Lamotrigine Serum Concentrations Research Articles

Ethosuximide lowers lamotrigine serum concentrations: Evidence for a clinically relevant interaction.

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.

Lamotrigine and exogenous estrogen among females with epilepsy: A retrospective analysis of administrative claims data

ObjectiveExogenous estrogen reduces lamotrigine serum concentrations. Little is known about whether providers adjust lamotrigine doses for addition of exogenous estrogen among people with epilepsy, despite expert recommendations. We determined the incidence of dose increases in lamotrigine following incident prescription of estrogen among females with epilepsy (FWE) in claims data. MethodsWe used Optum’s de-identified Clinformatics® Data Mart Database to create a cohort of U.S. FWE prescribed lamotrigine at a stable dose, with a subsequent prescription for estrogen from 2011 to 2021. We calculated cumulative incidence functions of dose increases in lamotrigine following prescription of exogenous estrogen. We performed a Cox proportional hazards model for multiple candidate predictors of a lamotrigine dose increase. ResultsThe cohort included 643 FWE, with median age of 31 (interquartile ratio [IQR] 20–42). The cumulative incidence of any lamotrigine increase was 28% (95% confidence interval [CI] 25%–32%). The median number of days after the first estrogen fill until the first lamotrigine adjustment was 118 (IQR 48–188). In unadjusted Cox models, older age, use of estrogen in hormone replacement therapy as opposed to contraception, and annual household income of $50,000-$99,999 (compared with <$50,000) were significant negative predictors of a dose adjustment in lamotrigine with hazard ratios (HRs) of 0.82 (95% CI 0.72–0.92), 0.63 (95% CI 0.42–0.95), and 0.62 (95% CI 0.40–0.95). In the adjusted Cox model, age and income remained significant predictors with HRs of 0.79 (95% CI 0.66–0.94) and 0.59 (95% CI 0.36–0.95). ConclusionDose increase of lamotrigine following addition of exogenous estrogen is rare among U.S. FWE, with potential disparities based on age and income level. More guidance may be needed for providers on this topic.

Decreased serum concentrations of antiseizure medications in children with drug resistant epilepsy following treatment with ketogenic diet.

To examine the potential influence of a ketogenic diet on serum concentrations of antiseizure medications (ASMs) in children with drug resistant epilepsy. We investigated the serum concentrations of ASMs in 25 children with drug resistant epilepsy, 2-13 years of age, treated with a classical ketogenic diet for 12 weeks. The patients were recruited from the National Centre for Epilepsy from August 15th, 2017, to January 24th, 2022. Changes in ASM serum concentrations were analyzed using a mixed effect model analysis. Significance level was set at P < 0.05 for all comparisons. The participants used 12 different ASMs during the study. The mean number of ASMs was 2.4 (±SD 0.7). None of the participants changed the type or dose of the ASMs during the intervention period. The serum concentrations of clobazam (n = 9, P = 0.002), desmethylclobazam (n = 9, P = 0.010), and lamotrigine (n = 6, P = 0.016) decreased significantly during the dietary treatment. The analytes with the largest reduction in serum concentration after 12 weeks of dietary treatment were clobazam (mean change -38%) and desmethylclobazam (mean change -37%). We found no significant change in the serum concentrations of levetiracetam, topiramate, and valproic acid. We identified a significant decrease in the serum concentrations of clobazam, desmethylclobazam, and lamotrigine following a 12-week ketogenic diet intervention in children with drug resistant epilepsy. An unintended decrease in the serum concentrations of ASMs may render the patient prone to seizures. Measurements of ASM serum concentrations might be useful in patients on a ketogenic diet, especially in patients with lack of efficacy of the dietary treatment.

Epilepsy Care in Transgender Patients.

The goal of this review is to outline the main considerations when treating transgender patients with epilepsy. Points to be addressed include the gender affirming hormone therapy regimens and how they interact with anti-seizure medications and seizure control, as well as common co-morbidities in the transgender epilepsy population. Gender affirming hormone therapy (GAHT) may affect seizure control directly, due to proconvulsant or anticonvulsant properties. GAHT may interact with anti-seizure medications; most notably, estrogen will decrease serum concentration of lamotrigine. Enzyme-inducing anti-seizure medications may decrease hormone levels, potentially interfering with goals of GAHT. Transgender epilepsy patients are at risk for co-morbidities such as decreased bone mineral density and depression. There are minimal direct studies on treatment or outcomes in the transgender epilepsy population. Providers must be knowledgeable about the bi-directional interactions between gender affirming hormone therapy and anti-seizure medications, as well as direct hormonal influences on seizure control. Future research should directly evaluate outcomes in transgender epilepsy patients with regard to seizure control, success of hormone therapy, and management of co-morbidities, to further educate providers and patients how to best manage their healthcare.

Monitoring of lamotrigine concentrations in mothers, colostrum, and breastfed newborns during the early postpartum period

ObjectiveTo analyse the concentrations of lamotrigine in maternal serum, colostrum, and serum of breastfed newborns, and to evaluate the effect of comedication with enzyme-inducing antiseizure medication and valproic acid. MethodsThis cohort study collected data from 158 women and 143 breastfed newborns. Maternal serum, milk (i.e., colostrum), and newborn serum samples were collected between the 2nd and 5th postnatal days, and lamotrigine concentrations were measured by high-performance liquid chromatography. ResultsThe median lamotrigine concentrations were 2.7 mg/L in maternal serum, 1.4 mg/L in milk, and 1.7 mg/L in newborn serum. The median milk/maternal serum concentration ratio was 0.60, the median newborn/maternal serum concentration ratio was also 0.60, and the median newborn serum/milk concentration ratio was 1.00. A significant correlation was observed between milk and maternal serum concentrations and between newborn serum and milk concentrations, maternal serum concentrations, maternal daily dose, and dose related to maternal body weight. ConclusionsExposure to lamotrigine in breastfed newborns is lower than exposure during pregnancy. However, by the same dose by the same mother, lamotrigine concentrations in both maternal serum and milk increase significantly after delivery. This finding, together with the immature function of eliminating enzymes in newborns, may be the reason for reaching concentrations in the reference range used for the general epileptic population in breastfed newborns. Therapeutic monitoring of breastfed newborns serum concentrations of lamotrigine is not mandatory; however, if signs of possible adverse events are noted, newborn serum concentrations should be analysed.

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.

The possible role of ursolic acid in Covid-19: A real game changer.

Ursolic acid (UA) is a pentacyclic terpenoid is usually found in the fruit peels and stem bark as secondary metabolites. UA has antiviral, antibacterial, and antiparasitic properties. UA has a wide spectrum of pharmacological activities against different infections. Because of the greatest antiviral and anti-inflammatory properties of UA, so it could be a plausible therapeutic herbal medicine in Covid-19 treatment. Covid-19 is a recent worldwide virulent disease pandemic due to severe acute respiratory coronavirus disease 2 (SARS-CoV-2). The pathogenesis of SARS-CoV-2 infection is related to the direct cytopathic effect and exaggerated immune response by which acute lung injury (ALI) and/or acute respiratory distress syndrome might be developed in critical cases. UA may inhibit main protease of SARS-CoV-2, and inhibits the interface flanked by SARS-CoV-2 viral proteins and its entry point commonly recognized as angiotensin converting enzyme 2 (ACE2). In addition, UA attenuates SARS-CoV-2-induced inflammatory reactions and oxidative stress.Therefore, UA could avert SARS-CoV-2 infection from causing ALI. This opinion proposed that UA might be a potential candidate therapy against Covid-19 and can mitigate post-Covid-19 complications such as lung fibrosis. In this regards, forthcoming studies are reasonable to substantiate the therapeutic role of UA in Covid-19. However, taken into account that Covid-19 is yet to be investigating for further evaluations, therefore, clinical trials are recommended regarding use and dose of UA in Covid-19 treatment, as well as secondary effects.

Acute liver failure associated with lamotrigine in children with epilepsy: A report of two cases and thoughts on pharmacogenomics

Pediatric acute liver failure (PALF) is a rare and life-threatening clinical syndrome for which drug-induced liver injury is a cause. Lamotrigine (LTG) is generally a safe and effective antiseizure medication, and PALF related to LTG has rarely been reported. Here, we describe two cases of PALF associated with LTG in children with epilepsy. In both patients, LTG was used in combination with valproic acid at an initial dose exceeding the recommended dose, which increased the risk of adverse reactions. In addition, single nucleotide polymorphisms of genes associated with the pharmacokinetics and pharmacodynamics of LTG were selected for pharmacogenomic testing. However, the results revealed that genotypes of the patients had variable effects on the serum concentration and therapeutic responsiveness of LTG and therefore did not explain the clinical manifestations well. The findings of this case report caution clinicians to be aware of the risk of liver failure when using antiseizure medication in polytherapy, especially LTG in combination with valproic acid. When administered to children, the recommended dosage of LTG should be strictly followed. Further pharmacogenomic studies are needed to help improve the efficacy and safety of epilepsy treatment in the future.

Redefining the age-specific therapeutic ranges of lamotrigine for patients with epilepsy: A step towards optimizing treatment and increasing cost-effectiveness

ObjectiveThe pharmacokinetics of lamotrigine exhibits age-related characteristics. Nevertheless, current evidence regarding the therapeutic range of lamotrigine has been derived almost exclusively from studies in adult patients, and the applicability of this therapeutic range to the pediatric population remains unclear. The purpose of this study was to establish the appropriate age-specific therapeutic ranges of lamotrigine corresponding to adequate clinical responses for patients with epilepsy. MethodsThis prospective cohort study of therapeutic drug monitoring included 582 Chinese epilepsy patients receiving lamotrigine monotherapy. Patients were divided into three age-related subgroups: (1) toddler and school-age group (2–12 years old, n = 168), (2) adolescent group (12–18 years old, n = 171), and (3) adult group (>18 years old, n = 243). Patients with a reduction in seizure frequency of 50 % or greater than baseline were defined as responders, and the remaining patients were non-responders. The relationship between lamotrigine serum concentrations and clinical response was assessed using multivariate logistic regression analysis. A receiver operating characteristic curve was generated to determine the representative cut-off values of lamotrigine trough levels, to distinguish responders from non-responders. The upper margin of the therapeutic range of lamotrigine was determined by developing concentration-effect curves for the three age-related subgroups. ResultsThe median trough levels of lamotrigine were significantly higher in responders than in non-responders from all three age-related groups (P < 0.0001). Results of logistic regression analysis revealed that higher serum concentrations of lamotrigine predicted a higher probability that seizure frequency would be reduced by more than 50 % compared to baseline (adjusted odds ratio: 1.228, 95 % CI: 1.137–1.327; P < 0.0001), and younger children were less likely to be responders (adjusted odds ratio: 1.027, 95 % CI: 1.012–1.043; P = 0.001). Based on a trade-off between sensitivity and specificity, the optimal cut-off values for lamotrigine trough concentrations corresponding to clinical response were 3.29 mg/L, 2.06 mg/L, and 1.61 mg/L in the toddler and school-age group, adolescent group, and adult group, respectively. By reducing interpatient variability, the results of the concentration-effect curves suggested no additional clinical benefit from a continued increase of doses for lamotrigine concentrations exceeding 9.08 mg/L, 8.43 mg/L, and 10.38 mg/L in the toddler and school-age group, adolescent group, and adult group, respectively. In conclusion, the therapeutic ranges of lamotrigine trough concentrations corresponding to adequate clinical response were 3.29–9.08 mg/L in the toddler and school-age group, 2.06–8.43 mg/L in the adolescent group, and 1.61–10.38 mg/L in the adult group. ConclusionsThe study determined age-specific therapeutic ranges corresponding to optimal clinical efficacy for lamotrigine. Our findings lay the foundation for catalyzing novel opportunities to optimize treatment and reduce therapeutic costs. Based on the age-specific therapeutic ranges identified in this study, individualized and cost-effective algorithms for lamotrigine treatment of epilepsy patients may be developed and validated in larger cohort studies of therapeutic drug monitoring.

Contraceptive vaginal ring reduces lamotrigine levels

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

Lamotrigine Toxicosis Treated with Intravenous Lipid Emulsion Therapy in a Dog

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

Bidirectional interaction between oral contraception and lamotrigine in women with epilepsy – Role of progestins

PurposeTo 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. MethodsTwenty 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. ResultsLTG 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). ConclusionsThe 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.

Pharmacokinetic changes and therapeutic drug monitoring of lamotrigine during pregnancy.

ObjectivesTo evaluate the pharmacokinetic changes in lamotrigine (LTG) from prepregnancy to postpartum and to assess the impact of therapeutic drug monitoring (TDM) on seizure management during pregnancy in a Chinese population.MethodsA series of women who were on LTG monotherapy before conception or during pregnancy were included in this retrospective study. The clinical characteristics of the mothers and fetuses were collected. The apparent clearance (AC) and the ratio to target concentration (RTC) were calculated for each trimester or for each month. RTCs were compared between patients with and without an increase in the frequency of seizures. A receiver operating characteristic curve to determine the RTC threshold, which predicts increased seizure frequency best, was drawn.ResultsA total of 12 patients and their 12 pregnancies were reviewed retrospectively. AC increased by 82.5% during the first trimester (p = 0.0343), 203.2% during the second trimester (p = 0.0010), and 197.0% during the third trimester (p = 0.0061) compared with the prepregnancy level. The value returned to the prepregnancy level after delivery. Seven patients who had adequate baseline information were included to examine the association between serum LTG concentration and seizure frequency. The RTC values of patients with and without an increased frequency of seizures were significantly different (p = 0.0164), and increased seizure frequency was associated with a lower RTC. An RTC < 0.64 was a predictor of deteriorating seizures.ConclusionsThe pharmacokinetic changes in LTG during pregnancy displayed marked interpatient variation. TDM can support a rational treatment plan for LTG use during pregnancy. We recommend regular monitoring of LTG serum concentrations from prepregnancy to postpartum.

The influence of concomitant antiepileptic drugs on lamotrigine serum concentrations in Northwest Chinese Han population with epilepsy

ObjectiveThe 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.MethodsData 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.Results226 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.ConclusionsThere 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.

Relationship between UGT1A4 142T>G polymorphism and serum concentration of lamotrigine in Chinese epileptic patients: a meta-analysis

Objective: To investigate the relationship between the polymorphism of Uridine diphosphate glucuronosyltransferases (UGT)1A4 142T>G (*3, L48V, rs 2011425)and serum concentration of lamotrigine(LTG) in Chinese epileptic patients. Methods: Databases including Cochrane Library, PubMed, Embase, CNKI, VIP and Wanfang were searched for the studies on the relationship of the polymorphisms of UGT1A4 142T>G with concentration of LTG (from the establishment a database to December 1, 2017). Meta-analysis was performed by RevMan 5.3. Results: We pooled data from 6 literatures, including 903 Chinese epileptic patients. Meta-analysis: In terms of the effect of UGT1A4 142T>G polymorphism on the serum concentration/dose ratio(CDR)of LTG, there was no significant difference between the wild-type(TT genotype)group and mutant-type (TG+ GG genotype) group (MD=-0.08, 95% CI (-0.40-0.23)). Further subgroup analysis was performed on LTG monotherapy or valproic acid(VPA)co-administration. For patients treated with LTG as monotherapy, difference was not statistically significant between the 2 groups(MD=0.16, 95% CI(-0.25-0.57)). But in children treated with VPA co-administration, difference was statistically significant between the 2 groups (MD=-0.50, 95% CI(-0.75--0.26)). Conclusion: UGT1A4 142T>G polymorphism has an effect on LTG concentration only with VPA co-administration in Chinese epileptic pediatric patients and those children with wild-type (TT genotype) have a tendency to have a lower serum concentration of lamotrigine.

Clinically Relevant Effect of UGT1A4*3 on Lamotrigine Serum Concentration Is Restricted to Postmenopausal Women-A Study Matching Therapeutic Drug Monitoring and Genotype Data From 534 Patients.

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. 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. 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). 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.

Pharmacokinetics, Safety, and Tolerability of Lamotrigine Chewable/Dispersible Tablet Following Repeat‐Dose Administration in Healthy Chinese Volunteers

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 25mg to 50mg to 100mg over 42days and was followed up for 10-17days. 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 2.5hours postdose, with a mean terminal half-life of 36.8hours. The apparent lamotrigine oral clearance was 1577.88mL/h. The accumulation ratios (day14 vs day1) were 2.53 and 2.58 for area under the curve and peak concentration, respectively. Lamotrigine 25to 100mg 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 25mg and 50mg. 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.

Time course of reversal of valproate-mediated inhibition of lamotrigine

PurposeConversion to lamotrigine (LTG) monotherapy from sodium valproate (VPA) is complicated by the robust pharmacokinetic interaction between the two AEDs. This study examined changes in LTG serum concentrations immediately following VPA discontinuation. MethodsTen healthy female and male adult subjects were initiated on LTG (Lamictal) 10 mg orally every morning for 30 days and VPA (Depakote ER) 500 mg orally every morning for 14 days. Morning trough (pre-dose) venous blood samples were obtained for determination of LTG and VPA concentrations on study days 14, 15, 16, 18, 20, 22, 24, 26, 28, and 30. Following the collection of the blood sample on day 15, VPA was discontinued. ResultsDespite stable LTG dosage serum concentrations on study day 20, 22, 24, 26, and 28, all were significantly lower compared to baseline (p < 0.05). ConclusionsThese observations demonstrate that the pharmacokinetic interaction between LTG and VPA is reversible, and that de-inhibition appears to follow a predictable time course. Complete offset, or reversal of this interaction takes place 10–14 days after VPA discontinuation. Our data also confirms the observation that LTG oral clearance may be inhibited by very low concentrations of VPA. These data support the conversion algorithm suggested by the manufacturer, and provide guidance to the clinician. These data provide clinically useful information in developing a dosing algorithm for converting patients to LTG monotherapy.

Effect of ketogenic diet and other dietary therapies on anti-epileptic drug concentrations in patients with epilepsy.

The ketogenic diet (KD) is an effective high-fat, adequate-protein, low-carbohydrate diet for patients with refractory epilepsy. The aim of this study was to investigate the potential effects of the KD and other dietary therapies on the concentrations of anticonvulsants in patients with epilepsy. Patients with epilepsy who were treated with the KD and other dietary therapies for more than 30days with at least one measurement performed both before and during the diet were evaluated. The mean serum concentrations and the mean serum concentrations per weight per daily dose per bioavailability (F) of anti-epileptic drugs (AEDs) before and during the treatment were assessed. We also compared the rates of events out of reference ranges of the AEDs between before and during the KD and other dietary therapies. We compared the serum albumin, alanine transaminase and aspartate transaminase data of patients with valproic acid before and during the KD. One-hundred thirty-nine patients including 81 male patients were enrolled. The median age of the patients was 2.91 (0.15-15.46) years. The median duration of the dietary therapies was 153 (35-2307) days. After the dietary therapies, the serum concentrations of carbamazepine, lamotrigine, levetiracetam, topiramate and valproic acid decreased, whereas that of phenobarbital slightly increased. However, statistical significance was found only with valproic acid (67.07±25.89μg/mL vs 51.00±20.19μg/mL, P<.05). The serum concentrations per weight per daily dose per drug F significantly decreased for valproic acid (1.38±1.39×10-2 vs 0.82±0.82×10-2 μgdmL-1 F-1 ) and phenobarbital (6.66±7.20×10-2 vs 4.75±4.07×10-2 μgdmL-1 F-1 , P<.05). The rate of occurrence of events out of reference ranges significantly increased with valproic acid (36.08% vs 57.23%, P<.05). Most anti-epileptic drug serum concentrations remained stable during the KD and other related dietary therapies except those of valproic acid. Therefore, serum concentrations of valproic acid should be monitored when the KD and other dietary therapies are concomitantly administered.

Hormone replacement therapy with estrogens may reduce lamotrigine serum concentrations: A matched case-control study.

Lamotrigine (LTG) is an antiepileptic drug that is metabolized via glucuronidation. Since the glucuronidizing enzyme is inducible by estrogens, LTG serum concentrations may fall by 50-60% when combined with hormonal contraceptives that contain ethinyl estradiol (EE). Little is known about a possible interaction between estrogens used for hormone replacement therapy (HRT) and LTG, and the few available data are conflicting. Data from serum samples analyzed for LTG were therefore retrieved from a routine therapeutic drug monitoring database. Users of HRT and EE were identified and matched with controls for age and dose. No enzyme-inducing or enzyme-inhibiting comedication was allowed. LTG serum concentration-to-dose ratios (CDRs) were calculated. Case groups and their respective control groups were compared by the Mann-Whitney U test. Seventy-nine HRT users (dose range 1-4 mg/day) and 200 EE users (dose range 20-40 μg/day), as well as 158 and 400 matching controls, respectively, could be included. Both EE users and HRT users had significantly lower mean LTG CDRs than their respective matched controls. These results suggest that HRT with estrogens may reduce serum LTG concentrations.