Lamotrigine Concentrations Research Articles

Effects of antiseizure medications on placental cells: Focus on heterodimeric placental carriers

ObjectiveAppropriate placental nutrient transfer is essential for optimal fetal development. We have previously shown that antiseizure medications (ASMs) can alter the expression of placental carriers for folate and thyroid hormones. Here we extended our analysis to heterodimeric carriers that mediate the placental uptake of amino acids and antioxidant precursors. We focused on the L-type amino acid transporter (LAT)2/SLC7A8, the cystine/glutamate antiporter xCT/SLC7A11, and their chaperone 4F2hc/SLC3A2. MethodsBeWo cells were exposed for two or five days to therapeutic concentrations of valproate, levetiracetam, carbamazepine, lamotrigine, or lacosamide. Transcript levels were measured by quantitative PCR. Levetiracetam effects on placental carriers were further explored using a tailored gene array. ResultsAt five days, 30 μg/mL levetiracetam (high therapeutic concentrations) significantly reduced the expression of all studied genes (p < 0.05). Carbamazepine treatment was associated with lower SLC7A8 (LAT2) expression (p < 0.05), whereas valproate increased the transcript levels of this transporter by up to 2.0-fold (p < 0.01). Some of these effects were already observed after two incubation days. Lamotrigine did not alter gene expression, and lacosamide slightly elevated SLC3A2 levels (p < 0.05). The array analysis confirmed the trends observed for levetiracetam and identified additional affected genes. SignificanceAltered expression of placental heterodimeric transporters may represent a mechanism by which ASM affect fetal development. The placental effects are differential, with valproate, carbamazepine and levetiracetam as the more active compounds. The concentration-dependence of those ASM effects are in line with established dose-dependent teratogenicity implying that ASM doses should be adjusted during pregnancy with caution.

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.

A machine learning approach to personalized dose adjustment of lamotrigine using noninvasive clinical parameters

The pharmacokinetic variability of lamotrigine (LTG) plays a significant role in its dosing requirements. Our goal here was to use noninvasive clinical parameters to predict the dose-adjusted concentrations (C/D ratio) of LTG based on machine learning (ML) algorithms. A total of 1141 therapeutic drug-monitoring measurements were used, 80% of which were randomly selected as the "derivation cohort" to develop the prediction algorithm, and the remaining 20% constituted the "validation cohort" to test the finally selected model. Fifteen ML models were optimized and evaluated by tenfold cross-validation on the "derivation cohort,” and were filtered by the mean absolute error (MAE). On the whole, the nonlinear models outperformed the linear models. The extra-trees’ regression algorithm delivered good performance, and was chosen to establish the predictive model. The important features were then analyzed and parameters of the model adjusted to develop the best prediction model, which accurately described the C/D ratio of LTG, especially in the intermediate-to-high range (≥ 22.1 μg mL−1 g−1 day), as illustrated by a minimal bias (mean relative error (%) = + 3%), good precision (MAE = 8.7 μg mL−1 g−1 day), and a high percentage of predictions within ± 20% of the empirical values (60.47%). This is the first study, to the best of our knowledge, to use ML algorithms to predict the C/D ratio of LTG. The results here can help clinicians adjust doses of LTG administered to patients to minimize adverse reactions.

Sotalol does not interfere with the antielectroshock action of selected second-generation antiepileptic drugs in mice

BackgroundDue to blocking β-receptors, and potassium KCNH2 channels, sotalol may influence seizure phenomena. In the previous study, we have shown that sotalol potentiated the antielectroshock action of phenytoin and valproate in mice.Materials and methodsAs a continuation of previous experiments, we examined the effect of sotalol on the action of four chosen second-generation antiepileptic drugs (oxcarbazepine, lamotrigine, pregabalin, and topiramate) against the maximal electroshock in mice. Undesired effects were evaluated in the chimney test (motor impairment) and step-through passive-avoidance task (long-term memory deficits). Finally, brain concentrations of antiepileptics were determined by fluorescence polarization immunoassay, while those of sotalol by liquid chromatography–mass spectrometry.ResultsSotalol at doses of up to 100 mg/kg did not affect the electroconvulsive threshold. Applied at doses of 80–100 mg/kg, sotalol did not affect the antielectroshock action of oxcarbazepine, lamotrigine, pregabalin, or topiramate. Sotalol alone and in combinations with antiepileptics impaired neither motor performance nor long-term memory. Finally, sotalol significantly decreased the brain concentrations of lamotrigine and increased those of oxcarbazepine and topiramate. Pharmacokinetic interactions, however, did not influence the final antielectroshock effects of above-mentioned drug combinations. On the other hand, the brain concentrations of sotalol were not changed by second-generation antiepileptics used in this study.ConclusionSotalol did not reduce the antielectroshock action of four second-generation antiepileptic drugs examined in this study. Therefore, this antidepressant drug should not interfere with antiseizure effects of lamotrigine, oxcarbazepine, pregabalin, and topiramate in patients with epilepsy. To draw final conclusions, our preclinical data should still be confirmed in other experimental models and clinical conditions.

Coffee and cigarette smoking interactions with lamotrigine

The objective of this analysis was to determine possible interactions between lamotrigine (LTG) and coffee or cigarette use. As part of the statistical analysis of factors influencing LTG pharmacokinetics (PK) in the Equigen chronic dose study, we collected prospective data from enrolled patients on their use of coffee and cigarettes. Subjects were part of a crossover replication study of generic LTG products with rigorous blood sampling and were instructed to not change their typical consumption of these products for the duration of the study. A total of 35 subjects were enrolled, with 33 subjects having sufficient data for analysis. Higher consumption of coffee was associated with a significantly lower area under the curve (AUC) and maximum concentration (Cmax) of lamotrigine (LTG). Higher cigarette use did not result in a significant change in AUC or Cmax. Coffee, but not cigarette use, either induces LTG metabolism or inhibits LTG absorption.

Dosing Recommendations for Lamotrigine in Children: Evaluation Based on Previous and New Population Pharmacokinetic Models.

Lamotrigine is a broad-spectrum antiepileptic drug with high interindividual variability in serum concentrations in children. The aims of this study were to evaluate the predictive performance of pediatric population pharmacokinetic (PPK) models published on lamotrigine, to build a new model with our monitoring data and to evaluate the current recommended doses. A validation cohort included patients treated with lamotrigine who had a serum level assayed during therapeutic drug monitoring (TDM). PPK models published in the literature were first applied to the validation cohort. We assessed their predictive performance using mean prediction errors, root mean squared errors, and visual predictive checks. A new model was then built using the data. Dose simulations were performed to evaluate the doses recommended. We included 270 lamotrigine concentrations ranging from 0.5 to 17.9mg/L from 175 patients. The median (range) age and weight were 11.8 years (0.8-18 years) and 32.7kg (8-110kg). We tested 6 PPK models; most had acceptable bias and precision but underestimated the variability of the cohort. We built a 1-compartment model with first-order absorption and elimination, allometric scaling, and effects of inhibitor and inducer comedications. In our cohort, 22.6% of trough concentrations were below 2.5mg/L. In conclusion, we proposed a PPK model that can be used for TDM of lamotrigine in children. In our population, a high percentage of children had low trough concentrations of lamotrigine. As the intervals of recommended doses are large, we suggest aiming at the higher range of doses to reach the target concentration.

A High Plasma Lamotrigine Concentration at Week 2 as a Risk Factor for Lamotrigine-Related Rash.

Reportedly, a high plasma concentration of lamotrigine plays a role in the development of lamotrigine-related rash. The relationship between plasma concentrations of lamotrigine at week 2 and the lamotrigine-related rash was prospectively studied in 84 patients (22 males and 62 females) with treatment-resistant depressive disorder during an 8-week treatment of lamotrigine augmentation. Eighty-four depressed patients with an insufficient response to at least 3 psychotropics, including antidepressants, mood stabilizers, and atypical antipsychotics, were included. The diagnoses were major depressive disorder (n = 39), bipolar I disorder (n = 10), and bipolar II disorder (n = 35). The final doses of lamotrigine were 100 mg/d for 57 subjects who were not taking valproate and 75 mg/d for 27 subjects taking valproate. Blood sampling was performed at week 2. Lamotrigine plasma concentrations were measured using high-performance liquid chromatography. The development of lamotrigine-related rash was assessed during the 8-week treatment. Six females developed lamotrigine-related rash. The mean plasma lamotrigine concentrations at week 2 were significantly (P = 0.009) higher in the rash group (4.81 ± 1.23 μmol/L) than in the nonrash group (3.35 ± 1.39 μmol/L). Receiver-operating characteristic analysis indicated that a plasma lamotrigine concentration of 4.38 μmol/L or greater at week 2 was significantly (P < 0.0001) predictive of lamotrigine-related rash. The proportion of patients with a lamotrigine concentration of 4.38 μmol/L or greater was significantly divided by the cutoff point into the rash group and the nonrash group (5/1 versus 13/65, P = 0.001). This study suggests that a high plasma lamotrigine concentration during week 2 is a risk factor for lamotrigine-related rash and a plasma lamotrigine concentration of 4.38 μmol/L may be a considered a threshold for rash in treatment-resistant depressive disorder.

Misdiagnosis of lamotrigine toxicity as posterior circulation transient ischemic attack or stroke

PurposeLamotrigine (LTG) is one of the most used antiseizure medications (ASMs). Titration is indicated for incomplete seizure control, but toxicity with vertigo, ataxia, and diplopia may ensue. Lamotrigine concentration would be the optimal diagnostic test. However, patients often receive a stroke evaluation when presenting to the emergency department (ED), leading to unnecessary cost and delayed management. We investigated the frequency of stroke evaluation for symptoms associated with LTG toxicity and attempted to identify factors leading to this expensive evaluation. MethodsWe identified adult patients treated with LTG who presented to an emergency room with dizziness, ataxia, or diplopia and received a negative stroke evaluation, between 2003 and 2018. They were among 972 patients treated with LTG for epilepsy. We collected age at time of occurrence, symptoms presented, imaging studies performed, LTG dose and serum concentration, and the time the result was available. As a denominator, we also identified patients who developed clinical LTG toxicity during the same time period. ResultsThirteen patients with LTG toxicity had 16 negative stroke evaluations in the emergency room. Their mean age was 62 years (range: 43–79) as compared with 47 years for all patients treated with LTG (p < 0.0005). The mean daily LTG dose was 621 mg (range: 300–900 mg). A LTG serum concentration was requested on the day of evaluation in 7 instances, though the result was never available until at least the next day. In 4 instances, the LTG level was drawn 1–3 days after presentation. Five of the patients in this group were among 71 patients with clinical LTG toxicity and LTG concentration >20. ConclusionEmergency departments will frequently call a stroke alert for patients taking LTG and presenting with symptoms consistent with LTG toxicity, particularly in seniors at greater risk of stroke. This adds not only expense but also radiation and contrast exposure from computed tomography (CT) studies. We recommend that a rapid LTG assay be made available and always ordered in patients receiving LTG, avoiding the considerable expense of an unnecessary stroke evaluation.

Contraceptive vaginal ring reduces lamotrigine levels

ObjectiveThe objective of the study was to describe the effect of the vaginal ring and transdermal patch on lamotrigine serum levels in women with epilepsy. BackgroundPrevious studies demonstrate that oral hormonal contraceptives containing synthetic estrogen increase lamotrigine clearance through induction of glucuronidation. This leads to variable lamotrigine serum concentrations throughout monthly cycles in women who are on combined oral contraceptives (COCs). The effects of estrogen-containing nonoral hormonal contraceptive methods, including the vaginal ring and transdermal patch, on lamotrigine pharmacokinetics are not well described. MethodsRetrospective chart review was performed to identify serum lamotrigine levels drawn from women with epilepsy while on the active phase of vaginal ring or transdermal patch and while off contraception. Wilcoxon signed-rank tests for paired data were used to compare the difference in dose-corrected lamotrigine concentration in plasma between values while on hormonal contraception to those while off contraception in patients using a vaginal ring. ResultsSix patients were using the vaginal ring, and one patient was using the transdermal patch. Lamotrigine dose-corrected concentrations were decreased during the active phase of the vaginal ring compared with concentrations during the period off contraception (p = .04). There was one patient without a decrease in concentration, but the other five patients on the vaginal ring had a decrease in dose-corrected lamotrigine concentration ranging from 36 to 70% while on the vaginal ring. Similarly, one patient using the transdermal patch had a decrease of 37% in dose-corrected lamotrigine concentration while on the patch. ConclusionsThe findings support that the vaginal ring contraceptive method decreases lamotrigine concentrations during the active phase of treatment. This has important implications for contraceptive counseling and maintaining therapeutic levels in women of childbearing age with epilepsy.

Dosing Recommendations Based on Population Pharmacokinetics of Lamotrigine in Mexican Adult Patients With Epilepsy

Dose individualization is essential in epilepsy treatment, especially in antiepileptic drugs that present high interindividual variability such as lamotrigine. We aimed an observational study to develop a population pharmacokinetic model for quantitative evaluation of the factors that influence lamotrigine pharmacokinetics in Mexican adults with epilepsy. Patients on stable treatment with lamotrigine therapy were included, plasma concentrations were analyzed by a high-performance liquid chromatography method and UGT2B7–161C > T polymorphism was determined. The data were analyzed by NONMEM® 7.3, model validation was performed using bootstrap approach and visual predictive check. Finally, stochastic simulations were carried out to propose dosage regimens. A total of 73 lamotrigine plasma concentrations from 2 h after last dose and up to 0.5 h prior to next administration were fitted to a one-compartment open model. The final population pharmacokinetic model for lamotrigine indicates that concomitant treatment with valproic acid and carbamazepine should be considered to individualize epilepsy treatment with this drug. Based on this model, we proposed dosage regimens to achieve trough lamotrigine concentrations within reference interval (2.5–15 mg/L). These results provide clinical useful data to give more rational anticonvulsant therapy in our population.

Lamotrigine Toxicosis Treated with Intravenous Lipid Emulsion Therapy in a Dog

A female spayed dachshund/mixed-breed dog was evaluated following ingestion of lamotrigine tablets with subsequent rapid onset of vomiting, diarrhea, and generalized tremoring. On initial examination, the dog was moderately obtunded and nonambulatory with intermittent myoclonus and hyperesthesia. Electrocardiogram revealed sinus tachycardia with prolongation of the QT interval. Intravenous lipid emulsion (ILE) infusion was initiated, with reduction in tremoring and improved patient mentation being noted after ∼20 min of therapy. An elevated cardiac troponin I value measured at 1.02 ng/mL the day after presentation. Serum toxicological assay revealed marked reduction in serum lamotrigine levels following ILE and continued reduction during hospitalization. The dog's clinical signs resolved, corrected QT interval returned to normal, and the patient was discharged 38 hr after presentation. Individual cases of lamotrigine toxicosis have not been fully reported in veterinary literature. This case report documents the rapid onset of clinical signs including neurologic dysfunction, cardiac arrhythmias, and transient corrected QT prolongation. Serial serum concentrations of lamotrigine showed a rapid reduction with ILE therapy and corresponded with clinical recovery, suggesting efficacy of ILE treatment in this case.

Multiobjective optimization of microemulsion- thin layer chromatography with image processing as analytical platform for determination of drugs in plasma using desirability functions

A new platform was developed for determination of drugs in plasma without extraction or instrumental analysis just using TLC, smart phone digital camera and free image processing software. Lamotrigine, antiepileptic drug was used as model analyte. The proposed platform depends on using oil-in-water (O/W) microemulsion to isolate the drug from plasma proteins and using water-in-oil (W/O) microemulsion as mobile phase for TLC which results in complete separation between lamotrigine and plasma as viewed under UV lamp. The composition of both microemulsions was optimized using Taguchi orthogonal array and Plackett- Burman design. The optimal (O/W) microemulsion predicted composition was 0.01 mL Butyl acetate, 4 mL butanol, 0.925 gm SDS and 8.6 mL water while the (W/O) mobile phase microemulsion was 9 mL Butyl acetate, 1 mL butanol, 0.25 gm SDS, 0.25 mL water. Separation was carried out on a silica gel 60F-254 plate eluted with the (W/O) microemulsion in about 30 min development time. The images of TLC plates were processed using 4 different programs, by comparing their results it was found that “integrated density” measured by Fiji software was the most accurate response that could measure the concentration of lamotrigine in spiked plasma in the range of (20–200) ng/spot. This method was applied also for determination of lamotrigine in lamictal® tablet dosage form using the same mobile phase. The precision of the method was satisfactory; the maximum value of relative standard deviations did not exceed 1.5%. While the accuracy was proved by the low values of % error and high values of recovery.

Therapeutic Drug Monitoring of Antiepileptic Drugs in Women with Epilepsy Before, During, and After Pregnancy.

During pregnancy, the pharmacokinetics of an antiepileptic drug is altered because of changes in the clearance capacity and volume of distribution. These changes may have consequences for the frequency of seizures during pregnancy and fetal exposure to antiepileptic drugs. In 2009, a review was published providing guidance for the dosing and therapeutic drug monitoring of antiepileptic drugs during pregnancy. Since that review, new drugs have been licensed and new information about existing drugs has been published. With this review, we aim to provide an updated narrative overview of changes in the pharmacokinetics of antiepileptic drugs in women during pregnancy. In addition, we aim to formulate advice for dose modification and therapeutic drug monitoring of antiepileptic drugs. We searched PubMed and the available literature on the pharmacokinetic changes of antiepileptic drugs and seizure frequency during pregnancy published between January 2007 and September 2018. During pregnancy, an increase in clearance and a decrease in the concentrations of lamotrigine, levetiracetam, oxcarbazepine's active metabolite licarbazepine, topiramate, and zonisamide were observed. Carbamazepine clearance remains unchanged during pregnancy. There is inadequate or no evidence for changes in the clearance or concentrations of clobazam and its active metabolite N-desmethylclobazam, gabapentin, lacosamide, perampanel, and valproate. Postpartum elimination rates of lamotrigine, levetiracetam, and licarbazepine resumed to pre-pregnancy values within the first few weeks after pregnancy. We advise monitoring of antiepileptic drug trough concentrations twice before pregnancy. This is the reference concentration. We also advise to consider dose adjustments guided by therapeutic drug monitoring during pregnancy if the antiepileptic drug concentration decreases 15-25% from the pre-pregnancy reference concentration, in the presence of risk factors for convulsions. If the antiepileptic drug concentration changes more than 25% compared with the reference concentration, dose adjustment is advised. Monitoring of levetiracetam, licarbazepine, lamotrigine, and topiramate is recommended during and after pregnancy. Monitoring of clobazam, N-desmethylclobazam, gabapentin, lacosamide, perampanel, and zonisamide during and after pregnancy should be considered. Because of the risk of teratogenic effects, valproate should be avoided during pregnancy. If that is impossible, monitoring of both total and unbound valproate is recommended. More research is needed on the large number of unclear pregnancy-related effects on the pharmacokinetics of antiepileptic drugs.

Enhance the brain concentration and antiepileptic effect of drug lamotrigine by encapsulating inside the chitosan coated nanoliposomes for intranasal drug delivery system

Enhance the brain concentration and antiepileptic effect of drug lamotrigine by encapsulating inside the chitosan coated nanoliposomes for intranasal drug delivery system

Antiepileptic Drug Exposure in Infants of Breastfeeding Mothers With Epilepsy

There is limited information on infant drug exposure via breastfeeding by mothers who are receiving antiepileptic drug therapy. To provide direct, objective information on antiepileptic drug exposure through breast milk. This prospective cohort study was conducted between December 2012 to October 2016, with follow-up in children until 6 years of age at 20 sites across the United States. Data were collected via an observational multicenter investigation (Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs [MONEAD]) of outcomes in pregnant mothers with epilepsy and their children. Pregnant women with epilepsy who were aged 14 to 45 years, had pregnancies that had progressed to less than 20 weeks' gestational age, and had measured IQ scores of more than 70 points were enrolled and followed up through pregnancy and 9 postpartum months. Their infants were enrolled at birth. Data were analyzed from May 2014 to August 2019. Antiepileptic drug exposure in infants who were breastfed. The percentage of infant-to-mother concentration of antiepileptic drugs. Antiepileptic drug concentrations were quantified from blood samples collected from infants and mothers at the same visit, 5 to 20 weeks after birth. Concentrations of antiepileptic drugs in infants at less than the lower limit of quantification were assessed as half of the lower limit. Additional measures collected were the total duration of all daily breastfeeding sessions and/or the volume of pumped breast milk ingested from a bottle. A total of 351 women (of 865 screened and 503 eligible individuals) were enrolled, along with their 345 infants (179 female children [51.9%]; median [range] age, 13 [5-20] weeks). Of the 345 infants, 222 (64.3%) were breastfed; the data collection yielded 164 matching infant-mother concentration pairs from 138 infants. Approximately 49% of all antiepileptic drug concentrations in nursing infants were less than the lower limit of quantification. The median percentage of infant-to-mother concentration for all 7 antiepileptic drugs and 1 metabolite (carbamazepine, carbamazepine-10,11-epoxide, levetiracetam, lamotrigine, oxcarbazepine, topiramate, valproate, and zonisamide) ranged from 0.3% (range, 0.2%-0.9%) to 44.2% (range, 35.2%-125.3%). In multiple linear regression models, maternal concentration was a significant factor associated with lamotrigine concentration in infants (Pearson correlation coefficient, 0.58; P < .001) but not levetiracetam concentration in infants. Overall, antiepileptic drug concentrations in blood samples of infants who were breastfed were substantially lower than maternal blood concentrations. Given the well-known benefits of breastfeeding and the prior studies demonstrating no ill effects when the mother was receiving antiepileptic drugs, these findings support the breastfeeding of infants by mothers with epilepsy who are taking antiepileptic drug therapy.

Comparison of plasma, saliva, and hair lamotrigine concentrations

BackgroundIn some clinical situations (pregnancy, aging, drug resistance, toxicity), measurements of lamotrigine plasma levels may be reliable. Limited studies indicate that saliva and hair could be alternative sources for monitoring lamotrigine therapy. The drug content in hair can also be used to assess the history of drug therapy and to ascertain long-term patient compliance. The aims of this study were to 1) determine the correlations among plasma, saliva, and hair lamotrigine concentrations, 2) evaluate saliva as an alternative matrix for monitoring drug levels and 3) evaluate hair as a source of information on adherence to antiepileptic treatment and on the correlation of hair concentrations with clinical outcomes in patients with epilepsy. MethodsPlasma, saliva, and hair lamotrigine concentrations were measured by liquid chromatography–tandem mass spectrometry in positive ionization mode. The study group (n = 85) was recruited among the epileptic patients at the Institute of Psychiatry and Neurology, Warsaw, Poland. ResultsPlasma concentrations were not influenced by sex, age, or the concomitant use of other antiepileptic drugs. Lamotrigine saliva and plasma concentrations were strongly correlated (r = 0.82, p < 0.001). Lamotrigine hair concentrations were correlated with the plasma concentrations (r = 0.53, p < 0.001) and daily dose in mg/kg (r = 0.23, p = 0.024). The analysis revealed no significant correlation between lamotrigine hair levels and the number of seizures in the previous 3 months (r = -0.1, p > 0.05). ConclusionsThe lamotrigine saliva concentration is strongly correlated with its plasma level, and saliva can be used as an alternative matrix to plasma for monitoring. Lamotrigine can also be successfully measured in hair, and the drug levels in hair tend to be correlated with the levels in plasma. However, lamotrigine levels in hair may not correspond to clinical outcomes (i.e., seizure episodes).

Pharmacokinetic interaction of brivaracetam on other antiepileptic drugs in adults with focal seizures: Pooled analysis of data from randomized clinical trials

ObjectiveTo assess the effect of brivaracetam (BRV) on steady-state plasma concentrations of commonly prescribed antiepileptic drugs (AEDs). MethodsData were pooled from five randomized, double-blind, placebo-controlled efficacy studies (NCT00175929, NCT00175825, NCT00490035, NCT00464269, and NCT01261325) in which adults with refractory epilepsy, and receiving stable doses of 1–2 AEDs, initiated adjunctive treatment with BRV (or placebo) for up to 12 weeks, following a 4–8 week baseline period. Concentrations of carbamazepine, carbamazepine epoxide, clobazam, clonazepam, lacosamide, lamotrigine, levetiracetam, oxcarbazepine (MHD), phenobarbital, phenytoin, pregabalin, topiramate, valproic acid and zonisamide, were measured during baseline and during BRV or placebo evaluation periods. Log-transformed data for patients receiving BRV dosages of 50–200 mg/day (or placebo) were evaluated using repeated measures analysis of covariance. Geometric least-squares means ratios of respective AED concentrations (treatment vs baseline) and their 90% confidence intervals (CIs) were calculated. Relevant interaction of BRV on the respective AED was inferred if CIs were entirely outside of 0.80–1.25 limits. ResultsWithin the population for analysis (n = 1402), relevant interaction was observed for carbamazepine epoxide alone which increased up to 2-fold from baseline due to inhibition of epoxide hydrolase by BRV, and the effect size was not influenced by concomitant valproic acid. Relevant interaction was not observed for other AEDs. ConclusionIn adults with focal seizures, adjunctive BRV treatment does not affect plasma concentrations of the evaluated AEDs but increases carbamazepine epoxide metabolite. Carbamazepine dose reduction should be considered if tolerability issues arise.

Solubility Enhancement and Pharmacokinetic Assessment of Chemically Modified Lamotrigine in Rat Blood Plasma by HPLC

Aims:&#x0D; &#x0D; Synthesis/preparation of Lamotrigine (LMN) complexes with β-CD, Caffeine, Nicotinamide, EDTA and&#x0D; Development of a new reverse phase liquid chromatographic (HPLC) method for the investigation of Lamotrigine in rat plasma after oral administration and pharmacokinetic assessment of Lamotrigine.&#x0D; &#x0D; Study Design: The present work describes the formation of LMN drug complexes with β-Cyclodextrin, Caffeine, Nicotinamide and Disodium EDTA. Physical mixture, kneading and solvent evaporation methods were used to prepare LMN complexes (In ratios 1:1, 1:2, 2:1). Further characterization was performed by UV, FTIR, PXRD, and DSC. A reverse phase HPLC method was developed for the investigation of LMN in rat plasma using internal standardization method after oral administration of LMN and its complexes.&#x0D; Place and Duration of Study: Department of Pharmaceutical Chemistry, Smt. Kishoritai Bhoyar College of Pharmacy, RTMN University, Nagpur, between July 2018 and June 2019.&#x0D; Methodology: LMN complexes with β-CD, Caffeine, Nicotinamide, EDTA was prepared in three ratios i.e. 1:1, 1:2 and 2:1 and characterized by UV, FTIR, PXRD, and DSC. In-vitro Solubility study was performed by saturation solubility study, further % practical yield, drug content, melting point was determined. In-vitro dissolution study of prepared complexes was performed in dissolution apparatus using the paddle method, according to USP Type II. Dissolution studies were carried out using 900 mL 0.1M HCl at 37± 0.5°C at 50 revmin−1 (US FDA guidelines).The interaction of LMN with these hydrophilic complexing agents was characterized by UV, FTIR, PXRD and DSC.&#x0D; A reverse phase HPLC bioanalytical method was developed and validated as per ICH guidelines for the quantitative determination of LMN in rat plasma using internal standardization method (HTZ) after oral administration of LMN and its complexes. The method was successfully applied for the pharmacokinetic study in rat. The pharmacokinetic parameter like AUCt, AUCi, MRTi, Cmax, Tmax, t1/2, were calculated using pharmacokinetic software PK solver 2. The efficient separation was carried out for High Performance Liquid Chromatography (HPLC) method on Eclipse XDB-C18 (150×4.6×5 µ) column using a mobile phase consisting of filtered and degassed mixture of potassium dihydrogen orthophosphate buffer (pH 7.0) and Methanol in the ratio 65:35 v/v at a flow rate of 0.8 mL/min and UV detection at 307 nm.&#x0D; Results: The LMN complexes were successfully prepared and characterized by UV, FTIR, PXRD, and DSC from which solvent evaporation method was found to be best as per result of in-vitro dissolution study. In-vitro dissolution study reveals that LMN-Caffeine (C1) and LMN-NTM (N1) complexes showed 100.14 and 100.01% drug release at 15 min and 20 min respectively as compared to pure drug (LMN) which shows only 50.56% drug release at 75 min.&#x0D; LMN concentration in blood plasma reached (Cmax) was found to be 19.4732 µg/mL at Tmax of 5h, Whereas Cmax of LMN complexes were found to be 48.4876 (B1), 72.2160 (C1), 62.2739 (N1) and 49.3170 (E1) µg/mL at Tmax of 5h out of which complex C1 and N1 in the present study resulted in a sharp increase in Cmax. All complexes showed 4 to 5 time enhancement of Cmax as compared to LMN.. The results demonstrated that complexes of Lamotrigine were successful strategy to improve the solubility and dissolution behavior of Lamotrigine. The complex B1 shows maximum t1/2 and MRTi of 36.224 h and 52.441 h as compared to C1, N1 and E1 having t1/2 of 14.1575, 16.258 and 21.702 h and MRTi of 19.997, 22.994 and 30.883 h respectively. Hence B1 required lesser dosing frequency as compared to other complexes.&#x0D; Conclusion: The Lamotrigine complexes were prepared and confirmation of prepared complexes was done by physical characterization (FTIR. DSC, PXRD and UV) and solubility determination by saturation solubility study. The bioanalytical method was developed for estimation of plasma drug concentration of LMN. The method was validated according to ICH guidelines to estimate the mean plasma concentration of LMN after oral administration using internal standardization method (HTZ). Method was reproducible and high recovery of LMN from its complexes was achieved. The method was found to be highly satisfactory sensitive, accurate, linear and specific.

Effects of Comedication and Genetic Factors on the Population Pharmacokinetics of Lamotrigine: A Prospective Analysis in Chinese Patients With Epilepsy.

Lamotrigine (LTG) is a second-generation anti-epileptic drug widely used for focal and generalized seizures in adults and children, and as a first-line medication in pregnant women and women of childbearing age. However, LTG pharmacokinetics shows high inter-individual variability, thus potentially leading to therapeutic failure or side effects in patients. This prospective study aimed to establish a population pharmacokinetics model for LTG in Chinese patients with epilepsy and to investigate the effects of genetic variants in uridine diphosphate glucuronosyltransferase (UGT) 1A4, UGT2B7, MDR1, ABCG2, ABCC2, and SLC22A1, as well as non-genetic factors, on LTG pharmacokinetics. The study population consisted of 89 patients with epilepsy, with 419 concentrations of LTG. A nonlinear mixed effects model was implemented in NONMEM software. A one-compartment model with first-order input and first-order elimination was found to adequately characterize LTG concentration. The population estimates of the apparent volume of distribution (V/F) and apparent clearance (CL/F) were 12.7 L and 1.12 L/h, respectively. The use of valproic acid decreased CL/F by 38.5%, whereas the co-administration of rifampicin caused an increase in CL/F of 64.7%. The CL/F decreased by 52.5% in SLC22A1-1222AA carriers. Patients with the ABCG2-34AA genotype had a 42.0% decrease in V/F, whereas patients with the MDR1-2677TT and C3435TT genotypes had a 136% increase in V/F. No obvious genetic effect of UGT enzymes was found relative to the concentrations of LTG in Chinese patients. Recommended dose regimens for patients with different gene polymorphisms and comedications were estimated on the basis of Monte Carlo simulations and the established model. These findings should be valuable for developing individualized dosage regimens in adult and adolescent Chinese patients 13–65 years of age.

A Short Communication: Lamotrigine Levels in Milk, Mothers, and Breastfed Infants During the First Postnatal Month.

Lamotrigine has become the most frequently prescribed drug in the treatment of pregnant women with epilepsy. Although some relevant studies have found a wide milk/maternal serum as well as infant/maternal serum concentration ratio, different infant ages at the time of sampling and small number of patients preclude comparison. The aim of this study was to provide a consistent evaluation. Data of 43 nursing women treated by lamotrigine were evaluated retrospectively. The authors followed the transport of lamotrigine during the first postnatal month from mothers to breastfed infants through maternal milk between the years 2002 and 2017. Lamotrigine concentrations varied from 1.1 to 14.9 mg/L in the maternal serum, from <0.66 to 9.1 mg/L in the milk and between <0.66 and 6.9 mg/L in the infant serum. The milk/maternal serum concentration ratio ranged from <0.18 to 0.74 and the infant/maternal serum concentration ratio measured between <0.15 and 0.74. Highly significant correlations were found between milk and maternal serum levels and between infant serum levels and milk, maternal serum levels, lamotrigine daily dose, and also maternal dose related to the body weight. The authors confirmed the wide range of the milk/maternal serum concentration ratio and the infant/maternal serum concentration ratio. Although the degree of lamotrigine exposure to the breastfed infants was smaller than during gestation, 16% of the infant serum levels measured were within the therapeutic range used for the general epileptic population. Lamotrigine concentration monitoring in breastfed infant, in our opinion, is the most relevant aspect for the analysis of actual lamotrigine exposure in infants, especially in those with clinical symptoms.