Absorption, Distribution and Excretion
Lacosamide is completely absorbed after oral administration, with negligible first-pass effect. Its absolute bioavailability is approximately 100%. Food does not affect its absorption rate or extent. The time to peak concentration (Tmax) is 1 to 4 hours. Steady-state plasma concentrations are reached after three days with repeated dosing twice daily. The pharmacokinetics of lacosamide are dose-proportional across the 100 to 800 mg dose range and are not affected by time, exhibiting low inter- and intra-individual variability. The time to peak concentration (Tmax) of lacosamide's major O-demethyl metabolite is longer, ranging from 0.5 to 12 hours. After intravenous administration, peak plasma concentration (Cmax) is reached at the end of the infusion. 30-minute and 60-minute intravenous infusions are bioequivalent to oral tablets. For a 15-minute intravenous infusion, AUC0-tz meets the bioequivalence criteria, but Cmax does not. The point estimate of Cmax was 20% higher than that of the oral tablets, and the 90% confidence interval of Cmax exceeded the upper limit of the bioequivalence range. Bioequivalence of the two formulations was confirmed in a trial comparing the oral tablets and an oral solution containing 10 mg/mL lacosamide. A single loading dose of 200 mg achieved a steady-state concentration equivalent to twice-daily oral administration of 100 mg. Lacosamide is primarily eliminated from systemic circulation via renal excretion and biotransformation. Following oral and intravenous administration of 100 mg of radiolabeled lacosamide, approximately 95% of the radioactive material was recovered in the urine, and less than 0.5% in the feces. The main excreted compounds were unchanged lacosamide (approximately 40% of the dose), its O-demethylated metabolite (approximately 30%), and a polar moiety of unknown structure (approximately 20%). The volume of distribution is approximately 0.6 L/kg, close to the total body water volume.

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Metabolism/Metabolites
Lacosamide is metabolized via CYP3A4, CYP2C9, and CYP2C19 to O-desmethyllacosamide, which is the main, pharmacologically inactive metabolite in the human body. Lacosamide does not exhibit enantiomeric interconversion.

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Biological Half-Life
The elimination half-life of the parent drug is approximately 13 hours, and different doses, multiple administrations, or intravenous administration do not affect its elimination half-life. The elimination half-life of the main O-desmethyl metabolite of lacosamide is 15 to 23 hours.

Hepatotoxicity
In premarket clinical trials, 7 out of 935 patients (0.7%) who received lacosamide in addition to standard antiepileptic therapy experienced ALT levels exceeding three times the upper limit of normal, compared to none in the placebo group (356 patients). One case of hepatitis with jaundice was also reported during lacosamide treatment. Since lacosamide's approval, although a few cases of clinically significant liver injury have been reported, clinical features suggest hepatic ischemia or the combined use of lacosamide with other antiepileptic drugs may be the causative factor. These cases occurred within days to months of treatment, presenting with hepatocellular elevations of serum enzymes; one case was asymptomatic with mild symptoms, while the other had severe symptoms. Both recovered rapidly.
Probability Score: D (Possibly a rare cause of clinically significant liver injury)

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Effects during Pregnancy and Lactation
◉ Overview of Use During Lactation
Limited information suggests that low concentrations of the drug in breast milk are observed when the mother takes 200 mg daily. While one infant exposed to the drug during pregnancy and lactation experienced drooling and poor feeding, several other infants did not experience adverse reactions while breastfeeding. Infants exposed to the drug developed normally. Lacosamide should only be used under close monitoring for somnolence and weight gain during lactation, especially in breastfed newborns or preterm infants, until more data are available.
◉ Effects on Breastfed Infants
One pregnant woman developed sinus thrombosis and two minor intracranial hemorrhages at 8 weeks of gestation, followed by status epilepticus. She received levetiracetam 1000 mg and lacosamide 100 mg twice daily for the remainder of pregnancy and postpartum, while also taking enoxaparin and labetalol. Her baby was delivered at 36 weeks of gestation, and was breastfed approximately 50% of the time in the first few days after birth. The baby was lethargic and had feeding difficulties, but stopping breastfeeding did not improve the baby's condition. After stopping breastfeeding 15 days postpartum, the baby's condition gradually improved. The baby was developing normally at 7 months of age. Lacosamide and levetiracetam may have been the cause of the baby's lethargy and feeding difficulties. A medical center reported three mothers with epilepsy who took lacosamide while breastfeeding. The extent of breastfeeding was not specified, but one mother only partially breastfed her baby. The first mother took 2000 mg of levetiracetam daily and 200 mg of lacosamide twice daily, breastfeeding her baby for 7 months. The baby was 24 months old without any adverse reactions. The second mother took 300 mg of lacosamide daily, partially breastfeeding her baby for 8 months. The baby's developmental milestones at 6, 12, and 18 months of age were all normal. A third mother took 400 mg of lacosamide daily and breastfed for 9 months. Her infant, at 36 months, showed no feeding or alertness problems, cognitive changes, or developmental delays.
One woman took lacosamide and levetiracetam throughout her pregnancy and while exclusively breastfeeding. Despite relatively high drug levels in breast milk, the infant reported reaching all developmental milestones at 6 months postpartum without any health problems.
One mother took brivaracetam, lacosamide, and perampanel, exclusively breastfed her infant for 6 weeks, then switched to partial breastfeeding. The infant did not experience reduced arousal or feeding difficulties. The mother reported normal development at one year of age.
One mother took 200 mg of lacosamide daily during pregnancy and postpartum. During a 9-month follow-up period, her exclusively breastfed infant did not experience any drug-related adverse events.
A center reported three women who took lacosamide during pregnancy and lactation. One woman took 200 mg of lacosamide twice daily and breastfed for 12 months. The infant showed no health problems or developmental delays at 12 months. Another woman took 150 mg of lacosamide twice daily and breastfed for 6 months. The child's developmental milestones were normal at 12 months, and no health problems were observed. A third woman breastfed for 7 months while taking 200 mg/day twice daily. The child showed no health problems or developmental delays at four years of age.
◉ Effects on breastfeeding and lactation
As of the revision date, no relevant published information was found.

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Protein binding
Lacosamide binds to plasma proteins at less than 15%.

Pharmacodynamics
Lacosamide is an oral, highly potent, stereoselective antiepileptic drug with anticonvulsant activity. It exhibits analgesic activity by blocking voltage-gated sodium channels in sensory neurons that mediate neuropathic pain responses. Lacosamide is a chiral functionalized amino acid. Its S-stereoisomer does not possess 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.)