Absorption, Distribution and Excretion
Lacosamide is completely absorbed after oral administration with negligible first-pass effect. It has a high absolute bioavailability of approximately 100%. Food does not affect the rate and extent of absorption. The Tmax ranges from one to four hours. Steady-state plasma concentrations are achieved after three days of twice-daily repeated administration. The pharmacokinetics of lacosamide are dose-proportional over the dose range between 100 and 800 mg, and time-invariant, with low inter- and intra-subject variability. The major O-desmethyl metabolite of lacosamide has a longer Tmax that ranges from 0.5 to 12 hours. After intravenous administration, Cmax is reached at the end of infusion. The 30- and 60-minute intravenous infusions are bioequivalent to the oral tablet. For the 15-minute intravenous infusion, bioequivalence was met for AUC0-tz but not for Cmax. The point estimate of Cmax was 20% higher than Cmax for oral tablet and the 90% CI for Cmax exceeded the upper boundary of the bioequivalence range. In a trial comparing the oral tablet with an oral solution containing 10 mg/mL lacosamide, bioequivalence between both formulations was shown. A single loading dose of 200 mg approximates steady-state concentrations comparable to the 100 mg twice-daily oral administration.
Lacosamide is primarily eliminated from the systemic circulation by renal excretion and biotransformation. After oral and intravenous administration of 100 mg radiolabeled lacosamide, approximately 95% of the radioactivity 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-desmethyl metabolite (approximately 30%), and a structurally unknown polar fraction (~20%).
The volume of distribution is approximately 0.6 L/kg and thus close to the volume of total body water.

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Metabolism / Metabolites
Lacosamide is metabolized by CYP3A4, CYP2C9, and CYP2C19 to form O-desmethyl lacosamide, which is a major, pharmacologically inactive metabolite in humans. There is no enantiomeric interconversion of lacosamide.

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Biological Half-Life
The elimination half-life of the unchanged drug is approximately 13 hours and is not altered by different doses, multiple dosing or intravenous administration. The major O-desmethyl metabolite of lacosamide has an elimination half-life ranging from 15 to 23 hours).

Hepatotoxicity
In prelicensure clinical trials, addition of lacosamide to standard anticonvulsant therapy was reported to be associated with ALT elevations above 3 times the upper limit of normal (ULN) in 7 of 935 patients (0.7%) compared to none of 356 treated with placebo. A single case of hepatitis with jaundice during lacosamide therapy was also reported. Since approval, there have been rare isolated reports of clinically apparent liver injury associated with lacosamide used, but the clinical features suggested that hepatic ischemia or other anticonvulsants combined with lacosamide may have been responsible. The onset was within a few days to several months after starting and the presentation was with a hepatocellular pattern of serum enzyme elevations, one case being asymptomatic and mild and the other severe. In both instances, there was rapid recovery.
Likelihood score: D (possible rare cause of clinically apparent liver injury)

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Limited information indicates that a maternal dose of 200 mg daily produce low levels in milk. Although one infant who was exposed during pregnancy and breastfeeding was seepy and fed poorly, several others have been breastfed with no adverse effects. Development of exposed infants has been normal. Until more data are available lacosamide should only be used with careful monitoring for drowsiness and adequate weight gain during breastfeeding, especially while nursing a newborn or preterm infant.
◉ Effects in Breastfed Infants
A pregnant woman suffered blood clots in the sinuses and 2 small intracranial hemorrhages followed by status epilepticus at 8 weeks of gestation. She was treated with levetiracetam 1000 mg and lacosamide 100 mg twice daily as well as enoxaparin and labetalol for the rest of her pregnancy and postpartum. Her infant was delivered at 36 weeks gestation and about 50% breastfed for the first days of life. The infant was sleepy and fed poorly, but pauses in breastfeeding did not improve the infant's condition. Breastfeeding was discontinued at 15 days postpartum and the infant gradually improved. The infant showed normal development at 7 months of age. Lacosamide and levetiracetam were probably the cause of the infant's sedation and poor feeding.
One center reported 3 mothers with epilepsy who took lacosamide while breastfeeding their infants. The extent of breastfeeding was not clearly stated, but one woman only partially breastfed her infant. The first mother took levetiracetam 2000 mg daily plus lacosamide 200 mg twice daily and breastfed her infant for 7 months with no infant adverse effects at 24 months of age. The second mother took lacosamide 300 mg daily and partially breastfed her infant for 8 months with normal developmental milestones at 6, 12 and 18 months of age. The third mother took lacosamide 400 mg daily and breastfed for 9 months without any feeding or alertness problems and no cognitive alterations or developmental delays at 36 months of age.
A woman took lacosamide and levetiracetam throughout pregnancy and while exclusively breastfeeding her infant. Despite receiving a relatively high dose in breastmilk, the infant reportedly had achieved developmental milestones and had no health problems at 6 months postpartum.
An infant was exclusively breastfed by a mother taking brivaracetam, lacosamide and perampanel for 6 weeks, then partially breastfed. The infant did not exhibit reduced wakefulness or feeding problems. At one year of age, the mother reported normal development.
A mother was taking lacosamide 200 mg daily during pregnancy and postpartum. Her exclusively breastfed infant had no drug-related adverse events during the 9-month follow-up period.
Three women taking lacosamide during pregnancy and lactation were reported by one center. One woman breastfed for 12 months while taking 200 mg twice daily. No medical problems or developmental delays were detected when the child was 12 months of age. The second woman breastfed for 6 months while taking 150 mg twice daily. Normal developmental milestones were reached at 12 months of age, and no health problems were detected. The third woman breastfed for 7 months while taking 200 mg twice daily. No medical issues or developmental delays were identified when the child reached the age of four years of age.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
Lacosamide is less than 15% bound to plasma proteins.

Pharmacodynamics
Lacosamide is an antiepileptic drug with high oral potency, stereoselectivity, and anticonvulsant effects. By blocking sensory neuronal voltage-gated sodium channels that mediate neuropathic pain responses, lacosamide was shown to possess analgesic activity. Lacosamide is a chiral functionalized amino acid. The S-stereoisomer does not exhibit antiepileptic activity.

C13H18N2O3

250.2

250.131

175481-36-4

219078

Typically exists as solid at room temperature

1.1±0.1 g/cm3

536.4±50.0 °C at 760 mmHg

141-143?C

278.2±30.1 °C

0.0±1.4 mmHg at 25°C

1.520

0.9

2

3

6

18

275

1

O(C([H])([H])[H])C([H])([H])[C@]([H])(C(N([H])C([H])([H])C1C([H])=C([H])C([H])=C([H])C=1[H])=O)N([H])C(C([H])([H])[H])=O

VPPJLAIAVCUEMN-GFCCVEGCSA-N

InChI=1S/C13H18N2O3/c1-10(16)15-12(9-18-2)13(17)14-8-11-6-4-3-5-7-11/h3-7,12H,8-9H2,1-2H3,(H,14,17)(H,15,16)/t12-/m1/s1

(2R)-2-acetamido-N-benzyl-3-methoxypropanamide

ADD243037 ADD-243037ADD 243037erlosamide Vimpat

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)