Changes in Perampanel Pharmacokinetics and Cytochrome P450 3A4 Activity Before, During, and After Pregnancy.

ABSTRACT: This study evaluated perampanel pharmacokinetics and cytochrome P450 3A4 (CYP3A4) activity, assessed using the level of 4ß-hydroxycholesterol (4ß-OHC) as an endogenous biomarker of CYP3A4, before, during, and after pregnancy in a woman with epilepsy and compared these measurements with those from a control group of nonpregnant women with epilepsy. A 21-year-old pregnant woman was being treated with perampanel (serum concentration: 1120 ng/mL), lacosamide, and lamotrigine. After the first trimester, the lamotrigine concentration decreased markedly; however, the perampanel concentration remained almost unchanged (range, 1130-1320 ng/mL). Similarly, serum 4ß-OHC levels did not change during pregnancy (before pregnancy, 78.2 ng/mL; during pregnancy, 62.2-83.2 ng/mL). To compare these measurements with those in nonpregnant women, we enrolled 27 nonpregnant women with epilepsy (age range, 16-40 years). In the control patients, we found a strong negative correlation between the concentration-to-dose ratio of perampanel and the 4ß-OHC level ( r = -0.78, P < 0.001). As there was no significant change in CYP3A4 activity, we concluded that the serum perampanel concentration did not change significantly before, during, or after pregnancy. More patients need to be studied to confirm these early results.

Lacosamide extended-release capsules are bioequivalent to lacosamide immediate-release tablets: Pharmacokinetic observations and simulations.

OBJECTIVES: Assess the bioequivalence of lacosamide extended-release (XR) capsules and immediate-release (IR) tablets and answer real-world clinical questions regarding the use of lacosamide XR. METHODS: An open-label, randomized, two-treatment, two-sequence, oral comparative bioavailability study was conducted to assess the bioequivalence of two lacosamide formulations. Participants were randomized 1:1 to receive lacosamide XR capsules (400 mg once-daily) or IR tablets (200 mg twice-daily) in 1 of 2 sequences over 7-day periods. Primary outcome was the area under the lacosamide concentration-time curve over 24 h at steady-state (AUC0-τ,ss). Secondary outcomes were maximum (Cmax,ss) and minimum concentrations at steady-state (Cmin,ss). Bioequivalence was established when 90% confidence intervals (CIs) for geometric least square means ratios (GLSMs) were between 80% and 125%. Adverse events (AEs) and other safety outcomes were also assessed. Pharmacokinetic simulations, including adherent and partially adherent dosing scenarios with XR and IR formulations, modeled the clinical use of lacosamide XR. RESULTS: Thirty-five healthy adult males were enrolled in the bioequivalence study. After 7 days of study drug, mean AUC0-τ,ss, Cmax,ss, and Cmin,ss values were similar between XR and IR formulations; all 90% CIs for GLSMs were between 80% and 125%. AEs were mild and no serious AEs or other clinically significant safety findings were observed. Pharmacokinetic simulations suggested that partial adherence affected formulations similarly; and the best strategy for switching formulations was to take the morning lacosamide IR dose followed by the evening lacosamide XR dose, as this resulted in the most consistent lacosamide plasma concentrations. CONCLUSIONS: Once-daily lacosamide XR capsules were bioequivalent to twice-daily lacosamide IR tablets. Pharmacokinetic simulations indicated lacosamide XR and IR formulations were similarly affected by partial adherence, though once-daily dosing with lacosamide XR may offer clinical advantages, and formulations can be easily switched. These results support the use of lacosamide XR capsules as a once-daily alternative to lacosamide IR tablets.

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

OBJECTIVE: 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. METHODS: 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. RESULTS: 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 ± 3.1 µg/ml, p < .001). Based on this, we suggest a reference range for LCM in the Korean population (6-9 µg/ml). SIGNIFICANCE: 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.

Lacosamide induced Brugada I morphology in the setting of septicemia: A case report.

INTRODUCTION: Brugada syndrome may be unmasked by non-antiarrhythmic pharmaceuticals or drugs. Lacosamide is an antiepileptic agent with a novel mechanism of sodium channel inhibition and has the potential to cause cardiac sodium channel blockade. PATIENT CONCERNS: In this report, we describe the case of patient with a history of a seizure disorder who presented with Brugada I electrocardiogram morphology in the setting of septicemia. DIAGNOSIS: Brugada I electrocardiogram morphology was unmasked by lacosamide antiepileptic monotherapy. INTERVENTIONS: Lacosamide therapy was discontinued. OUTCOMES: Normalization of the electrocardiogram and resolution of Brugada morphology occurred on hospital day 1. CONCLUSION: Caution should be exercised in the use of lacosamide in those at risk for conduction delay, or in combination therapy with medications that impair renal clearance, metabolism of lacosamide, or that display inherent sodium channel blocking properties.

Therapeutic Drug Monitoring of Lamotrigine, Lacosamide, and Levetiracetam in Dried Capillary Blood-Determination of Conversion Factors for Serum-Based Reference Ranges.

BACKGROUND: Drug concentrations of antiepileptic drugs (AEDs) are routinely determined from blood serum or plasma at trough levels (before intake of morning dose). In capillary blood collection, blood is taken from the fingertip with the aid of a disposable tool and dried on absorbent material. The volumetric absorptive microsampling technique offers several advantages over the use of filter paper cards. The aim of this study was to determine conversion factors for the estimation of AED serum concentrations from capillary blood concentrations. METHODS: Venous and capillary blood samples were collected from adult inpatients with epilepsy who were treated with lacosamide (LCM, n = 30), lamotrigine (LTG, n = 40), and/or levetiracetam (LEV, n = 36). A validated liquid chromatography-mass spectrometry (LC-MS) method for dried blood samples for these AEDs was compared with routine serum laboratory methods. Method agreement was evaluated using different regression techniques, and the conversion factors were calculated. RESULTS: Regression analyses revealed a linear relationship between serum and capillary blood concentrations for all 3 AEDs (r ≥ 0.95). For LTG, the regression intercept was significantly different from 0, indicating that the relationship was linear, but not necessarily proportional. Although LEV and LCM concentrations tended to be lower in capillary blood than in serum (mean ratio of serum concentration to capillary blood concentration: 1.14 and 1.22, respectively), LTG concentrations were higher in capillary blood (mean ratio = 0.85). CONCLUSIONS: The estimation of serum concentrations from measured capillary blood concentrations is feasible for LCM, LTG, and LEV. A simple ratio approach using the mean ratio and Passing-Bablok regression showed the best results for all 3 AEDs. The volumetric absorptive microsampling technique facilitates the quantitative sample collection of capillary blood and overcomes the drawbacks associated with the classical dried blood spot technique.

Pharmacology of lacosamide: From its molecular mechanisms and pharmacokinetics to future therapeutic applications.

Epilepsy is one of the most common brain disorders, affecting more than 50 million people worldwide. Although its treatment is currently symptomatic, the last generation of anti-seizure drugs is characterized by better pharmacokinetic profiles, efficacy, tolerability and safety. Lacosamide is a third-generation anti-seizure drug that stands out due to its good efficacy and safety profile. It is used with effectiveness in the treatment of partial-onset seizures with or without secondary generalization, primary generalized tonic-clonic seizures and off-label in status epilepticus. Despite scarcely performed until today, therapeutic drug monitoring of lacosamide is proving to be advantageous by allowing the control of inter and intra-individual variability and promoting a successful personalized therapy, particularly in special populations. Herein, the pharmacology, pharmacokinetics, and clinical data of lacosamide were reviewed, giving special emphasis to the latest molecular investigations underlying its mechanism of action and therapeutic applications in pathologies besides epilepsy. In addition, the pharmacokinetic characteristics of lacosamide were updated, as well as current literature concerning the high pharmacokinetic variability observed in special patient populations and that must be considered during treatment individualization.

Use of Real-World Data and Pharmacometric Modeling in Support of Lacosamide Dosing in Pediatric Patients Under 4 Years of Age.

The antiepileptic drug lacosamide (LCM) is approved in the United States and the European Union as monotherapy as well as adjunctive therapy for the treatment of focal seizures in children ≥4 years of age and adults. Using real-world therapeutic drug monitoring data, we performed a pharmacometric analysis for 315 pediatric patients (>1 month to <18 years of age) who received lacosamide as both monotherapy and adjunctive therapy. Population pharmacokinetic modeling was performed using nonlinear mixed-effects modeling with a 1-compartment structural model with linear elimination, where clearance and volume of distribution were allometrically scaled for body weight, with no further need for age-associated maturation functions. A covariate analysis for age, sex, race, and coadministration of other antiepileptic drugs identified phenobarbital and felbamate to significantly increase lacosamide clearance (1.71- and 1.46-fold, respectively). Based on the developed population pharmacokinetic model, simulations were performed in virtual pediatric patients to explore age-associated dose requirements to match lacosamide exposure in patient groups of different age with the exposure achieved in children ≥4 year of age with the weight-based dosing recommendations provided by the US Food and Drug Administration. Based on this approach, our analysis suggested that children ≥3 years of age needed the same dose as recommended by the US Food and Drug Administration for children ≥4 years of age (12 mg/kg/d), while children 1 to 3 years of age may need 13 to 14 mg/kg/d and infants between 1 month and 1 year of age may need 15 to 18 mg/kg/d (based on their actual age) to match the exposure seen in children ≥4 years of age.

Bioequivalence and switchability of generic antiseizure medications (ASMs): A re-appraisal based on analysis of generic ASM products approved in Europe.

The safety of switching between generic products of antiseizure medications (ASMs) continues to be a hot topic in epilepsy management. The main reason for concern relates to the uncertainty on whether, and when, two generics found to be bioequivalent to the same brand (reference) product are bioequivalent to each other, and the risk of a switch between generics resulting in clinically significant changes in plasma ASM concentrations. This article addresses these concerns by discussing the distinction between bioequivalence and statistical testing for significant difference, the importance of intra-subject variability in interpreting bioequivalence studies, the stricter regulatory bioequivalence requirements applicable to narrow-therapeutic-index (NTI) drugs, and the extent by which currently available generic products of ASMs comply with such criteria. Data for 117 oral generic products of second-generation ASMs approved in Europe by the centralized, mutual recognition or decentralized procedure were analyzed based on a review of publicly accessible regulatory assessment reports. The analysis showed that for 99% of generic products assessed (after exclusion of gabapentin products), the 90% confidence intervals (90% CIs) of geometric mean ratios (test/reference) for AUC (area under the drug concentration vs time curve) were narrow and wholly contained within the acceptance interval (90%-111%) applied to NTI drugs. Intra-subject variability for AUC was <10% for 53 (88%) of the 60 products for which this measure was reported. Many gabapentin generics showed broader, 90% CIs for bioequivalence estimates, and greater intra-subject variability, compared with generics of other ASMs. When interpreted within the context of other available data, these results suggest that any risk of non-bioequivalence between these individual generic products is small, and that switches across these products are not likely to result in clinically relevant changes in plasma drug exposure. The potential for variability in exposure when switching across generics is likely to be greatest for gabapentin.

Inhibition of neuronal Na+ currents by lacosamide: Differential binding affinity and kinetics to different inactivated states.

Lacosamide is a new-generation anticonvulsant acting on Na+ channels. Compared to the classic anticonvulsants targeting Na+ channels, lacosamide is unique in structure and in its molecular action requiring longer membrane depolarization. Selective binding to the slow inactivated state of Na+ channels was then advocated for lacosamide, although slow binding to the fast inactivated state was alternatively proposed recently. In addition, quantitative characterization of lacosamide action has been deficient. We investigated the interactions between lacosamide and Na+ channels in native mammalian neurons, and found that the apparent dissociation constant (~13.7 µM) of lacosamide to the slow inactivated state is well within the therapeutic concentration range and is much (>15-fold) lower than the dissociation constant of lacosamide to the fast inactivated state. Besides, lacosamide has extremely slow binding rates (<400 M-1sec-1) to the fast but much faster binding rates (>3000 M-1sec-1) to the slow inactivated Na+ channels. Consistent with these biophysical characters, we further demonstrated that lacosamide is much more effective against the repetitive burst discharges with interburst intervals at -60 mV than -80 mV. With preponderant binding to the slow inactivation state in therapeutic concentrations and thus less propensity to affect normal discharges, lacosamide could be a drug of choice for seizure discharges characterized by relatively depolarized interburst intervals, during which more slow inactivated states could be generated and more binding of lacosamide would ensue.

Targeted delivery of lacosamide-conjugated gold nanoparticles into the brain in temporal lobe epilepsy in rats.

Temporal lobe epilepsy (TLE) is the most common form of epilepsy with focal seizures, and currently available drugs may fail to provide a thorough treatment of the patients. The present study demonstrates the utility of glucose-coated gold nanoparticles (GNPs) as selective carriers of an antiepileptic drug, lacosamide (LCM), in developing a strategy to cross the blood-brain barrier to overcome drug resistance. Intravenous administration of LCM-loaded GNPs to epileptic animals yielded significantly higher nanoparticle levels in the hippocampus compared to the nanoparticle administration to intact animals. The amplitude and frequency of EEG-waves in both ictal and interictal stages decreased significantly after LCM-GNP administration to animals with TLE, while a decrease in the number of seizures was also observed though statistically insignificant. In these animals, malondialdehyde was unaffected, and glutathione levels were lower in the hippocampus compared to sham. Ultrastructurally, LCM-GNPs were observed in the brain parenchyma after intravenous injection to animals with TLE. We conclude that glucose-coated GNPs can be efficient in transferring effective doses of LCM into the brain enabling elimination of the need to administer high doses of the drug, and hence, may represent a new approach in the treatment of drug-resistant TLE.

Selective quantification of lacosamide in human plasma using UPLC-MS/MS: Application to pharmacokinetic study in healthy subjects with different doses.

A practical, sensitive, and robust UPLC-MS/MS method was developed and validated to quantify lacosamide in human plasma. A simple one-step protein precipitation was used to extract lacosamide and labeled lacosamide-13C, D3 as an internal standard (IS) from 150-µL plasma. The extracts were analyzed on an Eclipse Plus C18 column (50 × 2.1 mm, 1.8 µm) using 0.1% formic acid in water and methanol:acetonitrile (50:50, v/v) under gradient conditions. The extracts were quantified on LCMS-8040 using electrospray ionization source operated in positive ionization and multiple reaction monitoring modes. The method showed good linearity from 0.02 to 20 µg/mL, which was adequate to cover lacosamide concentration assayed in formulations with different strengths. The bioanalytical assay was fully validated as per current regulatory guidelines. The intra-batch and inter-batch precision values of lacosamide were less than 4.6%. Lacosamide was found to be stable at different storage conditions. The extraction recoveries and IS-normalized matrix factors for lacosamide ranged from 97.17 to 99.68% and from 0.973 to 1.012, respectively. The validated method was successfully applied to a pharmacokinetic study with three lacosamide formulations (50, 100, and 200 mg) in 36 healthy subjects. The assay reliability was determined by reanalysis of 81 subject samples.

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, currently there is no well-established reference range. Overall, the recommended reference ranges varied from 2.2 to 20 mg/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 dialysis and 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.

Dronedarone (a multichannel blocker) enhances the anticonvulsant potency of lamotrigine, but not that of lacosamide, pregabalin and topiramate in the tonic-clonic seizure model in mice.

Accumulating experimental evidence indicates that some recently licensed antiarrhythmic drugs, including dronedarone (a multichannel blocker) play a crucial role in initiation of seizures in both, in vivo and in vitro studies. Some of these antiarrhythmic drugs elevate the threshold for maximal electroconvulsions and enhance the anticonvulsant potency of classical antiepileptic drugs in preclinical studies. This study was aimed at determining the influence of dronedarone (an antiarrhythmic drug) on the anticonvulsant potency of four novel antiepileptic drugs (lacosamide, lamotrigine, pregabalin and topiramate) in the maximal electroshock-induced seizure model in mice. To exclude any potential pharmacokinetic contribution of dronedarone to the observed interactions, total brain concentrations of antiepileptic drugs were measured. Dronedarone (50 mg/kg, i.p.) significantly enhanced the anticonvulsant potency of lamotrigine, by reducing its ED50 value from 7.67 mg/kg to 4.19 mg/kg (P < 0.05), in the maximal electroshock-induced seizure test in mice. On the contrary, dronedarone (50 mg/kg, i.p.) did not affect the anticonvulsant properties of lacosamide, pregabalin or topiramate in the maximal electroshock-induced seizure test in mice. Measurement of total brain concentrations of lamotrigine revealed that dronedarone did not significantly alter total brain concentrations of lamotrigine in experimental animals. Additionally, the combination of dronedarone with pregabalin significantly impaired motor coordination in animals subjected to the chimney test. In contrast, the combinations of other studied antiepileptic drugs with dronedarone had no negative influence on motor coordination in mice. It is advisable to combine dronedarone with lamotrigine to enhance the anticonvulsant potency of the latter drug. The combinations of dronedarone with lacosamide, pregabalin and topiramate resulted in neutral interactions in the maximal electroshock-induced seizure test in mice. However, a special caution is advised to patients receiving both, pregabalin and dronedarone due to some possible adverse effects that might occur with respect to motor coordination.

Highly sensitive UHPLC-DAD method for simultaneous determination of two synergistically acting antiepileptic drugs; levetiracetam and lacosamide: Application to pharmaceutical tablets and human urine.

A simple and highly sensitive ultra-high-performance liquid chromatographic-diode array (UHPLC-DAD) detection method was developed and validated for the simultaneous estimation of levetiracetam (LEV) and lacosamide (LAC). It was clinically proven that the combination of LEV and LAC exhibits a synergistic effect against refractory seizures in mice, which was the motivation for the analysis of this binary mixture both in bulk and in human urine samples. The binary mixture was resolved on a Hypersil BDS C18 analytical column, utilizing a mobile phase of 0.050 mol L-1 phosphate buffer (pH 5.60), methanol and acetonitrile in the ratio (80:10:10 v/v/v) using catechol as an internal standard. The mobile phase was pumped at a flow rate of 1.2 mL min-1 with diode array detection at 205 nm for both drugs and 270 nm for IS. Calibration curves were linear with correlation coefficient >0.9990 over the studied concentration range of 0.1-70.0 µg mL-1 for both drugs. The developed method was reproducible with low relative standard deviation values for intra- and inter-day precision (<2.0%). Both drugs were determined in bulk, pharmaceutical formulations and human urine samples without any interference from complex matrices.

Pharmacokinetic Variability and Clinical Use of Lacosamide in Children and Adolescents in Denmark and Norway.

BACKGROUND: The indication for the antiepileptic drug lacosamide (LCM) was recently extended to include children from the age of 4 years. Real-life data on the use and serum concentrations of LCM in children and adolescents are limited. The purpose of this study was to investigate the use of LCM in this patient group in relation to age, comedication, dose, serum concentrations and duration of treatment, and to examine pharmacokinetic variability. METHODS: Children and adolescents (<18 years) who had serum concentrations of LCM measured from January 2012 to June 2018 were retrospectively identified from the therapeutic drug monitoring databases at 2 national epilepsy centers in Norway and Denmark. Clinical data were collected from request forms and medical records. RESULTS: Data from 124 patients were included, 61 girls/63 boys. Weight was available for 76 patients. Median age was 15 years (range 2-17 years), dose of LCM 300 mg/d (76-600 mg/d), and serum concentration 18 µmol/L (5-138 µmol/L) [4.5 mg/L (1.3-34.5 mg/L)]. Pharmacokinetic variability was demonstrated as the concentration/(dose/kg) ratio ranged from 1.3 to 9.4 (µmol/L)/(mg/kg) and was affected by age. Polytherapy with 1-3 other antiepileptic drugs was noted in 107 patients (86%). Treatment was continued beyond 1 year in 71% (n = 45) of the 63 patients where such information was available, and all of these 45 patients had serum concentrations within the defined reference range. The 1-year retention rate was higher in patients not concomitantly using other sodium channel-blocking drugs (82% versus 56%). CONCLUSIONS: The study demonstrates pharmacokinetic variability in and between age groups, which indicates usefulness of therapeutic drug monitoring. More than two-thirds of patients continued treatment beyond 1 year, suggesting reasonable effectiveness.

Therapeutic Drug Monitoring of Lacosamide by LC-MS/MS.

High-performance liquid chromatography tandem mass spectrometry (LC-MS/MS) has become a primary analytical methodology in therapeutic drug monitoring of antiepileptic drugs (AEDs). To demonstrate the utility of LC-MS/MS in measuring drug concentrations in serum or plasma, analysis of lacosamide (Vimpat™) is discussed in this chapter. Lacosamide is an example of the newer-generation AEDs. The drug is extracted by protein precipitation and dilution of the serum specimen. A small volume of the extracted specimen is injected into a reversed-phase chromatography column, and lacosamide is identified by positive electrospray ionization (ESI) mass spectrometry in the multiple reaction monitoring (MRM) mode, which provides selectivity for quantitative analysis. A deuterated internal standard is used to correct for any loss of analyte during the process of extraction and analysis. A seven-point calibration curve and two levels of quality controls are included in each batch.

Modeling and simulation for the evaluation of dose adaptation rules of intravenous lacosamide in children.

A combined adult and pediatric population pharmacokinetic model including covariate effects was developed; simulations were subsequently performed to guide intravenous pediatric dosing adaptations. Two pharmacokinetic trials with sparse blood sampling were conducted in children with epilepsy and two trials in healthy adults with serial blood sampling. Lacosamide plasma concentration-time data were available from 43 healthy adults (18-45 years of age; body weight 50-101 kg; n = 1735 concentration vs time records), and from 79 children with epilepsy (6 months-17 years of age; body weight 6-76 kg; n = 402 concentration vs time records), with 14, 22, 25 and 18 participants in age groups <2 years, 2 to <6 years, 6 to <12 years and 12 to <18 years, respectively. A two-compartment population pharmacokinetic model was developed using nonlinear mixed effects modeling. Plasma clearance was scaled using a fixed allometric exponent on body weight, while central volume of distribution used a freely estimated allometric exponent. The model-based pharmacokinetic predictions suggested that there is no need to adapt the recommendations regarding intravenous infusion durations in children compared with adults.

Population Pharmacokinetics of Adjunctive Lacosamide in Pediatric Patients With Epilepsy.

A pediatric population pharmacokinetic model including covariate effects was developed using data from 2 clinical trials in pediatric patients with epilepsy (SP0847 and SP1047). Lacosamide plasma concentration-time data (n = 402) were available from 79 children with body weights ranging from 6 to 76 kg, and a balanced age distribution (6 months to <2 years: n = 14; 2 to <6 years: n = 22; 6 to <12 years: n = 25; 12 to <18 years: n = 18). A single-compartment population pharmacokinetic model with first-order absorption and elimination described the data adequately. Plasma clearance was modeled using allometric scaling on body weight with a freely estimated allometric exponent, while volume of distribution used a fixed theoretical allometric exponent. Covariate search identified a significant effect of enzyme-inducing antiepileptic drugs resulting in a 35% decrease in lacosamide average plasma concentration. No additional effects on clearance could be attributed to race, sex, age, or renal function. Different dosing adaptation schemes by body weight bands were simulated to approximate, in pediatric patients aged 4 to 17 years, the same average plasma concentration as in adult patients receiving the maximum recommended lacosamide daily dose.

Influence of Dose and Antiepileptic Comedication on Lacosamide Serum Concentrations in Patients With Epilepsy of Different Ages.

BACKGROUND: Lacosamide (LCM) is a new antiepileptic drug (AED). The purpose of the study was to investigate the effects of LCM dose, body weight, height, sex, age, and concomitant AEDs on LCM trough serum concentrations (at a steady state) in patients with epilepsy. METHODS: A total number of 3154 blood samples of 973 consecutive patients of the Mara Hospital (Bethel Epilepsy Centre) were evaluated. Generalized estimating equation (GEE) models were used for statistical analyses. RESULTS: GEE analyses showed that LCM trough serum concentrations were significantly correlated with the body weight-normalized LCM dose (range: 0.44-25.7 mg/kg; 45-1050 mg) and significantly dependent on comedication and age. Compared with adults (18-60 years), the LCM trough serum concentrations of children aged 6-12 years and children younger than 6 years were significantly lower (-21% to -38%, respectively) and those of elderly patients (>60 years) were significantly higher (+20%). Sex had no significant influence. Carbamazepine, phenytoin, primidone, phenobarbital, and methsuximide decreased LCM trough serum concentrations significantly by 30%, 32%, 34%, 39%, and 41%, respectively, whereas other AEDs (eg, oxcarbazepine, eslicarbazepine acetate, valproate) had no significant or only a minor impact (zonisamide) on LCM trough concentrations. In children, the effect of enzyme-inducing AEDs was more marked. Of note, the number of blood samples (n = 151) of patients younger than 12 (n = 78) was comparatively low. Alternative GEE models confirmed the effect of comedication, whereas the effect of age, especially in children, depended on adjustment of LCM dosage to body weight, body surface area, or approximated volume of distribution. CONCLUSIONS: In accordance with previous therapeutic drug monitoring studies, our results confirmed that enzyme inducers reduce the LCM trough serum concentrations by 30%-40%. In children, the effects of comedication are more pronounced but should be confirmed by further studies.

Lacosamide: A Review in Focal-Onset Seizures in Patients with Epilepsy.

Lacosamide (Vimpat®) is a functionalized amino acid (available orally and intravenously) approved in the EU and the USA for use as monotherapy and adjunctive therapy for the treatment of focal-onset seizures in adults, adolescents and children aged ≥ 4 years with epilepsy. In adults and adolescents (aged ≥ 16 years), oral lacosamide as adjunctive therapy to other antiepileptic drugs was generally effective in reducing seizure frequency during short-term (up to 18 weeks) treatment, with efficacy sustained over the longer-term (up to 8 years). Moreover, patients were effectively switched from adjunctive oral lacosamide to the same dosage of intravenous lacosamide. Oral lacosamide was an effective conversion to monotherapy agent in this patient population and as monotherapy demonstrated noninferiority to carbamazepine controlled release in terms of seizure freedom. Antiepileptic benefits were maintained during longer-term (≤ 2 years) monotherapy. The antiepileptic efficacy of lacosamide in children aged ≥ 4 years has been extrapolated from data from adults and adolescents, with a similar response expected provided paediatric dosage adaptations are used and safety is demonstrated. Indeed, preliminary data demonstrated the efficacy of short-term (16 weeks) adjunctive lacosamide in patients aged ≥ 4 to < 17 years. Oral lacosamide was generally well tolerated over the short- and longer-term when administered as adjunctive therapy, a conversion to monotherapy agent and monotherapy in adults and adolescents and when administered as adjunctive therapy in children aged ≥ 4 years. Thus, lacosamide is a useful option for the management of focal-onset seizures across a broad age range, starting as early as 4 years of age.