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Background: Lamotrigine is a new antiepileptic drug with substantial interindividual variability in its pharmacokinetics and therapeutic responses. This study aimed to develop population pharmacokinetic (PPK) models of lamotrigine and its N2-glucuronide metabolites for model-informed individualized therapy., Methods: A total of 353 plasma concentrations from Chinese patients with epilepsy receiving oral lamotrigine were used to develop a population PPK model using a nonlinear mixed effects modeling method. One- and two-compartment models were applied to the nonmetabolite and metabolite model, respectively. Forward addition and backward elimination were used to establish the final model. Model validation was performed using standard goodness-of-fit, bootstrap, visual predictive checks, and normalized prediction distribution errors. Finally, simulations were performed to propose lamotrigine dosages in different situations to achieve trough concentrations within the reference interval (2.5-15 mg/L)., Results: For both final population PPK models, coadministration with valproic acid (VPA) or enzyme inducer, and body weight significantly affected lamotrigine clearance. The final models for lamotrigine clearance were and for nonmetabolite and metabolite models, respectively. The precision of the PPK parameters was acceptable, and the models exhibited good predictability. Monte Carlo simulations revealed that the lamotrigine dosage administered to patients combined with an enzyme inducer must be tripled that administered with VPA to reach the target trough concentration., Conclusions: Variability in the pharmacokinetics of lamotrigine is large. Coadministration of VPA or an enzyme inducer and body weight are the most important factors in lamotrigine clearance in Chinese patients with epilepsy. The developed population PPK models might support further optimization of lamotrigine dosing regimens., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: There is limited evidence to support the currently suggested lamotrigine (LTG) therapeutic reference range of 2.5-15 mg/L for the treatment of seizures. The objective of this study was to evaluate the association of LTG plasma concentrations with the efficacy and toxicity of the treatment in patients with epilepsy., Methods: Patients whose LTG plasma concentration was measured between January 2013 and February 2022 were included. Efficacy was defined as seizure freedom for at least 6 months around the time of measured LTG concentration. Toxicity was defined as any LTG-related adverse drug effect documented in each patient's health record or when the reason for measuring the LTG concentration was toxicity. In addition, the dose-concentration relationship of LTG was assessed., Results: In total, 549 concentrations from 259 patients with epilepsy were included. The most common reasons for therapeutic drug monitoring were suspected inefficacy (39%) and pregnancy (21%). The LTG plasma concentration was not associated with efficacy (adjusted odds ratio = 0.94; 95% confidence interval, 0.85-1.04). The LTG plasma concentration was positively associated with the incidence of toxicity after adjusting for age, sex, and number of antiepileptic drugs (odds ratio = 1.11; 95% confidence interval, 1.04-1.19). The daily dose had a significant linear correlation with the LTG plasma concentration ( P < 0.001)., Conclusions: The LTG plasma concentration was associated with toxicity, whereas no association with efficacy was found. A reference range of 2.5-10 mg/L may be considered to decrease the risk of toxicity while maintaining similar efficacy. Therapeutic drug monitoring may be useful when LTG-related toxicity is suspected and in cases of pharmacokinetic changes (eg, pregnancy and concomitant use of interacting drugs) that can influence the LTG plasma concentration., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: The purpose of this study was to evaluate the effect of UGT1A4 and UGT2B7 polymorphisms on the plasma concentration of lamotrigine in Chinese patients with bipolar disorder., Methods: A total of 104 patients were included in this study. Steady-state plasma lamotrigine concentrations were determined in each patient after at least 21 days of continuous treatment with a set dose of the drug. Lamotrigine plasma concentrations were ascertained using ultra-performance liquid chromatography. Simultaneously, plasma samples were used for patient genotyping., Results: The age, sex, BMI, daily lamotrigine dose, plasma lamotrigine concentration, and lamotrigine concentration/dose ratio of patients exhibited significant differences, and these were associated with differences in the genotype [ UGT1A4 -142T>G and UGT2B7 -161C>T ( P  < 0.05)]. Patients with the GG and GT genotypes in UGT1A4 -142T>G had significantly higher lamotrigine concentration/dose values (1.6 ± 1.1 and 1.7 ± 0.5 μg/ml per mg/kg) than those with the TT genotype (1.4 ± 1.1 μg/ml per mg/kg). Likewise, patients with the UGT2B7 -161C>T TT genotype had significantly higher lamotrigine concentration/dose values (1.6 ± 1.1 μg/ml per mg/kg) than those with the CC genotype (1.3 ± 1.3 μg/ml per mg/kg). Multiple linear regression analysis showed that sex, lamotrigine dose, UGT1A4 -142T>G, and UGT2B7 -161C>T were the most important factors influencing lamotrigine pharmacokinetics ( P  < 0.001)., Conclusion: The study results suggest that the UGT1A4 -142T>G and UGT2B7 -161C>T polymorphisms affect lamotrigine plasma concentrations in patients with bipolar disorder., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: The authors have demonstrated that a plasma lamotrigine concentration of 12.7 μmol/L may be a threshold for a good therapeutic response to lamotrigine augmentation therapy in treatment-resistant depressed patients. Lamotrigine is a substrate of P-glycoprotein, breast cancer resistant protein and organic cation transporter 1, which are encoded by ABCB1 , ABCG2 , and SLC22A1 , respectively. There have been several polymorphisms that affect its function. The present study investigated the relationship between these polymorphisms and the steady-state plasma concentrations (Css) of lamotrigine in treatment-resistant depressed patients receiving lamotrigine as augmentation therapy., Methods: One hundred twenty-nine treatment-resistant depressed patients were included in this study. Treatment resistance is defined as lack of therapeutic response to at least 3 psychotropics despite adequate doses and duration. Their diagnoses were as follows: major depressive disorder (n = 58), bipolar II disorder (n = 52), and bipolar I disorder (n = 19). Lamotrigine augmentation therapy for 8 weeks was conducted. The final lamotrigine doses were 75 mg/d for 39 patients with valproate and 100 mg/d for 90 without it. Blood was sampled at 8:00 am after the 8th week of treatment. Plasma lamotrigine levels were quantified by using LC/MS/MS. The polymorphisms of ABCB1 1236C>T, 2677G>T/A, 3435C>T, ABCG2 421C>A, and SLC22A1 1222G>A were detected by polymerase chain reaction analyses., Results: No significant relationships were observed between these polymorphisms and the Css of lamotrigine in the patients with or without valproate., Conclusions: The present study suggests that these genetic polymorphisms do not play a role in controlling the Css of lamotrigine in treatment-resistant depressed patients treated with lamotrigine augmentation therapy., Competing Interests: Conflicts of Interest and Sources of Funding: K. Mihara has received honoraria from GlaxoSmithKline and Otsuka. A. Nakamura has received honoraria from Dainippon Sumitomo Pharma, Otsuka, and Pfizer. T. Kondo has received honoraria from Eli Lilly, GlaxoSmithKline, and Otsuka. The other authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: Therapeutic drug monitoring is performed routinely in patients on anti-epileptic drugs (AEDs) for optimisation and individualisation of therapy. The dried blood spot (DBS) sampling technique is a suitable, more patient-friendly alternative for conventional venous sampling methods. However, before DBS can be used in routine care, data are needed to establish the correlation between standard plasma concentrations obtained from venous puncture and concentrations measured through DBS obtained by finger prick. This study aims to investigate the correlation between carbamazepine, lamotrigine and levetiracetam drug concentrations in venous blood and DBS samples in the same patients at the same time., Methods: Clinical validation was conducted by direct comparison of paired DBS and venous plasma samples. Method agreement was evaluated using Passing-Bablok regression analysis and Bland-Altman plots to provide insight into the relationship between the two analytically validated methods. For Bland-Altman analysis the acceptance limit required by both FDA and EMA guidelines is at least two-thirds (67%) of the paired samples within 80-120% of the mean of both methods., Results: Paired samples from 79 patients were studied. For all three AEDs, plasma and DBS concentrations correlated highly (r=0.90 for carbamazepine, r=0.93 for lamotrigine and r=0.93 for levetiracetam), indicating a linear relationship. For carbamazepine and lamotrigine, no proportional or constant bias was revealed. For levetiracetam, concentrations were higher in plasma samples than in DBS (slope 1.21), implying a conversion factor is needed. The acceptance limit was met for carbamazepine and levetiracetam with a value of 72% and 81%, respectively. For lamotrigine, this acceptance limit was not met with a value of 60%., Conclusions: The method was successfully validated and will be used for therapeutic drug monitoring in patients using carbamazepine, lamotrigine and/or levetiracetam., Competing Interests: Competing interests: None declared., (© European Association of Hospital Pharmacists 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Abstract: This study evaluated perampanel pharmacokinetics and cytochrome P450 3A4 (CYP3A4) activity, assessed using the level of 4β-hydroxycholesterol (4β-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 4β-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 4β-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., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Importance: Precise estimation of a patient's drug metabolism capacity is important for antiseizure dose personalization., Objective: To quantify the differences in plasma concentrations for antiseizure drugs associated with variants of genes encoding drug metabolizing enzymes., Data Sources: PubMed, Clinicaltrialsregister.eu, ClinicalTrials.gov, International Clinical Trials Registry Platform, and CENTRAL databases were screened for studies from January 1, 1990, to September 30, 2023, without language restrictions., Study Selection: Two reviewers performed independent study screening and assessed the following inclusion criteria: appropriate genotyping was performed, genotype-based categorization into subgroups was possible, and each subgroup contained at least 3 participants., Data Extraction and Synthesis: The Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines were followed for data extraction and subsequent quality, validity, and risk-of-bias assessments. The results from the included studies were pooled with random-effect meta-analysis., Main Outcomes and Measures: Plasma concentrations of antiseizure drugs were quantified with the dose-normalized area under the concentration-time curve, the dose-normalized steady state concentration, or the concentrations after a single dose at standardized dose and sampling time. The ratio of the means was calculated by dividing the mean drug plasma concentrations of carriers and noncarriers of the pharmacogenetic variant., Results: Data from 98 studies involving 12 543 adult participants treated with phenytoin, valproate, lamotrigine, or carbamazepine were analyzed. Studies were mainly conducted within East Asian (69 studies) or White or European (15 studies) cohorts. Significant increases of plasma concentrations compared with the reference subgroup were observed for phenytoin, by 46% (95% CI, 33%-61%) in CYP2C9 intermediate metabolizers, 20% (95% CI, 17%-30%) in CYP2C19 intermediate metabolizers, and 39% (95% CI, 24%-56%) in CYP2C19 poor metabolizers; for valproate, by 12% (95% CI, 4%-20%) in CYP2C9 intermediate metabolizers, 12% (95% CI, 2%-24%) in CYP2C19 intermediate metabolizers, and 20% (95% CI, 2%-41%) in CYP2C19 poor metabolizers; and for carbamazepine, by 12% (95% CI, 3%-22%) in CYP3A5 poor metabolizers., Conclusions and Relevance: This systematic review and meta-analysis found that CYP2C9 and CYP2C19 genotypes encoding low enzymatic capacity were associated with a clinically relevant increase in phenytoin plasma concentrations, several pharmacogenetic variants were associated with statistically significant but only marginally clinically relevant changes in valproate and carbamazepine plasma concentrations, and numerous pharmacogenetic variants were not associated with statistically significant differences in plasma concentrations of antiseizure drugs.

Surface-enhanced Raman spectroscopy (SERS) is a powerful method in analytical chemistry, but its application in real-life medical settings has been limited due to technical challenges. In this work, we introduce an innovative approach that is meant to advance the automation of microfluidics SERS to improve reproducibility and label-free quantification of two widely used therapeutic drugs, methotrexate (MTX) and lamotrigine (LTG), in human serum. Our methodology involves a miniaturized solid-phase extraction (μ-SPE) method coupled to a centrifugal microfluidics disc with incorporated SERS substrates (CD-SERS). The CD-SERS platform enables simultaneous controlled sample wetting and accurate SERS mapping. Together with the assay we implemented a machine learning method based on Partial Least Squares Regression (PLSR) for robust data analysis and drug quantification. The results indicate that combining μ-SPE with CD-SERS (μ-SPE to CD-SERS) led to a substantial improvement in the signal-to-noise ratio compared to combining CD-SERS with ultrafiltration or protein precipitation. The PLSR model enabled us to obtain the limit of detection and quantification for MTX as 2.90 and 8.92 μM, respectively, and for LTG as 10.76 and 32.29 μM. We also validated our μ-SPE to CD-SERS method for MTX against HPLC and immunoassay (p-value <0.05), using patient samples undergoing MTX therapy. In addition, we achieved a satisfactory recovery rate (80%) for LTG when quantifying it in patient samples. Our results show the potential of this newly developed approach as a strategy for therapeutic drugs in point-of-care clinical settings and highlight the benefits of automating label-free SERS assays., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: Lamotrigine as a broad-spectrum antiepileptic drug, is widely applied and its clinical efficacy is highly recognized. However, significant differences are observed in blood drug concentration of lamotrigine among individuals, which may have an impact on its efficacy. UGT1A4 is the main metabolic enzyme. However, it was inconsistent for the influence of UGT1A4 genetic polymorphism on concentration and efficacy of lamotrigine therapy. This study aimed to evaluate the influences of UGT1A4*3 genetic polymorphisms on lamotrigine concentration and therapeutic effect through meta-analysis., Methods: The literature search was conducted in Medline, Embase, PubMed, Web of Science, Wan Fang Database, China National Knowledge Infrastructure, China Science and Technology Journal Database until January 2024. The primary outcome included the mean serum concentration, concentration-to-dose-ratio by body weight (CDR), or efficacy related to different UGT1A4*3 genotype for lamotrigine therapy. Data were collected to access the Mean Difference or odds ratio with 95% confidence interval. Meta-analysis was performed by RevMan 5.2., Results: A total of eleven studies were enrolled. The meta-analysis for mean serum concentration of lamotrigine showed no significant difference between patients carrying TT genotypes and TG and GG genotypes group (MD: 0.12, 95% [-0.35, 0.58], P = 0.62). There was significant difference in CDR (MD: 0.49, 95% [0.03, 0.94], P = 0.04) and therapeutic efficacy (OR: 7.18, 95% [4.01, 12.83], P<0.00001) of lamotrigine, however no significant difference was found in subgroup analysis of CDR of children (MD: 0.03, 95% [-0.35, 0.42], P = 0.87) between patients carrying TT genotypes and TG and GG genotypes group., Conclusions: Polymorphism of UGT1A4*3 influenced the CDR and therapeutic efficacy of lamotrigine for antiepileptic therapy. Genotype analysis provided reference for personalized medication in the future. However, more high-quality evidences are necessary for precise and definitive conclusion., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Jiang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: Increasing evidence suggests that the physiological changes of pregnancy may impact pharmacokinetics of antiseizure medications (ASM), and this may affect treatment outcomes. The aim of this study was to quantify the pregnancy impact on the ASM pharmacokinetics., Methods: A systematic literature search was conducted in PubMed/EMBASE in November 2022 and updated in August 2023 for studies comparing levels of ASM in the same individuals during pregnancy and in the preconception/postpartum period. Alteration ratios between the 3rd trimester and baseline were estimated. We also performed a random-effects meta-analysis calculating between-timepoint differences in mean differences (MDs) and 95% confidence intervals (95%CIs) for dose-adjusted plasma concentrations (C/D ratios). Study quality was assessed using the ClinPK guidelines., Results: A total of 65 studies investigating 15 ASMs in 674 pregnancies were included. The largest differences were reported for lamotrigine, oxcarbazepine and levetiracetam (alteration ratio 0.42, range 0.07-2.45, 0.42, range 0.08-0.82 and 0.52, range 0.04-2.77 respectively): accordingly, C/D levels were lower in the 3rd trimester for lamotrigine, levetiracetam and the main oxcarbazepine metabolite monohydroxycarbazepine (MD = -12.33 × 10 -3 , 95%CI = -16.08 to -8.58 × 10 -3 (μg/mL)/(mg/day), p < 0.001, MD = -7.16 (μg/mL)/(mg/day), 95%CI = -9.96 to -4.36, p < 0.001, and MD = -4.87 (μg/mL)/(mg/day), 95%CI = -9.39 to -0.35, p = 0.035, respectively), but not for oxcarbazepine (MD = 1.16 × 10 -3 (μg/mL)/(mg/day), 95%CI = -2.55 to 0.24 × 10 -3 , p = 0.10). The quality of studies was acceptable with an average rating score of 11.5., Conclusions: Data for lamotrigine, oxcarbazepine (and monohydroxycarbazepine) and levetiracetam demonstrate major changes in pharmacokinetics during pregnancy, suggesting the importance of therapeutic drug monitoring to assist clinicians in optimizing treatment outcomes., Competing Interests: Declaration of competing interest Dr. Deligiannidis reported grants from the National Institutes of Health (Grant R01MH120313) during the conduct of study, nonfinancial support and personal fees from Sage Therapeutics Inc. (i.e., travel reimbursement, consulting), and Brii Biosciences (i.e., consulting); Dr. Kittel-Schneider has received speaker's and author's fee from Medice Arzneimittel Pütter GmbH & Co KG and Takeda; Dr. Paulzen has received speaker fees from Neuraxpharm, Langenfeld, Germany, and Lundbeck, Hamburg, Germany; Dr. Schoretsanitis has served as a consultant for Dexcel Pharma, HLS Therapeutics, Saladax and Thermo Fisher and has received speaker fees from HLS Therapeutics and Saladax; All other authors declare no conflicts of interest. The research study did not receive funds or support from any source., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Lamotrigine was previously reported to reduce serum concentration of quetiapine. The aim of this study was to investigate whether lamotrigine dose or quetiapine formulation was of importance for the drug interaction., Methods: Patients combining lamotrigine with quetiapine (cases) were included retrospectively from a routine therapeutic drug monitoring (TDM) service, as were a control group of patients using quetiapine without any interacting drugs. The case and control groups were divided into groups using immediate release (IR) and extended release (XR) quetiapine. The case group was further split into high-dose (> 200 mg/day) and low-dose (≤ 200 mg/day) lamotrigine users. Quetiapine concentration-to-dose (C/D) ratio and metabolite-to-parent ratio (MPR) were compared between the control group and dose-separated case groups using ANOVA test and t-tests., Results: In total, 406 patients were included. The mean C/D ratio of IR quetiapine was 46% lower in the high-dose lamotrigine group compared with the control group (P < 0.001), while no interaction effect was present in the low dose lamotrigine group (P = 0.7). Regardless of lamotrigine dose, there was no difference in quetiapine C/D ratio for patients using the XR formulation (P = 0.4). The quetiapine MPR was unaffected regardless of formulation and lamotrigine dose (P ≥ 0.06)., Conclusion: The effect of lamotrigine in reducing quetiapine concentration is only significant for patients using quetiapine IR tablets who are treated with lamotrigine doses > 200 mg/day. Because of high variability in the interaction effect, TDM of quetiapine should be recommended during co-prescription of high-dose lamotrigine., (© 2024. The Author(s).)

We investigated the effect of comedication with ethosuximide (ESM) on lamotrigine (LTG) blood levels. Based on observations from clinical practice, we hypothesized that ESM reduces the LTG serum concentration. We additionally evaluated this effect in the presence of concomitant valproic acid (VPA). We retrospectively analyzed samples of inpatients from our department who had been treated with a combination of ESM and LTG between 2017 and 2021. We additionally used data on LTG serum concentrations from a previously published cohort from our center. Generalized estimation equations (GEEs) were used for statistical analyses. We included 523 samples from 209 patients. GEE analyses showed that LTG trough serum concentrations were significantly lower in samples with ESM comedication and significantly higher in samples with concomitant VPA. The effect of ESM was moderated by patients' age; in children and adolescents, LTG serum concentrations were 37% lower than in samples without ESM, whereas in adults, LTG serum concentrations were 14% lower. The effect we found in our data is relevant to daily clinical practice, if patients are not seizure-free despite typical daily LTG dosage, or if they develop side effects during ESM withdrawal. It should be considered especially in children and adolescents., (© 2024 International League Against Epilepsy.)

Purpose: The aim of the study was to appraise the current evidence on the optimal serum level for lamotrigine (LAM) in the treatment of mood disorders (major depressive disorder, bipolar disorder)., Methods: Major databases were searched for randomized controlled trials, open-label trials, and observational studies reporting serum LAM levels in adult patients treated with LAM for mood disorders., Results: A total of 814 abstracts were screened and 24 articles were selected for full-text review. Seven studies (226 bipolar disorder and 17 major depressive disorder patients) including 1 randomized controlled trial (n = 43), 3 prospective (n = 53), and 3 retrospective (n = 147) studies met the study criteria with a study duration range from 6 to 96 weeks. Lamotrigine daily dosage varied from 25 to 425 mg/d among the studies. Studies reported inconsistent findings between LAM concentration and efficacy. Three studies did not identify a relationship between LAM levels and a significant improvement in mood symptoms. Two studies (n = 99) reported higher response rates with LAM serum levels of greater than 3.25 μg/mL and 1 study (n = 25) reported a wide therapeutic window of 5 to 11 μg/mL. Overall, LAM was well tolerated with no major significant adverse effects., Conclusions: Most studies showed a minimum LAM threshold level of 3 μg/mL in patients with mood disorders; however, the data are inconsistent regarding the therapeutic range for LAM. Based on the pooled data, there is inconsistent evidence to make conclusive recommendations on therapeutic LAM serum levels for mood improvement. Further studies including larger sample sizes are required to address this relevant clinical question., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

The unbound concentrations of 14 commercial drugs, including five non-efflux/uptake transporter substrates-Class I, five efflux transporter substrates-class II and four influx transporter substrates-Class III, were simultaneously measured in rat liver, muscle, and blood via microanalysis. K puu,liver and K puu,muscle were calculated to evaluate the membrane transport activity and cell metabolism on the unbound drug concentrations in the skeletal muscle and liver. For Class I compounds, represented by antipyrine, unbound concentrations among liver, muscle and blood are symmetrically distributed when compound hepatic clearance is low. And when compound hepatic clearance is high, unbound concentrations among liver, muscle and blood are asymmetrically distributed, such as Propranolol. For Class II and III compounds, overall, the unbound concentrations among liver, muscle, and blood are asymmetrically distributed due to a combination of hepatic metabolism and efflux and/or influx transporter activity., (© 2021 Pharmaron Beijing Co Ltd. Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)

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., Competing Interests: C. G. Bien obtained honoraria for speaking engagements from UCB (Monheim, Germany) and Desitin (Hamburg, Germany). He receives research support from the Deutsche Forschungsgemeinschaft (German Research Council, Bonn, Germany) and Gerd-Altenhof-Stiftung (Deutsches Stiftungs-Zentrum, Essen, Germany). Christian Brandt has received personal compensation from Arvelle Therapeutics (Zug, Switzerland), Desitin (Hamburg, Germany), Eisai (Woodcliff Lake, NJ), GW Pharmaceuticals (Histon, United Kingdom), Idorsia (Basel, Switzerland), and UCB Pharma (Monheim, Germany) for consulting services or speaking activities. The remaining authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

This study has developed and validated a novel UPLC method to quantify lacosamide (LCM), oxcarbazepine (OXC), and lamotrigine (LTG) in children with epilepsy in Xinjiang, China. Phenytoin sodium was used as the internal standard. The mobile phase contained ammonium dihydrogen phosphate solution (10 mmol/L, pH = 4.0) and methanol (55:45, v/v). The flow rate, injection volume, column temperature, and detection wavelength were 0.2 mL/min, 2 μL, 30°C, and 240 nm, respectively. The method was linear within 0.5-40, 2.5-80, and 2.5-40 μg/mL for LCM, 10-hydroxycarbazepine (MHD), and LTG, respectively (r 2  ≥ 0.998). The intra- and inter-day precision as measured by the relative standard deviation values was between 1.36 and 4.50, 0.54 and 1.91, and 0.58 and 1.56%. Recovery ranged from 96.58 to 106.22%. All serum samples could be maintained for up to 3 h at ambient temperature, 24 h at 4°C, 30 days at -30°C, and after successive freeze-thaw cycles (24 h per cycle) in the absence of significant degradation., (© 2020 John Wiley & Sons, Ltd.)

Perampanel is a third-generation antiepileptic drug (AED), while lamotrigine is a second-generation AED. Both drugs are subject to extensive pharmacokinetic variability between different patients. Furthermore, it has been reported that perampanel and lamotrigine may be implied in pharmacokinetic drug-drug interactions with other AEDs such as carbamazepine or valproate, with consequent alterations of plasma concentrations. This emphasizes the relevance of therapeutic drug monitoring of perampanel and lamotrigine with appropriate bioanalytical methods. Herein, the development and validation of a bioanalytical techique for the simultaneous quantification of perampanel and lamotrigine in human plasma samples is described. The reported method is based on high-performance liquid chromatography coupled with diode-array detection (HPLC-DAD) and sample preparation consists of liquid-liquid extraction. Chromatographic separation of the analytes (lamotrigine and perampanel) and the internal standard (entacapone) was achieved in 12 min on a reversed-phase C 18 column at 40 °C by applying a gradient elution program with a mobile phase composed of 0.1% ortho-phosphoric acid pH 2.79 (A) and acetonitrile (B) pumped at 1.0 mL/min. Perampanel was quantified at 320 nm while lamotrigine and the internal standard were monitored at 306 nm. Calibration curves were linear in the concentration range of 0.03-4.5 µg/mL (r 2  = 0.9978) for perampanel and in the concentration range of 0.25-30 µg/mL (r 2  = 0.9981) for lamotrigine. Overall precision did not exceed 14.3% and accuracy ranged from -6.08 to 12.66%. Some drugs potentially co-prescribed with perampanel and lamotrigine were tested and did not interfere with the retention times of the analytes and internal standard. The method was then successfully applied for the quantification of perampanel and lamotrigine in plasma samples obtained from 42 drug-resistant epileptic patients admitted to the Coimbra University Hospital Centre (CHUC.EPE, Coimbra, Portugal). In conclusion, it is a suitable method for the therapeutic drug monitoring of lamotrigine and perampanel in drug-resistant epileptic patients, as well as, for the assessment of drug-drug interactions. It can also be adopted by hospitals and laboratories, when HPLC with fluorescence and mass spectrometry detections are unavailable., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Genetic and nongenetic factors may contribute to lamotrigine (LTG) plasma concentration variability among patients. We simultaneously investigated the association of UGT1A1, UGT1A4, UGT2B7, ABCB1, ABCG2, and SLC22A1 variants, as well as antiepileptic drug co-treatment, on LTG plasma concentration in 97 Mexican Mestizo (MM) patients with epilepsy. UGT1A4*1b was associated with lower LTG dose-corrected concentrations. Patients with the UGT2B7-161T allele were treated with 21.22% higher LTG daily dose than those with CC genotype. Two novel UGT1A4 variants (c.526A>T; p.Thr185= and c.496T>C; p.Ser166Leu) were identified in one patient. Patients treated with LTG + valproic acid (VPA) showed higher LTG plasma concentration than patients did on LTG monotherapy or LTG + inducer. Despite the numerous drug-metabolizing enzymes and transporter genetic variants analyzed, our results revealed that co-treatment with VPA was the most significant factor influencing LTG plasma concentration, followed by UGT1A4*1b, and that patients carrying UGT2B7 c.-161T required higher LTG daily doses. These data provide valuable information for the clinical use of LTG in MM patients with epilepsy.

Objective: The objective of the study was to describe the effect of the vaginal ring and transdermal patch on lamotrigine serum levels in women with epilepsy., Background: Previous 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., Methods: Retrospective 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., Results: Six 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., Conclusions: The 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., Competing Interests: Declaration of competing interest The authors have no conflicts of interested related to this publication. Elizabeth E. Gerard has received research support from Xenon, Sunovion, and SAGE pharmaceuticals and from the following NIH/NINDS grants: U01-NS038455, 2U01-NS038455. She has received speaker/travel fees from UCB Pharma. Micheal P. Macken received research support and consulting fees from Liva Nova and UCB Pharma, as well as consulting fees from Sunovion. Alexa King, Elizabeth Bachman, and Jungwha Lee have no disclosures., (Copyright © 2020 Elsevier Inc. All rights reserved.)

This paper describes a new approach for the determination of carbamazepine and lamotrigine in biological samples by ionic liquid dispersive liquid-phase microextraction prior to high-performance liquid chromatography with ultraviolet detection. The effects of different ionic liquids (ILs) on the extraction efficiency of carbamazepine and lamotrigine were investigated. The highest extraction efficiencies of carbamazepine and lamotrigine were obtained using 30 ?L of 1-me-thyl-3-octylimidazolium hexafluorophosphate [C8MIM][PF6]. Several factors affecting the microextraction efficiency, such as the type and volume of extracting solvent, type and volume of disperser solvent, salt concentration, and pH of the sample solution have been optimized. The calibration plots were linear in the range of 0.1-20 mg L-1 for carbamazepine and 0.3-40 mg L-1 for lamotrigine with detection limits of 0.04 mg L-1 for carbamazepine and 0.07 mg L-1 for lamotrig-ine in plasma samples. The results confirm the suitability of the presented method as a sensitive method for the analysis of the target analytes in urine and plasma samples.

Background: 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., Methods: 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., Results: 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)., Conclusions: 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.

Nasal drug delivery has become a popular research field in the last years. This is not surprising since the nose possesses unique anatomical and physical properties. Via the nasal mucosa local, systemic, and directly central nerve systemic (CNS) effect is achievable. Powders have favorable physicochemical properties over liquid formulations. Lamotrigine (LAM) is an antiepileptic agent with a relatively mild side effect spectrum, but only available in tablet form on market. Reducing the particle size to the nano range can affect the bioavailability of pharmaceutical products. The aim of this article was to continue the work started, compare the in vitro properties of a nanonized lamotrigine containing nasal powder (nanoLAMpowder) and its physical mixture (PM) that were prepared by dry milling. Moreover, to study their trans-epithelial absorption to reach the blood and target the brain by axonal transport. Due to the dry milling technique, the particle size of LAM, their surface and also their structure changed that led to higher in vitro dissolution and permeability rate. The results of the in vivo tests showed that the axonal transport of the drug was assumable by both intranasal formulations because the drug was present in the brain within a really short time, but the LAM from the nanoLAMpowder liberated even faster.

Purpose: To investigate the effects of various progestins in combined oral contraceptives (COCs) on lamotrigine (LTG) serum concentrations and, vice versa, the potential impact of LTG on progestin serum levels during the menstrual cycle., Methods: Twenty women with epilepsy (WWE) undergoing LTG monotherapy and COC (LTG group; mean ± SD [median; range] age 24.2 ± 4.6 [23.0; 18-37] years) as well as fourteen controls on COC (24.9 ± 5.6 [22.5; 20-39] years) were assessed for eligibility and all agreed to participate in the study and remained for data analyses., Results: LTG levels differed significantly between phases of inactive pill and active pill use (p= 0.004), particularly with drospirenon (p= 0.018) and levonorgestrel (p= 0.068) as progestogen component but not with gestoden (p= 0.593). Furthermore, the LTG group showed significantly lower progestin levels during inactive pill when compared to active pill use with respect to levonorgestrel (p= 0.042) and drospirenon (p= 0.018) but not to gestoden (p= 0.109). Progestin concentrations did not differ between patients and controls (p> 0.05)., Conclusions: The findings suggest that drospirenon and levonorgestrel but not gestoden seem to reduce LTG serum concentrations when being co-administered in WWE which might be of importance concerning seizure risk. Vice versa, no effect of LTG on several progestins could be demonstrated, arguing against a potential loss of contraception safety with LTG., (Copyright © 2019 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Background: In 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., Methods: Plasma, 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., Results: Plasma 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)., Conclusions: The 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)., (Copyright © 2019 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Lamotrigine [LTG] is primarily an anti-epileptic drug used to treat seizure disorders, depression, and bipolar disease. It is generally well tolerated with limited side effects reported during routine use. Adverse events after overdose include neurotoxicity in the form of sedation and seizure activity, as well as cardiopulmonary toxicity in the form of sodium-channel blockade and cardiovascular collapse. There is no consensus regarding the role of hemodialysis (HD) in management of lamotrigine toxicity. Based on pharmacological properties, LTG is a candidate for extracorporeal removal, however, the successful use of HD for the treatment of this poisoning is not well described. We report the case of a 44 year-old female after a LTG overdose that experienced prolonged sedation that was ultimately treated with HD with an excellent response., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Lamotrigine, a frequently used antiepileptic drug, inhibits voltage-gated sodium-channels. By suppressing the release of glutamate and aspartate, lamotrigine acts as a membrane stabilizer, and it is also effective in bipolar disorder and migraine. However, lamotrigine is known to induce tremor among 4-10% of patients. We examined the lamotrigine-induced tremor in 28 epilepsy patients (age: 38.06 ± 13.56 years; 24 females and 4 males) receiving lamotrigine monotherapy and compared the data to 30 age- and sex-matched controls (age: 33.06 ± 10.71 years; 25 females and 5 males). Tremor was visually assessed by clinical tremor rating scales. Quantitative characteristics (intensity, center frequency and frequency dispersion) which are regularly used to differentiate various tremor syndromes were measured by validated, sensitive biaxial accelerometry in resting, postural and intentional positions. Regularity of repetitive finger and hand movements and reaction time were also determined. Data were statistically analyzed. Clinical tremor rating scales detected pathological tremor in three patients (10%), while accelerometry revealed tremor in seven patients (25%). Center frequency of patients with pathological tremor was similar to controls, but the frequency dispersion was significantly lower and tremor intensity was significantly higher in both postural and intentional positions. Rhythmic movements and reaction time were normal. Our results show that objective measurements detect pathological intention tremor in 25% of epilepsy patients receiving lamotrigine monotherapy. Quantitative characteristics suggest the involvement of the cerebellum in the pathomechanism of lamotrigine-induced tremor. Determining the parameters of drug-induced tremor syndromes might help to understand the complex action of tremor generator networks.

Garcinia cambogia supplements are widely used for weight loss. Knowing that epilepsy patients are at greater risk of developing overweight/obesity, the investigation of herb-drug interactions involving antiepileptic drugs of narrow therapeutic index is fully justified. This work was planned to assess potential pharmacokinetic-based interactions between G. cambogia extract and lamotrigine (LTG) through two independent pharmacokinetic studies. In the first study (co-administration study), rats were orally co-administered with a single-dose of G. cambogia extract (821 mg/kg) and LTG (10 mg/kg). In the second study (pre-treatment study), rats were orally pre-treated for 14 days with G. cambogia extract (821 mg/kg/day), being LTG administered (10 mg/kg) on the 15th day. Rats of the control groups received water instead of the extract. Following LTG administration, blood samples were collected until 96 h post-dose, and plasma LTG concentrations were determined and submitted to a non-compartmental analysis. Globally, no statistically significant effects were identified in the co-administration study of G. cambogia extract and LTG. In the 14-day pre-treatment study, a statistically significant decrease in the rate of systemic exposure to LTG and an increase of apparent volume of distribution were found. Even so, a minor or no clinical impact is expected from the administration of G. cambogia dietary supplements and LTG., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background and Objectives: Lamotrigine (Lamictal ® ) is a broad-spectrum antiepileptic drug available in both immediate-(IR) and extended-release (XR) formulations. Here, we present a new physiologically based pharmacokinetic (PBPK) model for IR and XR formulations of lamotrigine to predict disposition in adults and children, plus drug-drug interactions (DDIs)., Methods: Models for lamotrigine IR and XR formulations were constructed using a Simcyp ® Simulator. Concentration-time profiles were simulated for lamotrigine IR single (S D ) and steady-state (SS) doses ranging from 25 to 200 mg in adults, as well as 2 mg/kg (S D ), and 7.7-9.4 mg/kg (SS) in children aged between 4 and 17 years. Lamotrigine XR profiles were simulated for S D and SS doses ranging from 250 to 400 mg. DDI prediction with lamotrigine was simulated in adults with enzyme-inducing drugs, rifampin (rifampicin) and ritonavir, as well as the enzyme inhibitor, valproic acid., Results: The lamotrigine model predicted adult area-under-the-curve (AUC) and peak plasma concentration (C max ) results for IR S D within 35% of observed data; lamotrigine IR SS dosing was within 10% and 30% of observed data, respectively. Pediatric lamotrigine IR S D AUC and C max values were within 10% and 15% of observed data, respectively. AUC and C max values for lamotrigine XR S D simulated in adults were within 20% of observed data; similarly lamotrigine XR SS parameters were within 10%. Concerning DDI simulation in adults, predicted-to-observed lamotrigine AUC ratios [AUC DDI /AUC alone ] were within 15% for ritonavir and rifampin, and 20% for valproic acid., Conclusions: Our developed PBPK lamotrigine profile accurately predicts DDIs and lamotrigine IR/XR formulation disposition in adults and children. This PBPK model will be helpful in designing future DDI studies for co-administration of lamotrigine with other drugs and in designing individualized patient dosing regimens.

Lamotrigine is one of the most widely used antiepileptic drugs in the treatment of epilepsy. This kind of drug needs to be used in the long term and should be quantitatively detected in the blood of patients to avoid drug toxicity caused by individual differences and environmental and pathological changes in the process of taking. The detection of antiepileptic drugs in human blood is challenging because of their low contents and the interference of complex matrices. Thus, the sample enrichment method has been commonly used to improve the sensitivity of detection. In this work, we have synthesized a new "bi-(4-vinyl phenylquinoline) amide" compound and used it as the monomer to produce the hyper-cross-linked microporous polymer for the enrichment of lamotrigine. This material has a high adsorption capacity, specificity, and linearity, which can improve the detection sensitivity of lamotrigine by high-performance liquid chromatography (HPLC). The mechanism of this phenomenon has also been investigated. Finally, we have developed the microporous polymer enrichment coupled with HPLC method for the quantitative determination of lamotrigine in rat and human serum samples. This method has excellent precision, accuracy, and recovery, meeting the test of biological sample. The low limit of quantitation was 0.625 μg/mL. Graphical abstract.

Background: 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., Methods: 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., Results: 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., Conclusions: 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.

Objective: The aim of this study was to measure and investigate correlations of lamotrigine concentrations in maternal as well as umbilical cord blood, amniotic fluid, and breast milk to account for the distribution of the drug., Methods: Concentrations of lamotrigine were measured in 19 mother-infant pairs at the time of delivery. To account for the penetration ratio into amniotic fluid, cord blood and breast milk, the concentration of lamotrigine in the particular environment was divided by the concentration in maternal serum. A no-intercept model was applied for associations between maternal serum concentrations, amniotic fluid, umbilical cord blood, and breast milk concentrations., Results: The mean daily dosage of lamotrigine was 351.32 mg (range 50-650 mg). We detected associations between maternal serum and amniotic fluid (β = 0.088, p < 0.001), as well as umbilical cord (β = 0.939, p < 0.001) and breast milk (β = 0.964, p < 0.001). The median penetration ratio into amniotic fluid, cord blood, and breast milk was 0.68, 0.92, and 0.77, respectively., Conclusions: Lamotrigine concentrations in amniotic fluid, cord blood, and breast milk give evidence that the fetus/newborn is constantly exposed to lamotrigine. Maternal serum concentrations predicted exposure via amniotic fluid, umbilical cord, and breast milk. Data suggest that therapeutic drug monitoring can be recommended as part of the clinical routine in psychopharmacotherapy for pregnant or breastfeeding women.

Lamotrigine (LTG) has been widely prescribed as an antipsychotic drug, although it causes idiosyncratic drug-induced liver injury in humans. LTG is mainly metabolized by UDP-glucuronosyltransferase, while LTG undergoes bioactivation by cytochrome P450 to a reactive metabolite; it is subsequently conjugated with glutathione, suggesting that reactive metabolite would be one of the causes for LTG-induced liver injury. However, there is little information regarding the mechanism of LTG-induced liver injury in both humans and rodents. In this study, we established an LTG-induced liver injury mouse model through co-administration with LTG and a glutathione synthesis inhibitor, l-buthionine-(S,R)-sulfoximine. We found an increase in alanine aminotransferase (ALT) levels (>10 000 U/L) in C57BL/6J mice, with apparent interindividual differences. On the other hand, a drastic increase in ALT was not noted in BALB/c mice, suggesting that the initiation mechanism would be different between the two strains. To examine the cause of interindividual differences, C57BL/6J mice that were co-administered LTG and l-buthionine-(S,R)-sulfoximine were categorized into three groups based on ALT values: no-responder (ALT <100 U/L), low-responder (100 U/L < ALT < 1000 U/L) and high-responder (ALT >1000 U/L). In the high-responder group, induction of hepatic oxidative stress, inflammation and damage-associated molecular pattern molecules in mRNA was associated with vacuolation and karyorrhexis in hepatocytes. In conclusion, we demonstrated that LTG showed apparent strain and interindividual differences in liver injuries from the aspects of initiation and exacerbation mechanisms. These results would support interpretation of the mechanism of LTG-induced liver injury observed in humans., (© 2018 John Wiley & Sons, Ltd.)

Aim: Lamotrigine (LTG) is a widely used anti-epileptic drug that is administered to avoid seizures and to maintain seizure-free status. However, several factors reportedly cause individual differences of plasma LTG levels, and the therapeutic target range of LTG varies between individuals. Thus, to optimize effective doses of LTG, we developed a rapid and simple method for determining plasma LTG concentrations., Methods: Lamotrigine and the internal standard papaverine were extracted from human plasma using solid-phase extraction. After filtration, 5-μL aliquots of final samples were injected into the liquid chromatography-tandem mass spectrometry instrument and LTG and internal standard were separated using a Cadenza CD-C18 column (100 × 2 mm, 3 μm) with 0.1% formic acid in water/acetonitrile (2/1, v/v)., Results: The calibration curve was linear from 0.2 to 5.0 μg/mL, and assessments of recovery, intra- and inter-day precision and accuracy, matrix effects, freeze and thaw stability, and long-term stability demonstrated good reproducibility. Retention times of LTG and internal standard were 1.6 and 2.0 minutes, respectively, and the total run time was 3.5 minutes for each sample., Conclusion: We developed a rapid and simple method for determining plasma LTG concentrations. The present novel system could be used to inform LTG dose adjustments for individual patients., (© 2018 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsychopharmacology.)

Background: In a previous study, the authors had shown that in treatment-resistant depressive disorder, an early therapeutic response to lamotrigine augmentation therapy is dependent on its plasma concentrations. Lamotrigine is mainly metabolized by UGT1A4 and UGT2B7, and polymorphisms of said UGTs that affect enzyme activities have been reported. This study investigated the effect of these polymorphisms on the steady-state plasma concentrations (Css) of lamotrigine in patients with treatment-resistant depressive disorder receiving lamotrigine as augmentation therapy., Methods: The subjects were 103 depressed patients who had already shown insufficient response to at least 3 psychotropics including antidepressants, mood stabilizers, and atypical antipsychotics. The diagnoses were major depressive disorder (n = 46), bipolar II disorder (n = 44), and bipolar I disorder (n = 13). They received augmentation therapy with lamotrigine for 8 weeks. The final doses of lamotrigine were 100 mg/d for 67 subjects who were not taking valproate and 75 mg/d for 36 subjects taking valproate, respectively. Blood sampling was performed at the 8th week. Plasma concentrations of lamotrigine were measured by high-performance liquid chromatography. The genotypes of UGT1A4 142T>G, UGT2B7 -161C>T, and UGT2B7 372A>G were identified by polymerase chain reaction analyses., Results: There were no significant relationships between these polymorphisms and the Css of lamotrigine in the subjects regardless of valproate comedication., Conclusions: This study suggests that these genetic polymorphisms do not affect the Css of lamotrigine in patients with treatment-resistant depressive disorder receiving lamotrigine as augmentation therapy.

Objective: The aims of this study were to identify the influencing factors such as gender, age, dose and combinations of other antiepileptic drugs (AEDs), especially in triple combinations on the pharmacokinetic of Lamotrigine (LTG) in epilepsy patients of Northwest Chinese Han population., Methods: Data of the LTG concentration and clinical information were analyzed retrospectively from a therapeutic drug monitoring (TDM) database at the Clinical Pharmacy Laboratory of Xi'an Central Hospital between January 1, 2016 and January 1, 2018. The independent-sample t-test, one-way ANOVA analysis and Bonferroni and Tamhane T3 post-hoc test, the stepwise multivariate regression analysis were adopted by IBM SPSS, version 22.0., Results: 226 serum samples met the inclusion criteria and were evaluated. The mean LTG serum concentration was 5.48±3.83 μg/mL. There were no gender differences (P = 0.64), and there were no significant effects by age on LTG serum concentration after age stratification (3-14 years old, 14-45 years old, 45-59 years old) (P = 0.05). Multiple regression analysis showed that the daily LTG dose and co-administration of other AEDs significantly affected LTG serum concentrations. Combination with enzyme-inducer AEDs, the mean steady-state LTG concentration could be decreased by 30.73% compared with LTG monotherapy. Among enzyme-inducer AEDs, particularly strong inducer Carbamazepine (CBZ) could decrease the mean LTG concentration by 53.65%, but weak inducer AEDs such as Oxcarbazepine (OXC) and Topiramate (TPM) had no effect, Valproic acid (VPA) could increase the mean LTG concentration by 93.95%, and the inducer only partially compensated for the inhibitory effect of VPA in triple combination., Conclusions: There were no significant gender and age effects, but the LTG daily dose and co-administration of other AEDs significantly affected LTG serum concentration. Combination with enzyme-inducer AEDs, especially CBZ could significantly decrease LTG serum concentrations, VPA could significantly increase LTG serum concentrations, and the inducer only partially compensated for the inhibitory effect of VPA in triple combination. In the clinical setting, these findings can help to estimate LTG concentrations and adjust dosage and evaluate adverse drug reactions., Competing Interests: The authors have declared that no competing interests exist.

Background: The pharmacokinetics of lamotrigine (LTG) is complex and varies significantly among individuals, especially among children. Therefore, this study aimed to establish a population pharmacokinetic (PPK) model of LTG in Chinese children with epilepsy and to comprehensively evaluate the effects of genetic variations in drug-metabolizing enzymes, transporters, and a transcriptional regulator on LTG pharmacokinetics., Methods: Three hundred eighty-five steady-state plasma concentrations were obtained from 179 children (age 10.72 ± 3.05 years and body weight 46.23 ± 17.77 kg) with epilepsy during therapeutic drug monitoring. These patients were divided into the PPK-model group (n = 121) and the PPK-validation group (n = 58) and were genotyped for UGT1A4, UGT2B7, ABCB1, ABCG2, SLC22A1, and HNF4α. PPK analysis was performed by nonlinear mixed effects modeling., Results: In the final model, apparent clearance (CL/F) of LTG was estimated to be 1.48 L/h; 500 mg valproic acid, oxcarbazepine, and UGT2B7-161TT genotype changed the CL/F by -46.2, +31.1, and -21.8%, respectively. Body weight was also identified as a significant covariate affecting LTG CL/F., Conclusions: A PPK-pharmacogenetic model of LTG in Chinese children with epilepsy was successfully established with nonlinear mixed effects modeling. Genotyping for UGT2B7-161C>T may be useful in titrating the optimal LTG dose.

Citrus aurantium extracts have thermogenic and lipolytic activities and are largely used for weight loss/management. Once epilepsy and obesity are prevalent comorbid conditions and herb-drug interactions can compromise antiepileptic drugs safety, we aimed to evaluate the effects of C. aurantium extract on the pharmacokinetics of lamotrigine (LTG) in rats. In the first pharmacokinetic study, a single oral dose of C. aurantium extract (164 mg/kg; p.o.) was administered with a single oral dose of LTG (10 mg/kg; p.o.). In the following study, the C. aurantium extract was daily administered (164 mg/kg; p.o.) during 14 days followed by a single dose of LTG (10 mg/kg; p.o.) on the 15th day. From the pharmacokinetic analysis, no significant effects were observed after the co-administration of C. aurantium extract and LTG. After the 14-day pre-treatment period, the main effects of the extract were limited to a significantly decrease in the time to reach peak drug concentration (t max; p < 0.05). Considering the minor effects induced by C. aurantium extract on the pharmacokinetics of LTG in rats, no relevant interactions are expected to occur in the clinical practice. Notwithstanding, C. aurantium safety in patients under LTG therapy should be further assessed in controlled clinical trials., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objective: To determine how early lamotrigine clearance (LTG-CL/F) increases during early pregnancy in women with epilepsy and to quantify the relationship of LTG-CL/F to estradiol concentrations and gestational week., Methods: This was a multicenter, observational study of pregnant women with epilepsy on lamotrigine and no interacting concomitant medications, employing frequent blood sampling prior to and early in pregnancy. A population mixed-effects modeling approach was used to describe the relationship between LTG-CL/F and gestational week and between LTG-CL/F and estradiol. Akaike information criterion (AIC) compared goodness of fit between final models and a generalized estimating equation to compare differences between low and high percentage LTG-CL/F change groups (p < 0.05)., Results: Twenty-five pregnancies (22 participants) were available. Increases in LTG-CL/F were present at 5 weeks gestational age. Both estradiol and gestational week were highly correlated with LTG-CL/F changes; LTG-CL/F increased at the rate of 0.115l/h for every gestational week and 0.844l/h for every 1ng/ml of estradiol, with women in the high LTG-CL/F percentage change group changing at a faster rate (p < 0.001). Models using gestational week performed better than models using estradiol., Interpretation: Gestational week was a better predictor of changes in LTG-CL/F than estradiol concentration and may reflect additional factors, although neither was robust enough to use clinically due to substantial interpatient variability. Changes in LTG-CL/F begin as early as the 5th gestational week, often before women know they are pregnant, emphasizing the importance of planning and early detection of pregnancy and consideration of early implementation of therapeutic drug monitoring. Ann Neurol 2018;84:556-563., (© 2018 American Neurological Association.)

Background: Previous studies have reported inconsistent findings regarding the impact of the UGT1A4*3 variant allele on lamotrigine (LTG) exposure. As no studies have controlled for nongenetic factors, the aim of this study was to compare serum concentrations of LTG in carriers versus noncarriers of UGT1A4*3 adjusting for differences in age, sex, and valproic acid (VPA) comedication., Methods: Matched data on serum concentration of LTG and UGT1A4 genotype patients with known information about VPA comedication were included retrospectively from a therapeutic drug monitoring service. Linear mixed-model analysis was used to evaluate the impact of the UGT1A4*3 variant on dose-adjusted serum concentrations (C/D ratio) of LTG. Subanalyses were performed to assess the impact of UGT1A4*3 in relation to age, sex, and VPA comedication., Results: In total, 534 patients (1735 LTG serum concentrations) were included. In the study population, UGT1A4*3 carriers (n = 87; 16.3%) were estimated to have a 13% lower LTG C/D ratio compared with noncarriers (P = 0.01). Subanalyses showed that the quantitative impact of UGT1A4*3 was greatest in postmenopausal women (>50 years) without VPA comedication. In these patients (n = 99), UGT1A4*3 carriers displayed a 40% lower LTG C/D ratio than noncarriers (P = 0.001). The UGT1A4*3 variant had no significant effect on LTG C/D ratio in the other subpopulations (P > 0.1). Regardless of patient subgroup, the concomitant use of VPA was the strongest determinant of LTG exposure by increasing the C/D ratio 2.5-fold (P < 0.001)., Conclusions: This study shows that UGT1A4*3 generally has a modest impact on LTG exposure, but it could lead to clinically relevant lowering in LTG serum concentration among postmenopausal women. The clinical impact of UGT1A4*3 in these patients needs to be assessed in relation to comedication with VPA, which is associated with a substantial increase in serum concentration of LTG.

Objective: The objectives of this study were to investigate the effect of age on pharmacokinetic parameters of lamotrigine (LTG) and estimate parameter variability., Methods: Patients (>18 years old) who were already on a steady-state dose of LTG therapy with no interacting comedications were enrolled. Patients with significant cardiac disease, severe kidney dysfunction, or moderate-to-severe liver dysfunction were excluded. Fifty milligrams of a stable-labeled intravenous LTG formulation (SL-LTG) replaced 50 mg of a patient's normal daily oral LTG dose. Thirteen blood samples were collected in each person over 96 hours. SL-LTG and unlabeled LTG concentrations were measured simultaneously by gas chromatography-mass spectrometry. Concentration-time data were analyzed by nonlinear mixed-effects modeling (NONMEM version 7.3)., Results: Twenty-eight patients representing 16 young (18-48 years old) and 12 elderly (63-87 years old) patients were included, yielding 382 unlabeled and 351 SL-LTG concentrations. A two-compartment model with first-order absorption and elimination adequately described the plasma concentration-time data. Bioavailability of oral LTG was approximately 74% and did not differ by age. LTG clearance was 27.2% lower in elderly than in young patients (1.80 L/h for a 70-kg patient)., Significance: Although LTG bioavailability was not affected by age, LTG clearance was 27.2% lower in elderly versus young patients of comparable body weight, possibly indicating lower dosages being needed in this population., (Wiley Periodicals, Inc. © 2018 International League Against Epilepsy.)

Background: Therapeutic drug monitoring of antiepileptic drugs (AEDs) is often necessary to prevent associated destructive toxicities. Tandem mass spectrometry (MS/MS) with stable-isotope-labeled internal standards is considered the gold standard for the measurement of AEDs. This study presents the development and validation of a clinical ultra-performance liquid chromatography-MS/MS method for the concurrent measurement of gabapentin, lamotrigine, levetiracetam, monohydroxy derivative of oxcarbazepine, and zonisamide in human serum., Methods: To determine the optimal assay analyte range, one year of AED therapeutic drug monitoring results (n = 1825) were evaluated. Simple protein precipitation with acetonitrile containing isotopically labeled internal standards was used. Reverse-phase ultra-performance liquid chromatography chromatographic separation was used, having a total run time of 3 minutes. Quantification of analytes was accomplished using electrospray ionization in positive ion mode and collision-induced dissociation MS. Assay parameters were evaluated per Food and Drug Administration bioanalytical guidelines., Results: After evaluating internal patient data, the analytical measuring range (AMR) of the assay was established as 0.1-100 mcg/mL. All AEDs were linear across the AMR, with R values ranging from 0.9988 to 0.9999. Imprecision (% coefficient of variation) and inaccuracy (% difference) were calculated to be <20% for the lower limit of quantitation and <15% for the low, mid, and high levels of quality controls across the AMR. All AEDs demonstrated acceptable assay parameters for carryover, stability under relevant storage conditions, matrix effects, recovery, and extraction and processing efficiency. In addition, the assay displayed acceptable concordance to results obtained from a national reference laboratory, with Deming regression R of 0.99 and slope values ranging from 0.89 to 1.17., Conclusions: A simple, cost-effective, and robust ultra-performance liquid chromatography-tandem mass spectrometry method for monitoring multiple AEDs was developed and validated to address the clinical needs of patients at our institution.

Background and Aims: In this study, we evaluate the performance of allometric concepts to predict the implications of age and size on the pharmacokinetics of lamotrigine, and assess the dose rationale across different age groups from 0.2 to 91 years., Methods: An allometrically scaled pharmacokinetic model was developed using adolescent and adult data, taking into account the effect of comedications. Model parameters were then used to extrapolate lamotrigine pharmacokinetics to older adults (> 65 years), children (4-12 years) and infants and toddlers (0.2-2.0 years). In addition, simulations were performed to identify the implication of different doses and dosing regimens for each population, so as to ensure steady-state concentrations within a predefined reference range., Results: The pharmacokinetics of lamotrigine was best described using a one-compartment model with first-order absorption and elimination. Carbamazepine, phenytoin, and valproic acid changed systemic clearance (CL) by + 76.5, + 129, and - 47.4%, respectively. Allometric principles allowed accurate extrapolation of disposition parameters to older adults and children older than 4 years of age. A maturation function was required to describe changes in exposure in younger patients. Compared with adults, a child aged 1.7 years has a 31.5% higher CL, after correcting for body weight. Patients > 65 years of age showed a decrease in CL of approximately 15%., Conclusion: Population pharmacokinetic models are usually limited to a subgroup of patients, which may mask the identification of factors contributing to interindividual variability. The availability of an integrated model including the whole patient population provides insight into the role of age-related changes in the disposition of lamotrigine, and potential implications for maintenance dose optimisation in any future trials., Trial Registration: According to GlaxoSmithKline's Clinical Trial Register, data from the GlaxoSmithKline studies LAM100034 and LEP103944, corresponding to ClinicalTrials.gov identifiers NCT00113165 and NCT00264615, used in this work, have been used in previous publications (doi: https://doi.org/10.1212/01.wnl.0000277698.33743.8b , https://doi.org/10.1111/j.1528-1167.2007.01274.x ).

In this open-label, single-center study, the pharmacokinetics, safety, and tolerability of lamotrigine chewable/dispersible tablets were assessed in healthy Chinese volunteers. Each volunteer (N = 16) received repeat doses of oral lamotrigine titrated from 25 mg to 50 mg to 100 mg over 42 days and was followed up for 10-17 days. Safety and tolerability were assessed throughout the study. Lamotrigine pharmacokinetic parameters were estimated using noncompartmental analysis. Overall, 15 (94%) volunteers completed the study. Lamotrigine serum concentrations peaked 2.5 hours postdose, with a mean terminal half-life of 36.8 hours. The apparent lamotrigine oral clearance was 1577.88 mL/h. The accumulation ratios (day 14 vs day 1) were 2.53 and 2.58 for area under the curve and peak concentration, respectively. Lamotrigine 25 to 100 mg once daily exhibited dose-proportional pharmacokinetics (based on area under the curve and peak concentration), following repeat dosing. Nine volunteers reported adverse events, 2 experienced oropharyngeal pain, each receiving 25 mg and 50 mg. One volunteer withdrew due to an increase in liver enzymes. No deaths, serious adverse effects, or skin rashes were reported during the study. No new safety concerns were observed. Overall, the pharmacokinetic profiles after repeat doses of lamotrigine chewable/dispersible tablets once daily in a Chinese population were similar to those observed in Western populations., (© 2018, The American College of Clinical Pharmacology.)

Background: Pregnant women with epilepsy on antiepileptic drugs (AEDs) may experience a reduction in serum AED levels. This has the potential to worsen seizure control., Objective: To determine if, in pregnant women with epilepsy on AEDs, additional therapeutic drug monitoring reduces seizure deterioration compared with clinical features monitoring after a reduction in serum AED levels., Design: A double-blind, randomised trial nested within a cohort study was conducted and a qualitative study of acceptability of the two strategies was undertaken. Stratified block randomisation with a 1 : 1 allocation method was carried out., Setting: Fifty obstetric and epilepsy clinics in secondary and tertiary care units in the UK., Participants: Pregnant women with epilepsy on one or more of the following AEDs: lamotrigine, carbamazepine, phenytoin or levetiracetam. Women with a ≥ 25% decrease in serum AED level from baseline were randomised to therapeutic drug monitoring or clinical features monitoring strategies., Interventions: In the therapeutic drug monitoring group, clinicians had access to clinical findings and monthly serum AED levels to guide AED dosage adjustment for seizure control. In the clinical features monitoring group, AED dosage adjustment was based only on clinical features., Main Outcome Measures: Primary outcome - seizure deterioration, defined as time to first seizure and to all seizures after randomisation per woman until 6 weeks post partum. Secondary outcomes - pregnancy complications in mother and offspring, maternal quality of life, seizure rates in cohorts with stable serum AED level, AED dose exposure and adverse events related to AEDs., Analysis: Analysis of time to first and to all seizures after randomisation was performed using a Cox proportional hazards model, and multivariate failure time analysis by the Andersen-Gill model. The effects were reported as hazard ratios (HRs) with 95% confidence intervals (CIs). Secondary outcomes were reported as mean differences (MDs) or odds ratios., Results: A total of 130 women were randomised to the therapeutic drug monitoring group and 133 to the clinical features monitoring group; 294 women did not have a reduction in serum AED level. A total of 127 women in the therapeutic drug monitoring group and 130 women in the clinical features monitoring group (98% of complete data) were included in the primary analysis. There were no significant differences in the time to first seizure (HR 0.82, 95% CI 0.55 to 1.2) or timing of all seizures after randomisation (HR 1.3, 95% CI 0.7 to 2.5) between both trial groups. In comparison with the group with stable serum AED levels, there were no significant increases in seizures in the clinical features monitoring (odds ratio 0.93, 95% CI 0.56 to 1.5) or therapeutic drug monitoring group (odds ratio 0.93, 95% CI 0.56 to 1.5) associated with a reduction in serum AED levels. Maternal and neonatal outcomes were similar in both groups, except for higher cord blood levels of lamotrigine (MD 0.55 mg/l, 95% CI 0.11 to 1 mg/l) or levetiracetam (MD 7.8 mg/l, 95% CI 0.86 to 14.8 mg/l) in the therapeutic drug monitoring group than in the clinical features monitoring group. There were no differences between the groups on daily AED exposure or quality of life. An increase in exposure to lamotrigine, levetiracetam and carbamazepine significantly increased the cord blood levels of the AEDs, but not maternal or fetal complications. Women with epilepsy perceived the need for weighing up their increased vulnerability to seizures during pregnancy against the side effects of AEDs., Limitations: Fewer women than the original target were recruited., Conclusion: There is no evidence to suggest that regular monitoring of serum AED levels in pregnancy improves seizure control or affects maternal or fetal outcomes., Future Work Recommendations: Further evaluation of the risks of seizure deterioration for various threshold levels of reduction in AEDs and the long-term neurodevelopment of infants born to mothers in both randomised groups is needed. An individualised prediction model will help to identify those women who need close monitoring in pregnancy., Trial Registration: Current Controlled Trials ISRCTN01253916., Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 22, No. 23. See the NIHR Journals Library website for further project information., Competing Interests: Manny Bagary reports personal fees from Eisai Co., Ltd, and personal fees from UCB Pharma outside the submitted work. Angela Pullen reports grants from GlaxoSmithKline plc., Cyberonics, Inc., Sanofi S.A., Desitin Pharma Ltd and UCB Pharma Ltd outside the submitted work. Sandra Eldridge is a member of the Health Technology Assessment Clinical Trials Board and National Institute for Health Research Clinical Trials Unit Support Funding.

Objective: To evaluate the impact of maternal UGT1A4 and UGT2B7 genetic polymorphisms and sex of foetus on gestation-induced changes in lamotrigine (LTG) clearance during pregnancy and post-partum (PP)., Methods: Single nucleotide polymorphisms UGT1A4 142T > G, L48V (*3), UGT1A4 70C > A, P24T (*2) and UGT2B7 802C > T, H268Y (*2) were determined in 40 women (47 pregnancies) with epilepsy treated with LTG. Retrospectively collected data included LTG dosage and LTG plasma levels before pregnancy (T0), and LTG dosage and LTG plasma level changes in the first (T1), second (T2) and third trimester (T3), and post-partum (PP) as well as the sex of the foetus., Results: Reductions in the LTG concentration-to-dose ratio (C/D ratio) during pregnancy were seen in all genotype panels and varied between -53% and -74% in T3. Genetic polymorphism of UGT1A4 T142G (*3) and UGT2B7 C802T (*2) had the most pronounced influence on LTG clearance. Women with UGT1A4 142TG had a lower decrease in the C/D ratio in T3 than those with wild type: -53% (95%CI: -68% to -39%) versus -65% (95%CI: -69% to -60%) (p = 0.04). In homozygous carriers of UGT2B7 802TT the LTG C/D ratio was reduced significantly already in T1 (p = 0.015) as well as in T3 compared to the heterozygous carriers (802CT) (p = 0.04). Multiple regression analysis demonstrated that women who carried a female foetus had a significantly higher reductions in the LTG C/D ratio from T0 to the end of pregnancy than those with a male foetus (p = 0.003). In the univariate analysis the reductions in LTG C/D ratio were -64% in T2 (95%CI: -69% to -59%) and -67% in T3 (95%CI: -71% to -63%) in women who expected a female child compared to whose with a male child -58% in T2 (p = 0.002, 95%CI: -67% to -48%) and -57% in T3 (p < 0.001, 95%CI: -65% to -48%)., Conclusion: Genetic polymorphism in UGT1A4 and UGT2B7 may play a modest role in LTG clearance changes during pregnancy. In addition, our study indicates that the sex of the foetus influenced significantly the change in LTG clearance., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Context: Lamotrigine is a broad-spectrum anticonvulsant commonly used to treat seizure and bipolar mood disorders. Evidence from case series and retrospective studies indicate that lamotrigine overdose is usually benign. However, there are reported cases of cardiac arrest and mortality following lamotrigine overdose. We undertook a systematic review of the literature on lamotrigine overdoses to better understand the clinical severity, the relevance of serum concentrations, and therapeutic interventions for overdose., Objectives: To characterize manifestations of acute lamotrigine overdose, determine if serum concentrations predict poisoning severity, and evaluate the effectiveness of overdose management interventions., Methods: We performed a literature search across eight databases, including Medline, EMBASE, and the Cochrane Library, from database inception to April 2014. Major bibliographic databases were updated on 31 May 2017. Articles were eligible if they described acute or acute on chronic lamotrigine overdose. At least one serum lamotrigine concentration had to be reported for inclusion. Reports on chronic poisoning, studies describing adverse effects of therapeutic use, and animal studies were excluded., Results: We retrieved 6238 records; 48 (51 cases) met the inclusion criteria. Cases primarily involved adults (70.6%). Potentially life-threatening symptoms of overdose included seizures (55%), Glasgow Coma Scale ≤8 (20%), hypotension (12%), and wide complex tachycardia (WCT) and cardiac arrest (6%). Among the 25 cases exposed to lamotrigine alone (13 adult; 12 pediatric), 2 adult fatalities occurred (4 g and 7.5 g ingested) and 8 pediatric cases experienced seizures (all children ≤3.5-years-old, 75% without an underlying seizure disorder, ≥ 525 mg ingested). The lowest seizure-associated serum concentration was 3.8 mg/L and 25.6 mg/L for pediatric and adult patients, respectively, suggesting children may be more susceptible to CNS toxicity. Cardiovascular toxicities occurred primarily in adult patients (threshold >25 mg/L). Overdose interventions included benzodiazepines (53%), propofol or barbiturates (14%), NaHCO 3 (20%), lipid therapy (12%), and extracorporeal elimination (10%). NaHCO 3 yielded no response in four of nine cases with conduction delays; however, two of the four cases subsequently responded with lipid therapy., Conclusions: Most cases reporting lamotrigine exposures observed mild or no toxicity; however, large exposures were associated with severe CNS depression, seizures, cardiac conduction delays, wide complex tachycardia, and death. In adults with a serum concentration >25 mg/L, severe toxicity may occur. In patients ≤3.5 years of age, ingestions of ≥525 mg may produce severe CNS depression and seizures.

Aim: To estimate pharmacokinetic variability of lamotrigine (LTG) and its clinical significance., Material and Methods: One hundred patients, including 74 women, aged from 18 to 77 years (38.23±14.37 years), with focal epilepsy were examined. Monotherapy with LTG was administered to 54 patients, duotherapy to 46 patients (LTG and valproic acid combination to 27 patients, LTG and liver enzymes inducers to 19 patients). Patients underwent procedures of therapeutic drug monitoring (TDM). Minimal (Css min ) and maximal (Css max ) steady-state LTG plasma concentrations, and concentration-to-weight ratio (CDR) were calculated., Results and Conclusion: In patients who used LTG in monotherapy, LTG Css min was 5.6±4.65 mg/l, Css max 7.59±5.54 mg/l. In the group that received LTG in combination with valproate, LTG Сss min was 7.8 [5.4; 11.8] mg / l and Css max 11.4 [7.3; 15.3] mg/l. In the group that received LTG in combination with drug-inducers of glucuronidation, Css min was 2.5 [1.99; 4.32] mg/l, Css max 4.73 [2.91; 6.70] mg/l. Statistically significant differences in CDR parameter between groups with LTG monotherapy and duotherapy, both with inducer and with inhibitors, as well as between groups of duotherapy with inductors and with inhibitors were obtained. The results of the study indicate a pronounced pharmacokinetic variability of the LTG. Conducting TDM allows the establishment of individual therapeutic concentrations of LTG in blood plasma and setting a correction vector for antiepileptic therapy.