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.

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.

Association of Optimal Lamotrigine Serum Levels and Therapeutic Efficacy in Mood Disorders: A Systematic Review.

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.

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.

Development and validation of an innovative UPLC method to quantify lacosamide, oxcarbazepine, and lamotrigine in the serum of children with epilepsy in China.

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 (r2 ≥ 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.

Influence of genetic variants and antiepileptic drug co-treatment on lamotrigine plasma concentration in Mexican Mestizo patients with epilepsy.

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.

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

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.

Contraceptive vaginal ring reduces lamotrigine levels.

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.

Investigation of the Absorption of Nanosized lamotrigine Containing Nasal Powder via the Nasal Cavity.

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.

Lamotrigine clearance increases by 5 weeks gestational age: Relationship to estradiol concentrations and gestational age.

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.

Relationship Between UGT1A4 and UGT2B7 Polymorphisms and the Steady-State Plasma Concentrations of Lamotrigine in Patients With Treatment-Resistant Depressive Disorder Receiving Lamotrigine as Augmentation Therapy.

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.

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

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.

Microporous polymer based on the new compound "bi-(4-vinyl phenylquinoline) amide" for enrichment and quantitative determination of lamotrigine in rat and human serum.

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.

Management of lamotrigine overdose using hemodialysis.

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.

Strain and interindividual differences in lamotrigine-induced liver injury in mice.

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.

Lamotrigine Induces Tremor among Epilepsy Patients Probably via Cerebellar Pathways.

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.

Lamotrigine pharmacokinetics following oral and stable-labeled intravenous administration in young and elderly adult epilepsy patients: Effect of age.

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.

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.

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.

Development and Validation of an Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry Method for the Concurrent Measurement of Gabapentin, Lamotrigine, Levetiracetam, Monohydroxy Derivative of Oxcarbazepine, and Zonisamide Concentrations in Serum in a Clinical Setting.

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.