Lamotrigine Plasma Concentrations Research Articles

Variation in dose and plasma level of lamotrigine in patients discharged from a mental health trust.

The objectives of this study were to investigate the dose of lamotrigine when prescribed with an enzyme inhibitor or enzyme inducer in patients discharged from a mental health trust and to determine the corresponding lamotrigine plasma concentrations and the factors that may affect these. All patients discharged on lamotrigine between October 2007 and September 2012 were identified using the pharmacy dispensing database. We recorded demographic details, lamotrigine dose and plasma levels and coprescribed medication. During the designated period, 187 patients were discharged on lamotrigine of whom 117 had their plasma levels recorded. The mean lamotrigine daily dose was 226.1 mg (range 12.5-800 mg) and the mean plasma level 5.9 mg/l (range 0.8-18.1 mg/l). Gender, ethnicity, diagnosis and smoking status had no significant effect on dose or plasma levels. Patients taking an enzyme-inducing drug (n = 6) had significantly lower plasma levels [mean (SD) 3.40 (1.54) mg/l] than those not taking enzyme inducers [n = 111; 6.03 (3.13) mg/l; p = 0.043]. Patients taking an enzyme-inhibiting drug (n = 23) had significantly higher levels [7.47 (3.99) mg/l] than those not taking an inhibitor [n = 94; 5.52 (2.75) mg/l; p = 0.035]. No significant difference was found between the doses of lamotrigine in patients taking an enzyme inhibitor and those not taking one (p = 0.376). No significant difference was found between the doses of lamotrigine in patients taking an enzyme-inducing drug and those not taking any (p = 0.574). Current dosing recommendations indicate that lamotrigine doses should be halved in individuals taking enzyme inhibitors and doubled in those on enzyme inducers. In our survey these recommendations were rarely followed with the consequence that patients received too high or too low a dose of lamotrigine, respectively.

Specific OCT1 and ABCG2 polymorphisms are associated with Lamotrigine concentrations in Chinese patients with epilepsy

PurposeThe pharmacokinetics of Lamotrigine (LTG) varies widely among patients with epilepsy. In this study, we are aiming to investigate the effects of OCT1, ABCG2, ABCC2 and HNF4α genetic polymorphisms on plasma LTG concentrations and therapeutic efficacy in Chinese patients with epilepsy. MethodsThe study cohort comprised 112 Han Chinese patients with epilepsy who were receiving LTG monotherapy. Blood samples were taken and LTG levels were measured. The polymorphisms of OCT1 rs2282143, rs628031, ABCG2 rs2231142, rs2231137, ABCC2 rs2273697 and HNF4α rs2071197, rs3212183 were determined. The therapeutic efficacy of LTG at the 1-year time-point was assessed. Data analysis was performed using IBM SPSS Statistics 22.0. ResultsThere were significant associations between OCT1 rs628031, ABCG2 rs2231142 polymorphisms and normalized LTG concentrations in patients with epilepsy (P<0.05). On the other hand, polymorphisms of OCT1 rs2282143, ABCG2 rs2231137, ABCC2 rs2273697 and HNF4α rs2071197, rs3212183 exhibited no correlation with LTG concentrations. Additionally, no significant association existed between all the studied genotypes and LTG treatment response. ConclusionsThese results suggested that the polymorphisms of OCT1 rs628031 and ABCG2 rs2231142 may affect LTG metabolism in Chinese patients with epilepsy. However, future studies are necessary to be investigated in a larger cohort of epileptic patients.

An investigation of the influence of patient-related factors and comedications on lamotrigine clearance in patients with epilepsy.

Lamotrigine (LTG) is one of the most widely used antiepileptic drugs. Confusion still exists in the literature as to the relative influence of age, body weight, and concomitant drug therapy on LTG pharmacokinetics. So, the objective of this study is to evaluate the influence of patient-related factors and comedication on LTG apparent oral clearance (CL/F). A therapeutic drug-monitoring database was used to identify steady-state plasma LTG concentrations in 210 patients. LTG CL/F values were calculated for each patient according to the equationCL/F (L/h per kg)=LTG daily dose (mg/kg)/Css (steady state concentration) (mg/L)×24h. A linear-regression model was used to assess the influence of gender, dose, age, and body weight in LTG CL/F. The influence of comedication on LTG CL/F was investigated by applying the Bonferroni post-test. The lowest LTG CL/F was found in patients comedicated with valproate (VPA) (mean, 0.0183L/h per kg), followed by patients receiving VPA+ enzyme inducers (0.0271L/h per kg), patients on LTG monotherapy (0.0298L/h per kg) and patients comedicated with enzyme inducers (0.056L/h per kg) LTG CL/F correlated significantly with LTG dose (P<0.01), but showed no significant relationship with gender, weight, and age. LTG CL/F is influenced by the type of antiepileptic comedication. The correlation with dose may be a spurious finding related to the fact that physicians, in adjusting dosage according to clinical response, are more likely to use larger doses in patients with high clearance values.

Prediction of an Optimal Dose of Lamotrigine for Augmentation Therapy in Treatment-Resistant Depressive Disorder From Plasma Lamotrigine Concentration at Week 2

The authors have previously shown that an early therapeutic response to lamotrigine augmentation therapy is dependent on its plasma concentration and that a plasma lamotrigine concentration of 12.7 μmol/L may be a threshold for a good therapeutic response in treatment-resistant depressive disorder. The present study investigated whether or not an optimal dose of lamotrigine could be predicted from plasma lamotrigine concentration at week 2. The subjects were 37 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 = 15), bipolar I disorder (n = 6), and bipolar II disorder (n = 16). They received augmentation therapy with lamotrigine for 8 weeks. The final doses of lamotrigine were 100 mg/d for 16 subjects who were not taking valproate and 75 mg/d for 21 subjects taking valproate, respectively. Blood sampling was performed at weeks 2 and 8. Plasma concentrations of lamotrigine were measured by high-performance liquid chromatography. There were significant linear relationships between the plasma lamotrigine concentrations at week 2 (x) and those at week 8 (y) for subjects who were not taking valproate (P < 0.01) and those taking valproate (P < 0.01). Regression equations were y = 2.032x + 2.549 for the former and y = 3.599x + 5.752 for the latter, respectively. Based on the equations, a nomogram to estimate an optimal dose of lamotrigine could be calculated. The present study suggests that an optimal dose of lamotrigine for augmentation therapy in treatment-resistant depressive disorder can be predicted from a plasma lamotrigine concentration at week 2.

Intrapatient variation in antiepileptic drug plasma concentration after generic substitution vs stable brand-name drug regimens

Generic substitution of antiepileptic drugs (AEDs) is still a matter of controversy and concern among clinicians and patients. We aimed to assess intrasubject variation in plasma concentrations of lamotrigine (LTG), levetiracetam (LEV) and topiramate (TPM) after generic substitution compared with a stable brand-name drug regimen in a population of patients with epilepsy. A retrospective analysis was performed on prospectively collected and stored data from our therapeutic drug monitoring (TDM) database for the years 2009–2014. The main outcome variable was the proportion of patients who, after switching from branded to generic formulations, showed a greater than ±20% change in AED plasma concentrations compared to the proportion of control patients showing a change in AED plasma concentrations of the same extent while receiving stable branded formulations over repeated TDM tests. Fifty patients on LTG, 27 on LEV and 16 on TPM showing at least one TDM test while receiving generic products fulfilled the inclusion/exclusion criteria for the analysis and were compared with 200 control patients for LTG, 120 for LEV and 80 for TPM. The proportion of patients showing an intrasubject change greater than ±20% in AED plasma concentrations was similar in the brand name vs generic group compared with the control one for LTG (22% vs 33%) and LEV (44% vs 38%), while it was higher in the control group for TPM (41% vs 6%, p<0.01). These are the first data in the literature about the within-patient variation in steady-state plasma concentrations of a series of stable treatments with brand-name AEDs in a real clinical setting. In conclusion, a significant interday variability in intrapatient LTG, LEV and TPM plasma concentrations can be observed even in patients stabilized with the same brand name product over time. This suggests that any change in plasma AED concentration and possible related clinical effects after generic substitution may be not necessarily related to the switch. Our results should be confirmed by large, prospective, blinded, randomized controlled studies in people with epilepsy.

Effects of Chronic Lamotrigine Administration on Maximal Electroshock- Induced Seizures in Mice.

The aim of the study was to determine anticonvulsant activity of lamotrigine (LTG) after acute and chronic treatment in four different protocols against maximal electroshock-induced seizures in mice. Such a knowledge seems to be valuable in view of the fact that all interactions between LTG and other drugs are evaluated in acute, not chronic, experiments. Electroconvulsions were produced by means of alternating current (50 Hz, 25 mA, 0.2 s) delivered via ear-clip electrodes. Motor impairment and long-term memory deficits in animals were assessed in the chimney test and in passive avoidance task, respectively. Brain and plasma concentrations of LTG were measured by HPLC. Chronic treatment with LTG (2 injections for 14 days) significantly potentiated the anticonvulsant effects of this antiepileptic in the maximal electroshock test in mice, significantly decreasing ED50 value for this antiepileptic. No impairment in motor coordination or long-term memory after acute or chronic treatment with LTG was noted. Nevertheless, prolonged treatment aggravated toxicity of LTG assessed in the chimney test as TD50 value. Repeated administration of LTG significantly increased plasma and brain concentrations of the antiepileptic drug when compared to the control group (single drug application). In conclusion, anticonvulsant action of LTG in the maximal electroshock test in mice may change, depending on the length of therapy. Both acute and chronic protocols are necessary in preclinical assessment of the anticonvulsant effects of drugs and possible interactions between them.

Quantification of lamotrigine in patient plasma using a fast liquid chromatography-tandem mass spectrometry method with backflush technology.

Recent concerns have been raised by neurologists and patients with epilepsy regarding the bioequivalence of generic lamotrigine to the brand Lamictal. Bioequivalence studies require the quantification of lamotrigine in human plasma, including in the presence of other drugs, for studies that will use patients with epilepsy rather than healthy volunteers. Lamotrigine was extracted from plasma through a simple protein precipitation and analyzed by fast liquid chromatography coupled to heated electrospray ionization with tandem mass spectrometric detection. A backflush step to remove interferent accumulation on column was included, and a stable isotope-labeled lamotrigine was used as an internal standard. The method was validated for accuracy, precision, interday and intraday coefficient of variation, specificity, lower limit of detection, lower limit of quantification, linearity, range, instrument precision, freeze-thaw, dilution integrity, and sample stability. Specificity evaluation included consideration of the impact of other antiepileptic drugs. The described method has a linear range of 8-10,000 ng/mL of lamotrigine (r = 0.9999) and a lower limit of detection of 1 ng/mL and a lower limit of quantification of 8 ng/mL. Intraday and interday reproducibility were less than 10.0% relative SD and 10.4% relative SD, respectively, and the percent recovery varied from 96.6% to 109.3% at various lamotrigine concentrations. A backflush step reduced matrix effects and no interference peak from plasma or other antiepileptic drugs were observed. A liquid chromatography-heated electrospray ionization-tandem mass spectrometry method including a backflush step was developed and validated to measure lamotrigine concentration in patient plasma. The method will be applied to bioequivalence studies that compare brand versus generic lamotrigine.

Influence of uridine diphosphate glucuronosyltransferase inducers and inhibitors on the plasma lamotrigine concentration in pediatric patients with refractory epilepsy

This study evaluated the influence of concomitant antiepileptic drugs (AEDs) on the plasma concentration of lamotrigine (LTG) in pediatric patients with epilepsy.We retrospectively reviewed 1653 plasma samples from 709 patients (aged 6 months to 16 years) and compared the concentration-to-dose ratio (CD ratio) of LTG among different AED regimens.The median CD ratio of patients receiving LTG monotherapy was 1.25 μg/mL/mg/kg. In patients receiving LTG plus VPA, the CD ratio was increased by about 140%. The CD ratio was elevated from a low VPA concentration (<40 μg/mL) and the increase was VPA concentration-dependent. In contrast, the median CD ratio of patients treated with LTG plus the inducers phenytoin, phenobarbital, and carbamazepine was 0.42, 0.63, and 0.66, respectively, and phenytoin significantly reduced the CD ratio in comparison with phenobarbital or carbamazepine (p < 0.001). Pediatric patients of all ages beyond infancy showed similar susceptibility to VPA or inducers, but infants had higher CD ratios compared with the other age groups. Among other AEDs, topiramate, ethosuximide, and rufinamide reduced the CD ratio.These findings should be useful for estimating interactions between LTG and concomitant AEDs.

Relationship between plasma concentrations of lamotrigine and its early therapeutic effect of lamotrigine augmentation therapy in treatment-resistant depressive disorder.

The relationship between plasma concentrations of lamotrigine and its therapeutic effects was prospectively studied on 34 (9 men and 25 women) inpatients with treatment-resistant depressive disorder during an 8-week treatment of lamotrigine augmentation using an open-study design. The subjects were 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 = 12), bipolar I disorder (n = 7), and bipolar II disorder (n = 15). The final doses of lamotrigine were 100 mg/d for 18 subjects who were not taking valproate and 75 mg/d for 16 subjects taking valproate. Depressive symptoms were evaluated by the Montgomery Åsberg Depression Rating Scale (MADRS) before and after the 8-week treatment. Blood sampling was performed at week 8. Plasma concentrations of lamotrigine were measured by high-performance liquid chromatography. There was a significant linear relationship between the plasma concentrations of lamotrigine and percentage improvements at week 8 (r = 0.418, P < 0.05). A stepwise multiple regression analysis showed that plasma lamotrigine concentrations alone had a significant effect on the percentage improvements at week 8 (standardized partial correlation coefficients = 0.454, P < 0.001). The receiver operating characteristics analysis indicated that a plasma lamotrigine concentration of 12.7 μmol/L or greater was significantly (P < 0.001) predictive of response (50% or more reduction in the MADRS score). The proportion of the responders was significantly higher in the groups with a lamotrigine concentration >12.7 μmol/L (11/15 versus 4/19, P < 0.01). The present study suggests that an early therapeutic response to lamotrigine is dependent on its plasma concentration and that a plasma lamotrigine concentration of 12.7 μmol/L may be a threshold for a good therapeutic response in treatment-resistant depressive disorder.

Enalapril enhances the anticonvulsant activity of lamotrigine in the test of maximal electroshock

BackgroundThe aim of this study was to find out whether angiotensin-converting enzyme (ACE) inhibitors, enalapril and cilazapril, affect the anticonvulsant action of some second-generation antiepileptics, lamotrigine (LTG), topiramate (TPM) and oxcarbazepine (OXC). MethodsThe effects of ACE inhibitors on antiepileptic drugs were examined in the mouse model of maximal electroshock. ResultsEnalapril (30mg/kg ip) potentiated the anticonvulsant action of LTG, decreasing its ED50 value from 5.3 to 3.6mg/kg (p<0.01). The anticonvulsant activity of TPM or OXC was not modified by enalapril. Cilazapril did not affect the protective activity of the studied antiepileptics. The interaction between enalapril and LTG could be pharmacodynamic in nature because enalapril did not change plasma and total brain concentrations of LTG. ConclusionsThis study shows that there are no negative interactions between the studied antiepileptic drugs and enalapril or cilazapril. Enalapril even enhanced the anticonvulsant activity of LTG in the MES test in mice that is thought to be a predictive model of human generalized tonic-clonic seizures.

Association Between Lamotrigine Concentrations and ABCB1 Polymorphisms in Patients With Epilepsy

Epilepsy is treated with a variety of anticonvulsants that are often used concomitantly. Therefore, therapeutic drug monitoring is often necessary. Along with clinical and environmental factors, genetic predisposition has been recognized to be relevant for interindividual variability in drug response. Polymorphic transporter proteins such as P-glycoprotein significantly influence pharmacokinetics and bioavailability of many structurally unrelated drugs. The aim of the study was to evaluate the impact of polymorphisms in the P-glycoprotein-encoding gene ABCB1 (C1236T, G2677T/A, C3435T) on antiepileptic drug disposition. We recruited 222 patients with epilepsy who were prescribed lamotrigine in monotherapy or polytherapy. Lamotrigine plasma concentrations were analyzed and compared with ABCB1 gene variants. The ABCB1 genotyping was performed by real-time polymerase chain reaction methods. The therapeutic drug monitoring was performed by high-performance liquid chromatography-diode array detector (DAD) and immunoassay. A significant correlation was confirmed between lamotrigine concentration and additional drugs (P < 0.001). In the whole group, statistical analysis showed correlations between lamotrigine concentrations and ABCB1 C1236T variants: 10.1 and 6.5 μmol/L for CC versus CT + TT, respectively (P = 0.021), and for dose corrected lamotrigine 0.068 and 0.053 μmol·L·mg, for CC versus CT + TT, respectively (P = 0.017). Analysis of a specific haplotype showed that 1236C-2677G-3435C carriers had higher lamotrigine concentrations than 1236T-2677G-3435T carriers (P < 0.001), followed by 1236T-2677T-3435C carriers (P < 0.001). ABCB1 C1236T, G2677T/A, C3435T polymorphisms have an influence on lamotrigine serum concentrations.

Population pharmacokinetics of lamotrigine in Indian epileptic patients

The aim of this analysis was to describe the pharmacokinetics of oral lamotrigine (LTG) in Indian epileptic patients using a population pharmacokinetic (PPK) modeling approach to confirm that the PK is similar to that of the Caucasian population, and to evaluate and confirm the impact of covariates predictive of inter-individual variability using a simulation platform. Blood samples were obtained from 95 patients, and LTG plasma concentrations were determined. Population PK modeling was performed using NONMEM. A one-compartment PK model with first-order absorption and elimination was used to describe the LTG PK. Log-likelihood profiling and normalized prediction distribution errors (NPDE) were used for model evaluation. A simulation study was performed to investigate dose regimens. Clearance (CL) was estimated to be 2.27L/h with inter-individual variability (IIV) of 29 CV%. Volume of distribution (V) was estimated to be 53.6L (31 CV% IIV). Body weight and concurrent use of carbamazepine and valproate were identified as significant covariates on clearance. Log-likelihood profiling indicated that parameters could be estimated with adequate precision, and NPDE indicated that the model adequately described the data observed. The simulation study illustrated the impact of carbamazepine and valproate on LTG PK, and negligible differences in PK between Indian and Caucasian patients. This is the first PK analysis of LTG in Indian patients. The population PK model developed adequately described the data observed. Comparison of identified PK parameters with previous PK analyses in Caucasian patients indicates that CL of LTG is similar, while V is somewhat lower compared with Caucasian patients, but this is not expected to lead to relevant differences in PK profiles during steady state.

Lack of Interaction between Sertraline and Lamotrigine in Psychiatric Patients: A Retrospective Study

This study evaluates the pharmacokinetic interaction between sertraline and lamotrigine in psychiatric patients. We identifi ed patients with at least 1 measurement of trough lamotrigine plasma concentration (at steady-state) during lamotrigine therapy and compared dose and plasma concentrations between patients who received lamotrigine with sertraline and patients who received lamotrigine without sertraline. The dose corrected concentration of lamotrigine in patients receiving lamotrigine in combination with sertraline was 60.4 μmol/L × 1,000/mg/day (SD: 31.1) (N = 7) compared to 51.1 μmol/L × 1 000/mg/day (SD: 27.6) (N = 44) in patients using lamotrigine without sertraline (p = 0.42). The slightly slower metabolism of lamotrigine in patients receiving lamotrigine with sertraline compared with those receiving lamotrigine alone is not believed to be of clinical signifi cance. However, due to the limited power, we may have overlooked a diff erence that could be clinically relevant.

Influence of Concomitant Antiepileptic Drugs on Plasma Lamotrigine Concentration in Adult Japanese Epilepsy Patients

Lamotrigine (LTG) is an antiepileptic drug (AED) that was approved in Japan in 2008. We evaluated the influence of AEDs that induce hepatic enzymes (including phenytoin (PHT), phenobarbital (PB), carbamazepine (CBZ)), valproic acid (VPA), and various combinations of these drugs, on plasma LTG concentration in adult Japanese epilepsy patients. A total of 621 patients (mean age 34.4±11.8 years) were evaluated retrospectively. We calculated the concentration to dose ratio (CD ratio) for LTG with different AED regimens, and employed multiple regression analysis to determine factors influencing the LTG concentration. There was a linear correlation between the dose and concentration of LTG in patients treated with LTG (group I), LTG+VPA (group II), LTG+inducers (group III), or LTG+VPA+inducers (group IV). The mean CD ratio of patients on LTG monotherapy was 1.43±0.4 (μg/mL)/(mg/kg). When LTG was combined with VPA, the CD ratio increased about 2.2-fold, but there was no significant correlation between the CD ratio and VPA concentration. The mean CD ratios calculated in patients receiving LTG+PHT, LTG+PB, and LTG+CBZ were 0.56, 0.84, and 0.91, respectively. Addition of PHT significantly reduced the CD ratio in a concentration-dependent manner, in comparison with PB and CBZ (p<0.005 and p<0.001, respectively). Stepwise multiple regression analysis showed that the coefficient of determination of groups I, II, III, and IV were 0.94, 0.94, 0.90, and 0.91, respectively. In the clinical setting, these findings can help to estimate LTG concentrations and predict the inducing or inhibiting effects of concomitant AEDs.

Algorithm for lamotrigine dose adjustment before, during, and after pregnancy

Treatment with lamotrigine (LTG) during pregnancy is associated with a pronounced risk of seizure deterioration, because pregnancy accelerates LTG elimination. The extent to which pregnancy affects LTG pharmacokinetics is unpredictable and varies considerably among patients. We propose an algorithm for systematic LTG plasma concentration monitoring and dose adjustment to guide the clinician between the risk of seizure deterioration and LTG toxicity by maintaining a stable LTG concentration, using the optimal prepregnancy target concentration as a reference. The reference LTG plasma concentration (RC) should be determined before pregnancy or as early in pregnancy as possible. After conception, plasma concentration of LTG should be measured every 4 weeks throughout pregnancy. When the LTG plasma concentration falls below the RC, the dose of LTG should be increased by 20-25%. Post-partum, the plasma concentration of LTG should be measured within the first or second week, and if the LTG plasma concentration is higher than the RC, the LTG dose should be reduced by 20-25% and the procedure repeated until RC is re-established. Seizure deterioration during pregnancy may be prevented or reduced by closely and systematically following our proposed algorithm.

Lamotrigine does not prolong QTc in a thorough QT/QTc study in healthy subjects, Dixon et al. 2008; request for publication of PR interval data

Dixon et al. reported the results of the most thorough study of lamotrigine effects on electrocardiogram (ECG) intervals that has been published to date [1]. In this placebo- and moxifloxacin-controlled trial, lamotrigine monotherapy at doses up to 400 mg day−1 was shown to not prolong the QTc interval in healthy subjects. The report stated that additional ECG conduction intervals were measured, including the PR interval and the QRS duration. While QRS duration results were reported in the paper, the PR interval results from the study were neither reported nor discussed. Approved labelling for lamotrigine does not include evidence indicating that lamotrigine has any effect on PR interval [2, 3]; however, the literature contains at least two trials where lamotrigine was reported to be associated with a small increase in mean PR (or PQ) interval in patients with epilepsy. Matsuo et al. reported a mean 5 ms increase in PR interval in epilepsy patients randomized to treatment with lamotrigine [4]. Recently, Saetre et al. reported that lamotrigine was associated with a mean 8.8 ms increase in PQ interval in a group of elderly epilepsy patients treated with a relatively low mean daily lamotrigine dose (∼110 mg day−1, serum concentration ∼2.6 µg ml−1) [5]. Given these findings, a complete reporting of the ECG data, including PR interval, is important for an accurate assessment of the cardiac profile of lamotrigine. The extensive ECG data acquisition and relatively high steady-state plasma concentrations of lamotrigine (9.6 µg ml−1 for the 400 mg day−1 dose group) evaluated in the Dixon et al. trial [1] would provide the specific data needed to determine whether there is an effect of lamotrigine on PR interval. As such, we respectfully request an addendum to this publication that would allow the inclusion of a graphical presentation of PR interval data, such as that used in the report for QRS duration, as well as a quantitative statement of the mean placebo-subtracted change from baseline for PR interval at steady state (Cmax) for the three lamotrigine doses that were studied.

Effect of lamotrigine on the PR interval in healthy subjects

In a thorough QT/QTc study of lamotrigine [1], healthy subjects received a single oral dose of moxifloxacin (400 mg) or placebo in crossover design, followed by a dose-escalating regimen of lamotrigine (n = 76) over a 77 day period, or matched placebo (n = 76). Digital 12-lead electrocardiograms (ECGs) were recorded and ECG intervals measured manually by a central reader. In a post hoc analysis, PR interval data were analysed using repeated-measures analysis of covariance (ancova) separately for day 42 (lamotrigine 50 mg twice daily), day 63 (lamotrigine 150 mg twice daily) and day 77 (lamotrigine 200 mg twice daily) as previously described [1]. Point estimates and corresponding 90% confidence intervals (CIs) were calculated for the difference between each dose of lamotrigine and the corresponding placebo at each time point. The same type of analysis was used to determine the difference between moxifloxacin and placebo, taking into account the crossover design. The normal range for PR interval is 120–200 ms. Small decreases in mean PR interval were observed after moxifloxacin compared with placebo. The maximal adjusted mean difference from placebo was −1.1 ms (90% CI −1.99, −0.22) at 6 h postdose. Small increases in mean PR interval were observed on lamotrigine compared with placebo (Figure 1). The largest mean differences from placebo at each dose level were 2.76 ms (90% CI 0.41, 5.12) 1 h postdose at the 50 mg twice daily dose level, 4.49 ms (90% CI 1.99, 6.99) 15 min postdose at the 150 mg twice daily dose level, and 5.11 ms (90% CI 2.48, 7.74) 15 min postdose at the 200 mg twice daily dose level. The median, steady-state, maximal plasma concentration occurred at around 1.0–1.5 h postdose across the three dose levels. Figure 1 Difference in adjusted mean PR interval compared with placebo over 12 h postdose at lamotrigine dose levels of 50, 150 and 200 mg twice daily (bd). Lamotrigine 50 mg bd vs placebo (); Lamotrigine 150 mg bd vs placebo (); Lamotrigine 200 mg bd vs placebo ... A mean increase in PR interval of 5 ms on lamotrigine compared with placebo is consistent with the paper by Matsuo et al. [2], which describes a placebo-controlled study in which the efficacy of lamotrigine was evaluated when added on to existing anti-epileptic medications in patients with refractory partial seizures. Whilst the lamotrigine doses used were similar (300 and 500 mg day−1), mean trough plasma concentrations were lower than in our study, 3.6 µg ml−1 at 500 mg day−1, compared with approximately 2, 5 and 7 µg ml−1 at the 50, 150 and 200 mg twice daily dose levels, respectively. However, in our study, even though plasma concentrations were dose proportional, the degree of PR interval prolongation was similar at the mid- and high-dose levels, suggesting that a maximal effect is achieved at these doses. In a more recent paper by Saetre et al. [3], the mean change from baseline in PQ interval after 40 weeks of treatment with lamotrigine (n = 29, mean dose of 111 mg) was an increase of 8.8 ms, although the median change from baseline was zero. The mean plasma lamotrigine concentration was 2.64 µg ml−1. In the carbamazepine comparator group, the mean change from baseline was larger (14.1 ms) than on lamotrigine. Comparison of our data with that of the paper by Saetre et al. [3] is limited by the absence of placebo in their study. Furthermore, the population has some important differences compared with the young healthy volunteer population in our study, being comprised of elderly subjects with epilepsy, some of whom had significant cardiovascular co-morbidities and frequent concomitant medications. A recent review of aggregate data in GlaxoSmithKline's safety database, which is comprised of all postmarketing spontaneous adverse event reports and all serious adverse events from clinical trials, for events including and relating to PR prolongation in patients on lamotrigine did not identify a safety concern. In conclusion, a rigorous study of the effects of lamotrigine on ECG intervals in a healthy volunteer population indicates that the PR interval may be slightly prolonged, especially at high doses of lamotrigine. However, postmarketing safety surveillance has not revealed this to be a clinically relevant adverse effect.

Oculogyric crises secondary to lamotrigine overdosage

We report four patients with no preexisting movement disorders who developed oculogyric crises secondary to lamotrigine toxicity and had resolution of these crises after dose reduction. Episode numbers ranged from 1-20 per day and episode duration from 2 s to several hours. Mean plasma concentration of lamotrigine at the time of oculogyric crisis was 15.5 μg/mL, with a mean dose of 16 mg/kg per day.

Intercambiabilidad entre equivalentes terapéuticos de lamotrigina en pacientes con epilepsia refractaria: riesgos y beneficios

Epilepsy is a condition characterized by signs and symptoms of neurological disorder. Lamotrigine has been widely used, mainly due to their greater tolerability and lower rate of drug interactions with other antiepileptic drugs however the newest antiepileptic drugs have high cost to patient. In Brazil there are three different sort of pharmaceutical equivalents (reference, generic and similar), and the Brazilian health care authorities offers to users the possibility to receive them free of charge. Moreover these pharmaceutical equivalents can change during the treatment of epilepsy because this authorities buy the cheapest by public tender two or three times a year. To evaluate the clinical and laboratory findings related to the most frequently used therapeutic equivalents of lamotrigine (reference drugs and similar products). Two similar formulations (A and B) and one reference (C) were tested in nine epileptic refractory patients. The study was divided into three periods of 42 days, one for each formulation, and medical data about the frequency of seizures, the occurrence of side effects and measurement of plasma concentrations of lamotrigine were collected. The average number of seizures/week and plasma concentration of lamotrigine for formulations A, B and C were not statistically significant differences. Three patients during the use of the formulation C presented mild and transitory side effects. Similar or reference drugs showed satisfactory results, however the interchangeability among the formulations raise the difficulty for the management of seizures in refractory epilepsy.

The relationship between lamotrigine concentration and change in resting motor threshold in a rodent model of motor cortex stimulation

The anticonvulsant sodium channel blocker lamotrigine (LTG) increases resting motor threshold (RMT) measured using transcranial magnetic stimulation (TMS) of the motor cortex in humans. However, studies suggest a weak relationship between LTG plasma concentration and increase in RMT. This undermines the possibility to use the technique to investigate the dose-efficacy relationship of lamotrigine or novel sodium channel blocking drugs. In order to investigate this relationship further, we have examined blood and brain concentrations of LTG in parallel with the drugs effects on RMT in a model in which electrical-stimulation is used to activate the motor cortex of propofol-anaesthetised rats. LTG (3-20 mg/kg s.c.) significantly increased RMT (P<0.001). There was a significant (P<0.01) positive correlation between LTG blood and brain concentration and increase in RMT; however correlation-coefficients were low (brain: r(2)=0.26 and blood r(2)=0.25), with evidence for non-responders, similar to human studies. The results show that the variation in RMT response is unlikely to be due to pharmacokinetic differences between subjects, and suggest that biological differences may underpin the variability. Understanding the source of this variability will be an important goal and, assuming some relationship between the effects of LTG on motor pathway excitability and the drugs anticonvulsant efficacy, could lead to a means to identify epilepsy patients that may be more likely to respond to treatment.