PHARMACOKINETICS/TOXICOKINETICS
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`ADME reviewed separately by Belinda Hayes, DAARP
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`III.
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`A. BRIEF SUMMARY
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`PK studies showed that LCM was rapidly and well absorbed after oral administration to mice,
`rats, rabbits and dogs; oral bioavailability was about 80% in rats and dogs based on absorption of
`radioactivity from radiolabeled drug. The rate and extent of systemic exposure was approximately
`linear in rabbits and dogs but less than dose proportionate in rodents. In mice, rats and dogs
`exposure was similar between sexes. Although the half-life was short (t1/2 ≈1.3 and 1.8 hr
`reported in rat and dog PK studies, but t1/2 of 5 hr determined in rat carcinogenicity study TK
`report), accumulation was generally observed with repeated dosing in toxicity studies,
`presumably due to saturation of clearance at higher doses. In vitro protein binding was very low in
`mouse, rat, dog, and human (unbound fraction 94, 95, 83 and 94%, respectively). Following
`single oral administration of [14C]-LCM to mice, rats and dogs, radioactivity was rapidly and
`extensively distributed throughout the tissues with highest concentrations in the gi tract, liver, and
`kidneys. In the brain few regional differences in the distribution of radioactivity were apparent.
`Levels of radioactivity in the brain were of the same order of magnitude as in plasma. There was
`no evidence that radioactivity was specifically binding to any tissue. No significant melanin
`binding was observed. In pregnant rats, [14C]-LCM-derived radioactivity crossed the placenta
`and was excreted into the breast milk (levels similar to plasma). Suckling neonates were exposed
`to LCM-derived radioactivity with a distribution similar to that of maternal tissues in pregnant rats.
`When 7-day old juvenile rats were orally administered LCM, up to 5-fold higher mean LCM
`plasma concentrations were determined than in adult animals. No such effect was observed in a
`dose-range-finding study in 8-week old juvenile dogs. Following oral administration to adult rats
`for up to 7 days, there were no notable effects on the concentrations of hepatic microsomal
`protein and cytochrome P450 or on the activities of CYP1A and CYP2B. The major human O-
`desmethyl metabolite SPM 12809 was found in mouse, rat and dog plasma in vivo. No major
`differences in systemic exposure to SPM 12809 were observed between species, doses, or sex,
`but relative exposure to SPM 12809 in animals was generally higher than that determined in
`clinical trials. The relative exposure to SPM 12809 in animals ranged from 22 to 51% in terms of
`Cmax and from 25 to 73% in terms of AUC. In human plasma the relative exposure to SPM
`12809 was less than 20% in terms of both Cmax and AUC at steady state. Measurable levels of
`the desacetyl derivative (SPM 6912), which is a minor human metabolite (found in urine but not
`plasma) and a degradation product of lacosamide in liquid formulations, were also present in
`mouse and rabbit plasma. Following oral and intravenous administration to mice, rats and dogs,
`[14C]-lacosamide-derived radioactivity was rapidly eliminated. Similar excretion patterns were
`observed in all species including human with the majority of radioactivity recovered in urine.
`Unchanged lacosamide and its O-desmethyl metabolite were the major components in urine of
`mouse, rat, dog and humans. LCM (R-enantiomer) is a chiral substance, but no bioconversion to
`the S-enantiomer was observed in rat plasma and dog urine samples. There were no apparent
`route-related differences in LCM disposition following iv and oral administration of labeled drug to
`rats and dogs.
`
`
`B. PLASMA LEVELS
`
`LCM plasma levels in the toxicity studies are compared to those in humans at the proposed
`MRHD of 300 bid in Table IIIB.1. There is little or no AUC coverage. Note that human AUC0-12h
`values are used, while AUC0-24h is given for animals. Data from clinical trial SP588, in which
`multiple oral doses of 300 mg bid (MRHD used by sponsor) were administered to healthy male
`subjects, were used for comparison with the nonclinical parameters. Combining the two AUC0-12h,
`ss values would give an AUC0-24h of 245 ug.h/ml. This is similar to the AUC0-∞ value of 231
`ug.h/ml reported in clinical study SP587 after a single dose of 600 mg. If 400 mg/day (200 bid) is
`
`
`
`12
`
`

`

`
`
`
`the highest dose approved, then an AUC0-24h of 200 ug.h/ml should be used (2X AUC0-12h, ss of
`100.3 ug.h/ml; from clinical trial SP640). The sponsor has argued that Cmax is more relevant
`than AUC, but while true for acute neurotoxic effects such as convulsions, which were dose
`limiting, it may not be true for other toxicities. The O-desmethyl metabolite (SPM 12809)
`represents less than 20% of the parent compound in human plasma after repeated oral
`administration of LCM. The relative exposure to SPM 12809 in % of the lacosamide exposure
`was 12% in terms of Cmax, ss and 15% in terms of AUC0-12h, ss when taking the molecular
`weights into account (n = 57 male and female healthy human subjects, 200 mg lacosamide twice
`daily (12 hours apart) for 6 days, SP640). SPM 12809 is the only major systemically available
`human metabolite. It was shown to have only weak pharmacological activity.
`
`
`Table IIIB.1
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`13
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`IV.
`
`A.
`
`B.
`
`1.
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`
`
`TOXICOLOGY
`
`REPEAT-DOSE ORAL TOXICITY
` Oral toxicity studies reviewed separately by Belinda Hayes, DAARP
`
`REPEAT-DOSE IV TOXICITY
`
`14-Day Intravenous Injection Toxicity Study of ADD 234037 in Rats (Study No. 6842-101;
`conducted by
`; Report dated 11/20/98; GLP)
`
`a.
`
`Methods
`
`LCM (Lot No. PEH-A-188 (2)) was administered by iv bolus (via tail vein) to SD
`rats (10/sex/group) at doses of 0, 12.5, 25, or 50 mg/kg/day for 2 weeks. Clinical
`observations, body weight and food consumption determinations, ophthalmologic
`exams, organ weights and gross pathological examinations were performed on
`all animals. Microscopic examinations were conducted on all gross lesions, on a
`standard list of tissues/organs in the C and HD groups and from rats that died
`prior to scheduled sacrifice, and on gross lesion, brain, liver, and kidney from LD
`and MD rats. (There were no TK determinations.)
`
`Doses were based on the results of the single iv dose study in which doses of 25,
`50, and 100 were give as an iv bolus and reduced right, limb weakness, ataxia,
`flattened posture, limb splay, and labored respiration were observed at the 2
`highest doses (but no convulsions). There were no deaths but gross pathology
`findings of pale kidneys and thinned areas in the stomach were found in these
`groups. The only PK in rats after iv administration came from a single dose study
`in which male rats received 0, 1, 3 and 10 mg/kg by iv bolus via a jugular
`catheter. PK parameters are shown in Table IVB.1.1 below.
`
`b.
`
`
`
`Results
`
`i.
`
`Mortality, clinical signs, body weight
`
`There were no deaths during the study. Clinical signs consisted of
`moderate to severe hypoactivity and ataxia, appearing within 30 minutes
`post dose on each study day, at the HD, with females more affected than
`males. BW gain was decreased in MD females and in HD animals of
`both sexes (BW decreased by -6.8% and -6.9% in HD males and
`females, respectively, at end of study; SS; Table IVB.1.2). There was a
`corresponding decrease in food consumption in these groups.
`
`Clinical Pathology
`
`RBC parameters were increased slightly in HD males and females
`(probably due to hemoconcentration). Serum Alk Phos, ALT, AST, and
`creatinine were increased in treated males (Table IVB.1.3). The ALT and
`AST changes primarily reflected the markedly increased activities in one
`HD male (C02730), but in no case were histological correlates observed.
`Similar changes were not seen in females. Urinalysis indicated a diuretic
`effect, with increased (SS) urine volume in HD males (+247%) and
`females (+402%) and lower concentrations of urinary solutes (potassium,
`sodium, creatinine and urea nitrogen) and lower specific gravity.
`
`Ophthalmology
`
`ii.
`
`
`iii.
`
`14
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`(b) (4)
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`

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`
`c.
`
`
`Table IVB.1.1
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`
`
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`Table IVB.1.2
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`
`
`iv.
`
`
`There were no findings considered treat