UGT2B10 is the Major UDP-Glucuronosyltransferase 2B Isoform Involved in the Metabolism of Lamotrigine and is Implicated in the Drug-Drug Interaction with Valproic Acid.

Lamotrigine is a phenyltriazine anticonvulsant that is primarily metabolized by phase II UDP-glucuronosyltransferases (UGT) to a quaternary N2-glucuronide, which accounts for ~ 90% of the excreted dose in humans. While there is consensus that UGT1A4 plays a predominant role in the formation of the N2-glucuronide, there is compelling evidence in the literature to suggest that the metabolism of lamotrigine is catalyzed by another UGT isoform. However, the exact identity of the UGT isoform that contribute to the formation of this glucuronide remains uncertain. In this study, we harnessed a robust reaction phenotyping strategy to delineate the identities and its associated fraction metabolized (fm) of the UGTs involved in lamotrigine N2-glucuronidation. Foremost, human recombinant UGT mapping experiments revealed that the N2-glucuronide is catalyzed by multiple UGT isoforms. (i.e., UGT1A1, 1A3, 1A4, 1A9, 2B4, 2B7, and 2B10). Thereafter, scaling the apparent intrinsic clearances obtained from the enzyme kinetic experiments with our in-house liver-derived relative expression factors (REF) and relative activity factors (RAF) revealed that, in addition to UGT1A4, UGT2B10 was involved in the N2-glucuronidation of lamotrigine. This was further confirmed via chemical inhibition in human liver microsomes with the UGT1A4-selective inhibitor hecogenin and the UGT2B10-selective inhibitor desloratadine. By integrating various orthogonal approaches (i.e., REF- and RAF-scaling, and chemical inhibition), we quantitatively determined that the fm for UGT1A4 and UGT2B10 ranged from 0.42 - 0.64 and 0.32 - 0.57, respectively. Finally, we also provided nascent evidence that the pharmacokinetic interaction between lamotrigine and valproic acid likely arose from the in vivo inhibition of its UGT2B10-mediated pathway.

Impact of UGT1A4 and UGT2B7 polymorphisms on lamotrigine plasma concentration in patients with bipolar disorder.

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 ±â€…1.1 and 1.7 ±â€…0.5 µg/ml per mg/kg) than those with the TT genotype (1.4 ±â€…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 ±â€…1.1 µg/ml per mg/kg) than those with the CC genotype (1.3 ±â€…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.

The impact of pregnancy on the pharmacokinetics of antiseizure medications: A systematic review and meta-analysis of data from 674 pregnancies.

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.

Influence of UGT2B7, UGT1A4 and ABCG2 Polymorphisms on the Pharmacokinetics and Therapeutic Efficacy of Lamotrigine in Patients with Epilepsy.

BACKGROUND AND OBJECTIVES: A substantial inter-individual variability has been observed in the pharmacokinetics of lamotrigine. The aim of the study was to investigate the impact of genetic polymorphism of the metabolizing enzymes (UGT2B7, UGT1A4) and transporter (ABCG2) on the pharmacokinetics and therapeutic efficacy of lamotrigine in patients with epilepsy. METHODS: The genetic analysis of single-nucleotide polymorphisms was conducted using polymerase chain reaction sequence. High-performance liquid chromatography/tandem mass spectrometry was employed to measure the plasma concentrations of lamotrigine. The efficacy of lamotrigine was assessed by evaluating the reduction rate of epileptic seizure frequency. RESULTS: This study included a cohort of 331 patients who were treated with lamotrigine as monotherapy. A linear correlation was observed between the lamotrigine concentration and daily dose taken (r = 0.58, p < 2.2e-16). Statistically significant differences were found in both the median plasma concentration and dose-adjusted concentration (C/D ratio) when comparing the ineffective to the effective group (p < 0.05). Multivariate analysis showed that UGT1A4 rs2011425, ABCG2 rs2231142 polymorphisms and age had a significant relationship with the lamotrigine concentrations (p < 0.05). Age was a predictive factor for C/D ratio (p < 0.001). Lamotrigine concentration and weight were good predictive factors for effective seizure outcomes (odds ratio [OR] = 0.715, 95% CI 0.658-0.776, p < 0.001; OR = 0.926, 95% CI 0.901-0.951, p < 0.001, respectively). The cut-off values of lamotrigine trough concentrations for clinical outcomes in the age-related groups were determined as 2.49 µg/ml (area under the receiver-operating characteristic curve [AUC]: 0.828, 95% CI 0.690-0.966), 2.70 µg/ml (AUC: 0.805, 95% CI 0.745-0.866) and 3.25 µg/ml (AUC: 0.807, 95% CI 0.686-0.928) for the adult group, adolescent group, and toddler and school-age group, respectively. CONCLUSIONS: UGT1A4 rs2011425 and ABCG2 rs2231142 were correlated with lamotrigine concentrations. Lower lamotrigine trough concentration was found in the ineffective group and the troughs were associated with seizure outcomes.

Population Pharmacokinetics of Lamotrigine and Its N2-Glucuronide Metabolite in Chinese Patients With Epilepsy.

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.

Association of Lamotrigine Plasma Concentrations With Efficacy and Toxicity in Patients With Epilepsy: A Retrospective Study.

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.

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

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

Dose-dependent effect of lamotrigine on quetiapine serum concentration in patients using instant release tablets.

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.

Dose Monitoring of Lamotrigine Monotherapy in Pregnancy: Are Pregnant Women with Epilepsy Currently Optimally Managed? A Systematic Review.

BACKGROUND: Lamotrigine monotherapy is the first-line treatment for epilepsy in pregnant women. However, altered pharmacokinetics during pregnancy can lead to suboptimal drug levels and increased seizure risk. This systematic review aimed to evaluate current therapeutic drug monitoring (TDM) strategies for lamotrigine monotherapy in pregnant women with epilepsy and provide guidance for monitoring and dose adjustments. METHODS: A systematic search was performed using the Ovid-MEDLINE, Ovid-EMBASE, and Ovid-Cochrane Central Register of Controlled Trials databases. Studies were included if data on lamotrigine dosing, concentration, TDM strategies, efficacy, or safety were available. RESULTS: Eleven studies were analyzed, revealing heterogeneity in outcomes with selective reporting of TDM strategies; however, clear similarities were observed. Blood samples were collected every 1-3 months during pregnancy to maintain prepregnancy baseline drug levels. Lamotrigine's apparent and relative clearance increased across trimesters, particularly in the second and third trimesters, coinciding with a period of increased seizure frequency and required dose adjustments. Details on dose adjustments were limited. Some studies have proposed using the threshold of the ratio to the target concentration to predict increased seizure risk. No distinct association was observed between adverse newborn outcomes and lamotrigine dose or serum concentration. Few maternal adverse effects have been reported after delivery, confirming the necessity of empirical postpartum tapering. CONCLUSIONS: Further studies are required to establish evidence-based standardized protocols encompassing all aspects of TDM. Early interventions, such as empirical dose increases during pregnancy and postpartum tapering, and routine monitoring from preconception to the postpartum period may enhance seizure control, reducing the risk of breakthrough seizures for the mother and unborn child.

Magnitude of Lamotrigine Exposure Through Breastfeeding.

Importance: Lamotrigine use during breastfeeding has significantly increased in the recent years, whereas breast milk lamotrigine pharmacokinetics data are still sparse. Objectives: To assess lamotrigine exposure in breastfed infants by monitoring maternal serum and breast milk concentrations. Methods: Breastfeeding women treated with lamotrigine were recruited to this study. Maternal trough breast milk and serum samples were collected, and additional breast milk samples were collected 1, 3, 6, 9, 12 hours after lamotrigine consumption. Trough breast milk/serum ratios (M/S ratio) and breast milk area under the curve (AUC) values were calculated. Results: Twenty-one breastfeeding women were recruited to this study, and the final dataset was based on the samples collected from 17 women. Lamotrigine trough serum and mother's milk concentrations were 5.1 ± 3.3 mg/L and 3.1 ± 1.9 mg/L, respectively (mean ± standard deviation). The trough M/S ratio of lamotrigine was 0.66 ± 0.22. The lamotrigine breast milk average AUC was 41.7 ± 24.6 mg·h/L. The estimated infant dose of lamotrigine was 0.52 ± 0.31 mg/kg/day and 0.26 ± 0.15 mg/kg/day for fully and partially breastfed infants, respectively. Significant correlation was found between the maternal lamotrigine serum trough concentrations and the breast milk parameters: trough breast milk concentrations (Spearman's rho = 0.986, p < 0.0001) and breast milk AUC values (Spearman's rho = 0.941, p < 0.0001). No significant correlation was found between the maternal lamotrigine daily dose and serum trough concentrations, breast milk trough concentrations, and breast milk AUC values (Spearman's rho = 0.294, 0.285, and 0.438, p = 0.252, 0.396, and 0.078, respectively). Conclusion and Relevance: High correlation between the maternal lamotrigine trough serum concentrations and the breast milk AUC values was found, implying that monitoring the maternal lamotrigine serum concentrations can be useful for prediction of exposure of infants to lamotrigine through the breast milk. The trial was registered in the Israeli trials registry MOH_2021-09-05_010243 at September 5, 2021 Retrospectively registered https://my.health.gov.il/CliniTrials.

Lamotrigine loaded nano-liposomes enhance brain selectivity in vivo.

For many patients with refractory epilepsy, antiepileptic drugs (AEDs) cannot reach effective therapeutic concentration in brain due to drugtolerance. In order to increase the selectivity of lamotrigine in brain, lamotrigine loaded nano-liposomes (LTG-NL) were designed, prepared, and the physio-chemical characterizations were observed. The distribution of LTG-NL in mice was studied by detecting the concentration of LTG extracted from animal organs, then targeting efficiency (TE) and targeting index (TI) were calculated to evaluate the brain targeting effect of LTG-NL. The mechanism of LTG-NL entry into cell was determined by A549 cell internalization experiments. The results showed that LTG-NL were small and uniform spherical particles with high entrapment efficiency and release. In vivo distribution study showed brain selectivity of LTG-NL, and TE and TI values further demonstrated the targeting capacity of LTG-NL. The cell internalization of LTG-NL was mainly by the pathway of clathrin-mediated endocytosis and macropinocytosis. These findings suggested this lipid formulation would be a drug delivery system for insoluble drugs to promote drug release and enhance brain selectivity.

Incorporating Breastfeeding-Related Variability with Physiologically Based Pharmacokinetic Modeling to Predict Infant Exposure to Maternal Medication Through Breast Milk: a Workflow Applied to Lamotrigine.

Current methods to assess risk in infants exposed to maternal medication through breast milk do not specifically account for infants most vulnerable to high drug exposure. A workflow applied to lamotrigine incorporated variability in infant anatomy and physiology, milk intake volume, and milk concentration to predict infant exposure. An adult physiologically based pharmacokinetic model of lamotrigine was developed and evaluated. The model was scaled to account for growth and maturation of a virtual infant population (n=100). Daily infant doses were simulated using milk intake volume and concentration models described by a nonlinear equation of weight-normalized intake across infant age and a linear function on the relationship of observed milk concentrations and maternal doses, respectively. Average infant plasma concentration at steady state was obtained through simulation. Models were evaluated by comparing observed to simulated infant plasma concentrations from breastfeeding infants based on a 90% prediction interval (PI). Upper AUC ratio (UAR) was defined as a novel risk metric. Twenty-five paired (milk concentrations measured) and 18 unpaired (milk concentrations unknown) infant plasma samples were retrieved from the literature. Forty-four percent and 11% of the paired and unpaired infant plasma concentrations were outside of the 90% PI, respectively. Over all ages (0-7 months), unpaired predictions captured more observed infant plasma concentrations within 90% PI than paired. UAR was 0.18-0.44 when mothers received 200 mg lamotrigine, suggesting that infants can receive 18-44% of the exposure per dose as compared to adults. UARs determined for further medications could reveal trends to better classify at-risk mother-infant pairs.

Estrogen profile- and pharmacogenetics-based lamotrigine dosing regimen optimization: Recommendations for pregnant women with epilepsy.

During pregnancy, various physiological changes occur that can alter the pharmacokinetics of antiepileptic drugs, such as lamotrigine (LTG). Anticipating the change in LTG dose required to achieve a pre-pregnancy target concentration is challenging. This study aimed to develop a refined population pharmacokinetic (PopPK) model of LTG in pregnant women with epilepsy (WWE) to identify factors explaining the variability in pharmacokinetics and to establish a model-informed individualized dosing regimen. On that basis, a coarsened model containing only clinical variables was also developed to examine its predictive performance compared to the refined model. In total, 322 concentration-time points from 51 pregnant WWE treated with LTG were employed to establish a refined PopPK model that included endogenous estrogen profiles, variants of candidate genes encoding LTG-metabolizing enzymes and -transporter proteins, and other clinical variables and a coarsened model that included only clinical variables, respectively. Data from an additional 11 patients were used for external validation of these two models. A nonlinear mixed-effect modeling approach was used for PopPK analysis of LTG. The standard goodness-of-fit method, bootstrap, normalized prediction distribution errors and external evaluation were adopted to estimate the stability and predictive performance of the candidate models. Akaike information criterion (AIC) was used to compare the goodness of fit between these two models. A lower AIC indicates a better fit of the data and the preferred model. Recommended dosing regimens for pregnant WWE were selected using Monte Carlo simulation based on the established optimal model. In the refined PopPK model, the population mean of apparent LTG clearance (CL/F) in pregnant WWE was estimated to be 2.82 L/h, with an inter-individual variability of 23.6%. PopPK analysis indicated that changes in estrogen profile during pregnancy were the predominant reason for the significant variations in LTG-CL/F. Up to the 3rd trimester, the concentration accumulation effect of E2 increased LTG-CL/F by 5.109 L/h from baseline levels. Contrary to effect of E2, E3 as the main circulating estrogen in pregnancy with a peak value of 34.41 ng/mL is 1000-fold higher than that in non-pregnancy reduced LTG-CL/F by 1.413 L/h. In addition, the UGT2B7 rs4356975 C > T and ABCB1 rs1128503 A > G variants may contribute to a better understanding of the inter-individual variability in LTG-CL/F. LTG-CL/F was 1.66-fold higher in UGT2B7 rs4356975 CT or TT genotype carriers than in CC genotype carriers. In contrast, ABCB1 rs1128503 GG genotype carriers had only 71.9% of the LTG-CL/F of AA or AG genotype carriers. In the coarsened PopPK model, the gestational age was a promising predictor of changes in LTG-CL/F. When comparing these two models, the refined PopPK model was favored over the coarsened PopPK model (AIC = -30.899 vs. -20.017). Monte Carlo simulation based on optimal PopPK model revealed that the LTG dosage administered to carriers of the UGT2B7 rs4356975 CT or TT genotype required a 33-50% increase to reach the pre-pregnancy target concentration, and carriers of the ABCB1 rs1128503 GG genotype required a 33-66% lower dose of LTG than carriers of the ABCB1 rs1128503 AA or AG genotype. Changes in estrogen profile during pregnancy was a better predictor of variations in LTG-CL/F than gestational age. The developed model based on estrogen profile and pharmacogenetics can serve as a foundation for further optimization of dosing regimens of LTG in pregnant WWE.

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

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

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.

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

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

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 17.9 mg/L from 175 patients. The median (range) age and weight were 11.8 years (0.8-18 years) and 32.7 kg (8-110 kg). 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 2.5 mg/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.

Development, Characterization, and in-vivo Pharmacokinetic Study of Lamotrigine Solid Self-Nanoemulsifying Drug Delivery System.

PURPOSE: This study aimed to prepare solid self-nanoemulsified drug delivery system (S-SNEDDS) of lamotrigine (LMG) for enhancing its dissolution and oral bioavailability (BA). METHODS: Nineteen liquid SNEDDS were prepared (R1-R19) using D-optimal design with different ratios of oil, surfactant (S), and cosurfactant (Cos). The formulations were characterized regarding robustness to dilution, droplet size, thermodynamic stability testing, self-emulsification time, in-vitro release in 0.1 N HCl and phosphate buffer (PB; pH 6.8). Design Expert® 11 software was used to select the optimum formulations. Eight S-SNEDDS were prepared (S1-S8) using 23 factorial design, and characterized by differential scanning calorimetry (DSC), powder x-ray diffraction (PXRD), and scanning electron microscopy (SEM). The optimum formulation was chosen regarding in-vitro drug released in 0.1 N HCl and PB, compared to pure LMG and commercial tablet (Lamictal®). The BA of LMG from the optimized S-SNEDDS formulation was evaluated in rabbits compared to pure LMG and Lamictal®. RESULTS: The optimized S-SNEDDS was S2, consisting of R9 adsorbed on Aeroperl® 300 in a ratio of 1:1, with the best results regarding in-vitro drug released in 0.1 N HCl at 15 min (100%) compared to pure LMG (73.40%) and Lamictal® (79.43%), and in-vitro drug released in PB at 45 min (100%) compared to pure LMG (30.46%) and Lamictal® (92.08%). DSC, PXRD, and SEM indicated that LMG was molecularly dispersed within the solid nano-system. The BA of S2 was increased 2.03 and 1.605 folds compared to pure LMG, and Lamictal®, respectively. CONCLUSION: S2 is a promising S-SNEDDS formulation. It can be a potential carrier for improving dissolution, and BA of LMG.

Sources of lamotrigine pharmacokinetic variability: A systematic review of population pharmacokinetic analyses.

BACKGROUND: Lamotrigine (LTG) is a new generation antiepileptic drug. However, relatively high interindividual pharmacokinetic variability of this drug has been documented. Therefore, several population pharmacokinetic studies of lamotrigine were conducted to identify factors influencing its pharmacokinetics. OBJECTIVE: This systematic review aimed to summarize significant factors influencing LTG pharmacokinetics and their relationships with pharmacokinetic parameters as well as the magnitude of pharmacokinetic variability. METHODS: Four databases i.e. PubMed, Scopus, CINAHL Complete, and Science Direct were systematically searched from their inception to March 2020. Population pharmacokinetic studies of LTG conducted in humans using a nonlinear-mixed effect approach were eligible for a systematic review. RESULTS: Nineteen studies were included in this systematic review. Most studies characterized LTG pharmacokinetics as a one-compartment model structure. The three most frequently identified significant covariates influencing LTG clearance included concomitant antiepileptic drugs, body weight, and genetic polymorphisms. Approximately 58% of the studies did not externally validate the models. CONCLUSIONS: For clinical application, LTG maintenance dose could be optimized using population pharmacokinetic models employing covariates such as concomitant antiepileptic drugs, body weight, and genetic polymorphisms. However, these models should be assessed for their predictability in the target population before utilizing such models in clinical settings.