Pharmacokinetics Of Lacosamide Research Articles

Characterization of lacosamide pharmacokinetics in older adults with epilepsy (P4-1.007)

<h3>Objective:</h3> This study aimed to characterize the relationship between lacosamide pharmacokinetics and renal function in older adults with epilepsy. <h3>Background:</h3> Lacosamide is an anti-seizure medication (ASM) indicated for focal-onset seizures which is primarily excreted through the renal route. Changes in clearance with increased age could lead to pharmacokinetic changes in medications that are eliminated via the kidney; therefore, older adults, being more sensitive to these changes may need lower doses than younger adults. <h3>Design/Methods:</h3> Data on patients diagnosed with epilepsy according to ICD10 codes and having at least one steady-state lacosamide concentration measurement between January 2015 and July 2020 met inclusion. A linear mixed model was developed to characterize differences in lacosamide dose normalized concentrations (DNCs = blood concentration/total daily dose) with respect to creatinine clearance (CLCR). CLCR was calculated using the Cockcroft-Gault equation as indicated for lacosamide dosing (package insert), thus incorporating the effect of patient age and sex. The model was controlled for covariates including ethnicity, route of administration (oral/intravenous), aspartate aminotransferase concentration, alanine aminotransferase concentration, regime (monotherapy/polytherapy), presence of CYP450 inducers &amp; inhibitors, and critically ill status as signified by prescription. Model significance was set to α≤0.05 (R software (version 4.1.2)). <h3>Results:</h3> 2291 lacosamide DNCs from 676 patients were included. The median[range] dose and DNC were 300 mg [50–1000 mg] and 23(ug/L)/mg [1–480(ug/L)/mg], respectively. For a given subject the mean DNC of lacosamide decreased by 6% (95% confidence interval: 3.5–8.9%, p&lt;0.01) per unit increase in the CLCR. Route of administration (p=0.01) and presence of a CYP450 inducer (p&lt;0.01) showed a statistically significant effect on DNCs. <h3>Conclusions:</h3> Creatinine clearance was a significant predictor of lacosamide DNCs in older patients with epilepsy. Thus, as CLCR changes are more pronounced as one ages, modification in dosing regimens may be required to maintain lacosamide concentrations in the tolerable and effective range. <b>Disclosure:</b> Miss Avachat has nothing to disclose. The institution of Dr. Reeder has received research support from American Epilepsy Society . Mr. Long has received personal compensation for serving as an employee of PharmaVelox. Dr. Leppik has nothing to disclose. The institution of Dr. Patel has received research support from Ucb. The institution of Dr. Birnbaum has received research support from National Institutes of Health. Dr. Birnbaum has received intellectual property interests from a discovery or technology relating to health care.

Effects of CYP2C19 genetic polymorphisms on the pharmacokinetics of lacosamide in Korean patients with epilepsy.

Many pharmacokinetic studies of lacosamide (LCM) have been reported, but no large-scale clinical study has been conducted on genetic polymorphisms that affect the metabolism of LCM. Therefore, we designed a pharmacogenetic study of LCM to explore the effect of genetic polymorphisms on serum LCM concentration. We evaluated the pharmacodynamic characteristics of LCM, including clinical efficacy and toxicity. Adult patients with epilepsy who received LCM at Seoul National University Hospital were enrolled. Blood samples were obtained from 115 patients taking LCM for more than 1 month with unchanged doses and were used to analyze the serum LCM concentration, the concentration/dose (C/D) ratio and the single nucleotide polymorphisms (SNPs) of the cytochrome P450 (CYP)2C9 and CYP2C19 genes. In addition, clinical information-including efficacy, toxicity, and concomitant drugs-was collected. The serum LCM concentration showed a linear correlation with the daily dose (r=.66, p < .001). In genetic analysis, 43 patients (38.7%) were extensive metabolizers (EMs), 51 (45.9%) were intermediate metabolizers (IMs), and 17 (15.3%) were poor metabolizers (PMs). In the group comparison, mean serum concentrations and the C/D ratio showed significant differences between the three groups (p=.01 and p < .001, respectively). The C/D ratios of IM (27.78) and PM (35.6) were 13% and 39% higher than those of EM (25.58), respectively. In the pharmacodynamic subgroup analysis, patients in the ineffective LCM group had significantly lower serum concentrations (6.39 ± 3.25 vs. 8.44 ± 3.68 μg/ml, p=.024), whereas patients with adverse events had higher serum concentrations than those without adverse events (11.03 ± 4.32 vs. 7.4 ± 3.1μg/ml, p < .001). Based on this, we suggest a reference range for LCM in the Korean population (6-9μg/ml). Genetic polymorphisms of the CYP2C19 gene affect the serum LCM concentration. Because efficacy and toxicity are apparently related to serum LCM levels, the genetic phenotype of CYP2C19 should be considered when prescribing LCM for patients with epilepsy.

A prospective, real‐world, clinical pharmacokinetic study to inform lacosamide dosing in critically ill patients undergoing continuous venovenous haemofiltration (PADRE‐02)

Although the use of continuous renal replacement therapy (CRRT) has increased, limited dosing information exists on the effect of CRRT on antiepileptic drug pharmacokinetics. The objectives of this practice-based study are to evaluate the pharmacokinetics of lacosamide and recommend individualized dosing recommendations in critically ill patients receiving continuous venovenous haemofiltration (CVVH). Seven patients receiving lacosamide and CVVH in a neurocritical care unit were enrolled. Pre-filter, post-filter and ultrafiltrate samples were obtained at baseline, right after the completion of the infusion, and up to six additional sampling time points post-administration. Patient-specific flow rates and clinical measures were also collected simultaneously at the time of sampling. Plasma concentrations were measured using a validated high-performance liquid chromatography with ultraviolet radiation detection (HPLC-UV) bioanalytical method. Non-compartmental analysis was utilized to characterize the pharmacokinetics of lacosamide. The observed mean sieving coefficient for lacosamide was 0.80 ± 0.10, suggesting high removal of lacosamide. Concentrations measured in six out of seven patients were observed to be outside the therapeutic range (5-12 mg/L). The estimated average volume of distribution was found to be similar to healthy patients (0.58 L/kg). The mean bias and precision of the estimated total clearance was -2.53% and 14.9%, respectively. Simulations of various doses suggest that effluent flow rate-based dosing regimens could be used to individualize lacosamide therapeutics. CVVH clearance contributed a major fraction of the total lacosamide clearance in neurocritically ill patients. Given that drug clearance increases with higher effluent flow rates, lacosamide dosing regimens should be increased to match exposures observed in patients with normal renal function.

Change in the pharmacokinetics of lacosamide before, during, and after pregnancy

Patients with epilepsy require long-term treatment with antiepileptic drugs (AEDs), and in female patients the management of epilepsy before, during, and after pregnancy is critical. Pregnancy is associated with pharmacokinetic changes, including increased volume of distribution, elevated renal clearance, and induction of drug-metabolizing enzymes (cytochrome p450 [CYP] family and uridine diphosphate glucuronosyltransferase [UGTs]). For example, the concentrations of lamotrigine, which is metabolized in the liver by UGTs, and levetiracetam, which is primarily eliminated by renal excretion, can decrease by 40% to 80% during pregnancy.

Is Therapeutic Drug Monitoring of Lacosamide Needed in Patients with Seizures and Epilepsy?

Lacosamide is an antiepileptic drug (AED) that has linear pharmacokinetics, predictable blood concentrations, and few drug interactions, setting it apart from other AEDs that require vigorous therapeutic drug monitoring (TDM) such as phenytoin and carbamazepine. However, there have been reports of altered lacosamide pharmacokinetics in some populations. The purpose of this review is to determine whether lacosamide pharmacokinetics are altered in certain patient populations, suggesting the need for TDM. A literature search of Medline, Scopus, Embase, and Cochrane trials was conducted on January 3, 2019 (and then updated on September 2, 2019) to search for articles relevant to the TDM or pharmacokinetics of lacosamide. A total of 56 relevant articles were found and included in this review. Dose of lacosamide is linearly correlated with plasma concentrations and efficacy. However, currentlythere is no well-established reference range. Overall, the recommended reference ranges varied from 2.2 to 20mg/L. Lacosamide has very few clinically relevant drug-drug interactions; however, there seems to be a significant drug interaction between lacosamide and enzyme-inducer AEDs. Based on available literature, it appears that lacosamide pharmacokinetics may be altered in severe renal dysfunction, in patients on dialysisand with extremes of age. More evidence is currently needed on lacosamide pharmacokinetics in pregnancy and critical illness. While it is not practical to utilize TDM for all patients, TDM may be useful in patients taking enzyme-inducer AEDs, in patients with decreased renal function or on dialysis, and older adults.

Effects of lacosamide "a novel antiepileptic drug" in the early stages of chicken embryo development.

Antiepileptic drugs (AEDs) are teratogens and confer a risk of congenital malformation. The estimated prevalence of major congenital malformations such as cardiac defects, facial clefts, hypospadias, and neural tube defects in epileptic women is 4-10%, which represents a two- to fourfold increase in pregnant women compared to the general population. However, there are no clear data for newer drugs. Lacosamide (LCM), a novel AED, is the first of the third-generation AEDs to be approved as adjunctive therapy for the treatment of partial-onset seizures. There are no data on the pharmacokinetics of LCM during pregnancy, and only some published data have reported on its effects during pregnancy. In this study, three different doses of LCM (0.12, 0.5, and 1.60mg in 0.18mL) were applied under the embryonic disks of specific pathogen-free Leghorn chicken embryos after a 30-h incubation. Incubation was continued for 80h, at which time all embryos were evaluated macroscopically and microscopically. There was growth retardation in all of the LCM-treated groups. Major malformations increased in a dose-dependent manner and were mostly observed in the supratherapeutic group. Based on our data, LCM may cause growth retardation or major congenital malformations. Nevertheless, more extensive investigations of its reliability are needed.

Effect of Age and Sex on Lacosamide Pharmacokinetics in Healthy Adult Subjects and Adults with Focal Epilepsy

Age- and sex-related differences in body composition could affect the pharmacokinetic parameters of administered drugs. The purpose of this post hoc analysis was to investigate the influences of age and sex on the pharmacokinetics of lacosamide. This post hoc analysis used pharmacokinetic data taken at steady state from (i) two phase I studies of oral lacosamide in healthy adult subjects (n = 66), and (ii) a population pharmacokinetic analysis carried out using data from two phase III studies of adjunctive oral lacosamide in adults (n = 565) with focal epilepsy taking 1-3 concomitant anti-epileptic drugs. Phase I data were stratified by age and sex as 'younger female' (aged 18-40 years), 'younger male' (aged 18-45 years) or 'elderly male/female' (aged ≥65 years), then normalized by body weight (lean body weight or fat-free mass), height or volume of distribution, and analysed using non-compartmental analysis. Population pharmacokinetic data were stratified by sex and analysed using a one-compartment model. Minor numerical differences between lacosamide exposure [the area under the concentration-time curve at steady state over the dosage interval (AUCτ,ss)] and the maximum plasma concentration at steady state (C max,ss) in subjects of different ages or sexes were noted. The differences could be explained by a scaling factor between the drug applied and the plasma concentration. Following normalization by lean body weight or volume of distribution, an analysis of relative bioavailability resulted in 90 % confidence intervals of the ratios for AUCτ,ss and C max,ss for age (elderly to younger) or sex (male to female) falling within the range accepted for equivalence (80-125 %); without normalization, the 90 % confidence intervals were outside this range. Minor numerical differences in lacosamide plasma concentrations were noted in the comparison between male and female patients (aged 16-71 years) with focal epilepsy. Simulations using different body weights demonstrated a minimal effect of body weight on lacosamide plasma concentrations in adult patients with focal epilepsy. Age and sex had no relevant effects on the rates of absorption and elimination of lacosamide in this post hoc analysis, as the minor numerical differences could be explained by the main scaling factor for body weight or volume of distribution. The pharmacokinetic profile of lacosamide was unaffected by age or sex in adults with focal epilepsy.

Lacosamide Serum Concentrations in Adult Patients With Epilepsy

Lacosamide (LCM), a new antiepileptic drug (AED) approved as adjunctive therapy for the treatment of patients with partial-onset seizures, has limited pharmacokinetic and drug interaction data. The main objectives of the present study were to investigate the effects of dose, age, gender, and hepatic enzyme-inducing AEDs on the pharmacokinetics of LCM as assessed by steady state serum LCM values. An LCM AED therapeutic drug monitoring database was analyzed with regard to LCM serum concentrations and other relevant patient and AED drug information. One hundred twenty eight sera were identified. These were collected from 68 women and 61 men aged 19-66 years, who were prescribed a median LCM dose of 300 mg (range 50-600 mg). Serum LCM concentrations were observed in the following main groupings: LCM monotherapy (n = 5), LCM with nonenzyme-inducing AEDs (n = 50), LCM with enzyme-inducing AEDs (n = 49), LCM with valproic acid (n = 20), and LCM with enzyme-inducing AEDs plus valproic acid (n = 4). Analysis of variance showed a correlation of dose with LCM concentrations (r = 0.53, P < 0.001), and women had statistically higher mean LCM concentration than did men, 37.2 ± 23.6 versus 26.8 ± 12.9 μmol/L (P = 0.001). Serum LCM concentrations were significantly lower (P = 0.002) in the enzyme-inducing AED group (carbamazepine and phenytoin) compared with the LCM monotherapy group and the nonenzyme-inducing group, 23.5 ± 11.0, 34.5 ± 7.7, and 32.7 ± 17.9 μmol/L, respectively. Serum LCM concentrations increased dose dependently, were age independent, and were higher in women compared with men. Carbamazepine and phenytoin can significantly decrease serum LCM concentrations, probably via induction of LCM metabolism.

Pharmacokinetics of Lacosamide and Omeprazole Coadministration in Healthy Volunteers: Results from a Phase I, Randomized, Crossover Trial

The antiepileptic drug lacosamide has a low potential for drug-drug interactions, but is a substrate and moderate inhibitor of the cytochrome P450 (CYP) enzyme CYP2C19. This phase I, randomized, open-label, two-way crossover trial evaluated the pharmacokinetic effects of lacosamide and omeprazole coadministration. Healthy, White, male volunteers (n = 36) who were not poor metabolizers of CYP2C19 were randomized to treatment A (single-dose 40 mg omeprazole on days 1 and 8 together with 6 days of multiple-dose lacosamide [200-600 mg/day] on days 3-8) and treatment B (single doses of 300 mg lacosamide on days 1 and 8 with 7 days of 40 mg/day omeprazole on days 3-9) in pseudorandom order, separated by a ≥ 7-day washout period. Area under the concentration-time curve (AUC) and peak concentration (C(max)) were the primary pharmacokinetic parameters measured for lacosamide or omeprazole administered alone (reference) or in combination (test). Bioequivalence was determined if the 90 % confidence interval (CI) of the ratio (test/reference) fell within the acceptance range of 0.8-1.25. The point estimates (90 % CI) of the ratio of omeprazole + lacosamide coadministered versus omeprazole alone for AUC (1.098 [0.996-1.209]) and C(max) (1.105 [0.979-1.247]) fell within the acceptance range for bioequivalence. The point estimates (90 % CI) of the ratio of lacosamide + omeprazole coadministration versus lacosamide alone also fell within the acceptance range for bioequivalence (AUC 1.133 [1.102-1.165]); C(max) 0.996 (0.947-1.047). Steady-state lacosamide did not influence omeprazole single-dose pharmacokinetics, and multiple-dose omeprazole did not influence lacosamide single-dose pharmacokinetics.

Lacosamide Therapeutic Monitoring in Patients With Epilepsy

Lacosamide (LCM) is one of the newer antiepileptic drugs (AEDs) licensed as add-on treatment for partial epilepsy. Data on LCM pharmacokinetics and interactions are limited and partly contradictory. The purpose of this study was to assess the effect of concomitant AED therapy on steady state plasma concentrations of LCM in a population of patients with epilepsy. Steady state plasma concentrations of LCM were assessed in a cohort of 75 consecutive patients with epilepsy referred to the Laboratory of Clinical Neuropharmacology for AED therapeutic monitoring over 16 months. Plasma LCM concentrations were measured by high-performance liquid chromatography with spectrophotometric detection. Median morning trough plasma concentration-to-weight-adjusted dose ratio of LCM [(mg/L)/(mg/kg/d)] was significantly reduced (0.94 versus 1.35, P < 0.001) in patients treated with LCM plus AED strong inducers of cytochrome P450 metabolism, namely, carbamazepine, phenobarbital, and phenytoin (group A, n = 33), compared with a pool of patients not comedicated with AED strong inducers, predominantly including oxcarbazepine, levetiracetam, lamotrigine, and valproic acid (group B, n = 42). The 2 groups were comparable for age, gender, weight, LCM daily dose, and dosing frequency. LCM plasma concentrations were linearly related to daily drug doses, regardless of concomitant AED therapy, over a dose range from 75 to 600 mg/d, although, at a given drug dose, a large interpatient variability was observed in matched, plasma drug concentration. Our findings confirm, in a real-patient clinical setting, preliminary evidence from randomized, clinical trials showing that carbamazepine, phenobarbital, or phenytoin significantly reduces the overall systemic exposure to LCM. From a practical point of view, patients on concomitant AED strong inducers may require a 30% higher dose of LCM compared with patients not receiving strongly inducing AED cotherapy, to achieve the same plasma drug concentration.

Pharmacodynamic and pharmacokinetic evaluation of coadministration of lacosamide and an oral contraceptive (levonorgestrel plus ethinylestradiol) in healthy female volunteers

To determine whether the antiepileptic drug lacosamide affects the pharmacokinetics or pharmacodynamics of a combined oral contraceptive (OC; ethinylestradiol 0.03mg plus levonorgestrel 0.15mg). This was an open-label trial in healthy female volunteers. Eligible women entered cycle 1 of the trial on the first day of menstruation. Cycle 1 was a medication-free, run-in phase of approximately 28days to confirm that normal ovulation occurred. Volunteers with confirmed ovulation entered the subsequent cycle and started taking OCs. After establishing ovulation suppression (defined as progesterone serum concentration <5.1nm on day 21 of the menstrual cycle) in volunteers taking the OCs in cycle 2, lacosamide 400mg/day was administered concomitantly in the subsequent cycle (cycle 3). The pharmacokinetic parameters of area under the concentration-time curve (AUC), maximum steady-state plasma drug concentration (Cmax ), and time to maximum concentration (tmax ) were measured for the OC components and lacosamide. A total of 37 volunteers completed cycle 1, and 32 completed cycle 2. In each of the 31 volunteers who completed the trial (through cycle 3), pharmacodynamic assessment showed progesterone serum concentration was <5.1nm on day 21 of cycle 2, when the OC was administered alone, and on day 21 of cycle 3, when lacosamide was administered concomitantly. The AUC of ethinylestradiol alone versus together with lacosamide was 1,067±404 versus 1,173±330pgh/ml. Corresponding values of Cmax were 116.9±48.8 versus 135.7±28.6pg/ml. For levonorgestrel, the AUC alone was 74.2±21.4 versus 80.9±18.5ngh/ml with lacosamide. Corresponding values of Cmax were 6.7±1.9 versus 7.4±1.5ng/ml. The AUC and Cmax point estimates and almost all 90% confidence intervals (except for Cmax of ethinylestradiol) for ethinylestradiol and levonorgestrel (with and without lacosamide) were within the conventional bioequivalence range, and no relevant changes in tmax were observed for ethinylestradiol (1.5±0.6h alone vs. 1.4±0.7h with lacosamide) or for levonorgestrel (1.5±1.0h alone vs. 1.1±0.6h with lacosamide). Lacosamide pharmacokinetics were consistent with those observed in previous studies of lacosamide alone, with values for AUC of 113.5±20.7μgh/ml, Cmax of 13.8±2.2μg/ml, and tmax of 1.1±0.4h. Lacosamide and an OC containing ethinylestradiol and levonorgestrel have low potential for drug-drug interaction; therefore, coadministration of the two drugs is unlikely to result in contraceptive failure or loss of seizure control.

No Pharmacokinetic Interaction Between Lacosamide and Valproic Acid in Healthy Volunteers

Two open-label, randomized, multiple-dose clinical studies evaluated the potential for pharmacokinetic interaction between the antiepileptic drugs lacosamide and valproic acid. The influence of lacosamide on valproic acid pharmacokinetics (trial A) and valproic acid on lacosamide pharmacokinetics (trial B) was investigated in 32 healthy male volunteers, 16 in each trial. Volunteers in trial A received valproic acid (300 mg bid) with randomization to either early or late addition of lacosamide (200 mg bid). Those in trial B received lacosamide (200 mg bid) with randomization to either early or late addition of valproic acid (300 mg bid). Area under the concentration-time curve during a 12-hour dosing interval at steady state (AUC(τ,ss)) and maximum steady-state plasma drug concentration (C(max,ss)) were measured for each drug alone and together and tested for equivalence. The point estimates (90% confidence intervals) for AUC(τ,ss) and C(max,ss) were 104% (99%-109%) and 101% (97%-107%), respectively, for valproic acid and 100% (98%-103%) and 101% (96%-107%), respectively, for lacosamide, which were within the generally accepted equivalence range of 80% to 125%. No changes in the rate or extent of absorption, terminal half-life, or time to maximum concentration were observed. These results suggest that lacosamide and valproic acid have no relevant pharmacokinetic drug-drug interaction.

Lacosamide in patients with pharmacoresistant epilepsy

Introduction: Lacosamide is a novel antiepileptic drug licensed in the US and Europe as adjunctive therapy for partial-onset seizures in adults. The efficacy, safety, tolerability and favorable pharmacokinetic profile in the adult population suggest that lacosamide could be of benefit for patients with partial-onset seizures.Areas covered: This paper reviews the available evidence and most recent data concerning the efficacy, safety, tolerability and pharmacokinetics of lacosamide in adults, as well as in the pediatric population.Expert opinion: Lacosamide is one of the newest drugs of the antiepileptic armamentarium, and it is expected to compete directly with compounds that are currently used for adjunctive therapy in adults with refractory partial epilepsy. The intravenous formulation may be used for replacement therapy in patients temporarily unable to take oral medication. An apparent lack of sedative or cognitive effects might render this drug preferable in patients with mental insufficiency and/or epileptic encephalopathy.

Pharmacokinetics of Lacosamide in Healthy Korean Male Volunteers

Aim: The aim of this study was to evaluate the pharmacokinetics (PK) of single and repeated doses of lacosamide in healthy male Korean volunteers and to compare the PK profile of lacosamide in Korean and Caucasian populations. Methods: In a double-blind, placebo-controlled, parallel-group, dose-escalation trial, 16 volunteers received a single dose (50 mg) of lacosamide or placebo, and 32 volunteers were administered single/repeated twice-daily doses (100 or 200 mg) of lacosamide or placebo. Results: For multiple doses of 100 and 200 mg twice daily, the geometric means C_max,ss were 6.23 (15.0) and 13.13 (8.9) µg/ml respectively, and AUC_τ_,s_s values were 52.10 (17.0) and 112.35 (13.0) µg·h/ml, respectively. Values for both parameters were relatively higher than those seen in Caucasians. To further describe ethnic differences, population PK analysis was assessed. A one-compartment model with first-order absorption and elimination was selected and effects of CL_creatinine on CL/F and body surface area on V/F were included in the final model. Conclusion: There were no other ethnic differences in the PK profile of lacosamide between Koreans and Caucasians based on the population PK analysis, except for the demographic differences.

Pharmacokinetics, brain distribution, and plasma protein binding of the antiepileptic drug lacosamide in rats

The study aimed to characterize the pharmacokinetics of lacosamide, a new antiepileptic drug, in rats after intravenous and oral administration at doses of 1, 3, 10, and 30 mg/kg. Moreover, brain distribution and plasma protein binding were estimated. After intravenous injection, terminal half-life, systemic clearance, and steady state volumes of distribution remained unaltered as a function of dose with values in the range 3.01-3.53 h, 221-241 mL/h/kg and 702-732 mL/kg, respectively. Following oral administration, absolute oral bioavailability was not dose dependent and was at 93.3-106%. However, the time to peak concentration and the dose-normalized peak concentration for 30 mg/kg were significantly different with those for other doses. The extent of urinary excretion of lacosamide was 17.1% and 16.5% for intravenous and oral doses, respectively, whereas fecal excretion was negligible. The brain to plasma ratio of lacosamide was consistent regardless of post-dosing time and the brain to plasma partition coefficient was 0.553. Further, the plasma protein binding of lacosamide was concentration independent with free fraction at 95.9%. Lacosamide showed linear pharmacokinetics at an intravenous dose of 1-30 mg/kg and an oral dose of 1-10 mg/kg but non-linear pharmacokinetics at a 30 mg/kg oral dose.

High‐performance liquid chromatographic analysis of lacosamide in canine serum using ultraviolet detection: application to pre‐clinical pharmacokinetics in dogs

A method for analysis of lacosamide [(R)-2-acetamido-N-benzyl-3-methoxypropionamide] is needed for both human and veterinary pharmacokinetic investigations. While lacosamide is currently used to manage partial-onset seizures in humans suffering from epilepsy, it is also presently being investigated for use in the treatment of canine epilepsy in veterinary medicine. Currently, no dosing regimen for the drug exists in dogs. A novel and simple high-performance liquid chromatography method was developed for determination of lacosamide in dog serum. Serum proteins (0.1 mL) were precipitated with -20.0°C acetonitrile after addition of the internal standard, daidzein. Separation was achieved with a Phenomenex® Luna® C₁₈ (2) (5 µm, 250 × 4.60 mm) column with ultraviolet detection at 210 nm. The calibration curves were linear ranging from 0.5 to 25 µg/mL. Precision of the assay was <13% (RSD) and was within 12% for all points in the calibration curve. The limit of quantitation for this method was 0.5 µg/mL. The assay was applied successfully to a pre-clinical study of lacosamide pharmacokinetics in dogs.

No Pharmacokinetic Interaction Between Lacosamide and Carbamazepine in Healthy Volunteers

Lacosamide is a new antiepileptic drug for adjunctive treatment of adult partial-onset seizures. Two open-label, multiple-dose clinical trials were conducted to evaluate the potential for pharmacokinetic interaction between lacosamide and carbamazepine. The influence of carbamazepine on lacosamide pharmacokinetics (trial A) and lacosamide on carbamazepine pharmacokinetics (trial B) was investigated in 19 (trial A) and 18 (trial B) healthy male participants. Trial A participants received lacosamide 200 mg bid alone and with carbamazepine 200 mg bid. Trial B participants received carbamazepine 200 mg bid alone and with lacosamide 200 mg bid. Pharmacokinetic parameters, area under the concentration-time curve during a dosage interval at steady state (AUC(tau,ss)), and maximum steady-state plasma drug concentration during a dosage interval (C(max,ss)) of lacosamide, carbamazepine, and carbamazepine-10,11-epoxide were measured and compared for each drug alone and together. The AUC(tau,ss) and C(max,ss) point estimates (combined vs sole treatment) showed relative bioavailability of approximately 100% for both drugs. All 90% confidence intervals of AUC(tau,ss) and C(max,ss) were within the generally accepted bioequivalence ranges of 80% to 125%. No changes in rate or extent of absorption or terminal half-life were observed. These results suggest that lacosamide and carbamazepine have a low potential for pharmacokinetic drug-drug interaction in clinical use.