Pharmacokinetics and safety of lamotrigine (Lamictal®) in patients with epilepsy

doi:10.1016/0920-1211(91)90012-5

Epilepsy Research

Volume 10, Issues 2–3, November–December 1991, Pages 191-200

https://doi.org/10.1016/0920-1211(91)90012-5 Get rights and content

Abstract

In a double-blind parallel study, patients with epilepsy on stable regimen of antiepileptic drugs (AEDs) were given lamotrigine (8 pts) or placebo (3 pts). Patients were sequentially dosed with 100, 200 and 300 mg/day given as a b.i.d. regimen. After steady state was achieved, timed plasma lamotrigine levels were obtained post dose. No medical, psychogenic, neurologic, or hematologie changes were observed and no subjective effects were detected as a result of treatment with lamotrigine. No changes in heart rhythm or blood pressure were observed related to lamotrigine. Pharmacokinetic parameters were calculated using 1-compartment and non-compartment models. The results were similar using both models. Area under the plasma concentration vs. time curves increased linearly with dose. Mean half life (13.5 h), volume of distribution (1.36 1/kg) and clearance (1.27 m1/min/kg) were similar to previously reported results and did not change with increasing dose. These findings indicate that lamotrigine pharmacokinetics can be described by the 1-compartment model, has linear kinetics, and does not induce its own metabolism in patients on concomitant AEDs.

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Cited by (131)

Mixture effects of tetrodotoxin (TTX) and drugs targeting voltage-gated sodium channels on spontaneous neuronal activity in vitro
2023, Toxicology Letters
Tetrodotoxin (TTX) potently inhibits TTX-sensitive voltage-gated sodium (Na_V) channels in nerve and muscle cells, potentially resulting in depressed neurotransmission, paralysis and death from respiratory failure. Since a wide range of pharmaceutical drugs is known to also act on Na_V channels, the use of medicines could predispose individuals to a higher susceptibility towards TTX toxicity. We therefore first assessed the inhibitory effect of selected medicines that act on TTX-sensitive (Riluzole, Chloroquine, Fluoxetine, Valproic acid, Lamotrigine, Lidocaine) and TTX-resistant (Carbamazepine, Mexiletine, Flecainide) Na_V channels on spontaneous neuronal activity of rat primary cortical cultures grown on microelectrode arrays (MEA). After establishing concentration-effect curves, binary mixtures of the medicines with TTX at calculated NOEC, IC₂₀ and IC₅₀ values were used to determine if pharmacodynamic interactions occur between TTX and these drugs on spontaneous neuronal activity. At IC₂₀ and IC₅₀ values, all medicines significantly increased the inhibitory effect of TTX on spontaneous neuronal activity of rat cortical cells in vitro. Subsequent experiments using human iPSC-derived neuronal co-cultures grown on MEAs confirmed the ability of selected medicines (Carbamazepine, Flecainide, Riluzole, Lidocaine) to inhibit spontaneous neuronal activity. Despite the need for additional experiments using human iPSC-derived neuronal co-cultures, our combined data already highlight the importance of identifying and including vulnerable risk groups in the risk assessment of TTX.
Effect of UGT1A4, UGT2B7, UGT2B15, UGT2B17 and ABC1B polymorphisms on lamotrigine metabolism in Danish patients
2022, Epilepsy Research
Citation Excerpt :
Patient reported adherence was not formally assessed and may have affected our results however we attempted to limit this effect by comparing pre- and post-recruitment LGT levels and only one was excluded due to a suspicion of non-adherence. A further limitation is that the timing for the blood tests was not standardized, which may have had a minor influence on our results, however, LTG has a relatively long half-life (13.5–24 h) Ramsay et al. (1991)) therefore only minor fluctuations in plasma levels would be expected. Lastly, the sample size for subgroup analyses was too small to reach statistical power however it was relatively large compared with other studies.Furthermore the female cohort in this study was larger than the male cohort, which could have had an influence on the statistical power.
To evaluate the impact of genetic polymorphisms of UGT enzymes (UGT1A4, UGT2B7, UGT2B15 and UGT 2B17) and the transporter protein ABCB1 on Lamotrigine (LTG) metabolism.
Single nucleotide polymorphisms UGT1A4*2 (P24T, c.70C>A), UGT1A4*3 (L48V c.142T>G), UGT2B7*2 (H802Y, c.802C>T), UGT2B15*2 (Y85D, c.253G>T), UGT2B17 deletion and transporters ABC 1236C> T and 3435C> T were determined in 337 Caucasian patients with epilepsy treated with LTG in Denmark. The prospectively collected data included LTG dosage, LTG plasma concentration, 2-N-GLU concentration, sex, smoking habits, concomitant medicine, oral contraceptives (OC).
The non-smokers with LTG monotherapy and LTG polytherapy with other non-interacting drugs NIAEDs (n = 199) were analyzed separately in univariant analyses. LTG ratios (LTG plasma concentration/ (LTG dose/weight)) in patients carrying wild type UGT1A4*2 C-allele were 22% lower than in heterozygous C-carriers (p = 0.013). Patients with UGT2B7*2 polymorphism TT genotype had 1.2-fold higher LTG ratios (p = 0.0078) and 0.78-fold lower GLU/LTG ratio (p = 0.0275) than patients homozygous for the C allele. The similar significant findings were also seen comparing homozygotes (TT) with heterozygotes patients (CT). Individuals homozygous for the UGT2B15*2 T allele displayed 18% lower LTG ratio concentrations than individuals homozygous for the G allele (p = 0.014),while significant difference in GLU/LTG ratio was only seen comparing wild type with homozygous patients (GG versus TT, p = 0.031). A copy number variation gene deletion polymorphism of UGT2B17 showed that individuals devoid of the gene (del/del) exhibited 1.3-fold higher LTG ratio (p = 0.015). For ABCB1c.1236 C>T and ABC1B1c.3435 C>T no associations with LTG and GLU ratios were found.
Sex specific differences in enzyme activity (most prominent effect in women) on LTG metabolism were found for UGT2B15, UGT2B17, UGT1A4 and UGT2B7 polymorphisms.
Multiple regression analysis confirmed the significant effect of OC, VPA and UGT1A4 * 2 and UGT2B7 * 2 on LTG metabolism.
Our study confirms the previous findings that genetic variations in UGT2B7 and UGT1A4 genes are associated with serum LTG concentrations.
Furthermore, our results indicate that it is possible that different UGT genotypes may exert larger impact on LTG metabolism in women than in men.
Sources of lamotrigine pharmacokinetic variability: A systematic review of population pharmacokinetic analyses
2020, Seizure
Lamotrigine (LTG) is a new generation antiepileptic drug. However, relatively high interindividual pharmacokinetic variability of this drug has been documented. Therefore, several population pharmacokinetic studies of lamotrigine were conducted to identify factors influencing its pharmacokinetics.
This systematic review aimed to summarize significant factors influencing LTG pharmacokinetics and their relationships with pharmacokinetic parameters as well as the magnitude of pharmacokinetic variability.
Four databases i.e. PubMed, Scopus, CINAHL Complete, and Science Direct were systematically searched from their inception to March 2020. Population pharmacokinetic studies of LTG conducted in humans using a nonlinear-mixed effect approach were eligible for a systematic review.
Nineteen studies were included in this systematic review. Most studies characterized LTG pharmacokinetics as a one-compartment model structure. The three most frequently identified significant covariates influencing LTG clearance included concomitant antiepileptic drugs, body weight, and genetic polymorphisms. Approximately 58% of the studies did not externally validate the models.
For clinical application, LTG maintenance dose could be optimized using population pharmacokinetic models employing covariates such as concomitant antiepileptic drugs, body weight, and genetic polymorphisms. However, these models should be assessed for their predictability in the target population before utilizing such models in clinical settings.
Misdiagnosis of lamotrigine toxicity as posterior circulation transient ischemic attack or stroke
2020, Epilepsy and Behavior
Lamotrigine (LTG) is one of the most used antiseizure medications (ASMs). Titration is indicated for incomplete seizure control, but toxicity with vertigo, ataxia, and diplopia may ensue. Lamotrigine concentration would be the optimal diagnostic test. However, patients often receive a stroke evaluation when presenting to the emergency department (ED), leading to unnecessary cost and delayed management. We investigated the frequency of stroke evaluation for symptoms associated with LTG toxicity and attempted to identify factors leading to this expensive evaluation.
We identified adult patients treated with LTG who presented to an emergency room with dizziness, ataxia, or diplopia and received a negative stroke evaluation, between 2003 and 2018. They were among 972 patients treated with LTG for epilepsy. We collected age at time of occurrence, symptoms presented, imaging studies performed, LTG dose and serum concentration, and the time the result was available. As a denominator, we also identified patients who developed clinical LTG toxicity during the same time period.
Thirteen patients with LTG toxicity had 16 negative stroke evaluations in the emergency room. Their mean age was 62 years (range: 43–79) as compared with 47 years for all patients treated with LTG (p < 0.0005). The mean daily LTG dose was 621 mg (range: 300–900 mg). A LTG serum concentration was requested on the day of evaluation in 7 instances, though the result was never available until at least the next day. In 4 instances, the LTG level was drawn 1–3 days after presentation. Five of the patients in this group were among 71 patients with clinical LTG toxicity and LTG concentration > 20.
Emergency departments will frequently call a stroke alert for patients taking LTG and presenting with symptoms consistent with LTG toxicity, particularly in seniors at greater risk of stroke. This adds not only expense but also radiation and contrast exposure from computed tomography (CT) studies. We recommend that a rapid LTG assay be made available and always ordered in patients receiving LTG, avoiding the considerable expense of an unnecessary stroke evaluation.
Dosing Recommendations Based on Population Pharmacokinetics of Lamotrigine in Mexican Adult Patients With Epilepsy
2020, Journal of Pharmaceutical Sciences
Dose individualization is essential in epilepsy treatment, especially in antiepileptic drugs that present high interindividual variability such as lamotrigine. We aimed an observational study to develop a population pharmacokinetic model for quantitative evaluation of the factors that influence lamotrigine pharmacokinetics in Mexican adults with epilepsy. Patients on stable treatment with lamotrigine therapy were included, plasma concentrations were analyzed by a high-performance liquid chromatography method and UGT2B7–161C > T polymorphism was determined. The data were analyzed by NONMEM® 7.3, model validation was performed using bootstrap approach and visual predictive check. Finally, stochastic simulations were carried out to propose dosage regimens. A total of 73 lamotrigine plasma concentrations from 2 h after last dose and up to 0.5 h prior to next administration were fitted to a one-compartment open model. The final population pharmacokinetic model for lamotrigine indicates that concomitant treatment with valproic acid and carbamazepine should be considered to individualize epilepsy treatment with this drug. Based on this model, we proposed dosage regimens to achieve trough lamotrigine concentrations within reference interval (2.5–15 mg/L). These results provide clinical useful data to give more rational anticonvulsant therapy in our population.
UGT polymorphisms and lamotrigine clearance during pregnancy
2018, Epilepsy Research
Citation Excerpt :
Furthermore, the timing for the blood tests PP was not standardized and varied widely, which may have influenced our results PP. The natural fluctuations in LTG concentrations may also, to a minor degree, have caused false results, but as LTG has a relatively long half-life (13.5–24 h) (Ramsay et al., 1991), only minor fluctuations in plasma levels can be expected. However, notwithstanding these limitations, this is the first study of its kind and our data underline that management of LTG treatment throughout pregnancy has to be individualized and that genetic polymorphism may contribute to this need.
To evaluate the impact of maternal UGT1A4 and UGT2B7 genetic polymorphisms and sex of foetus on gestation-induced changes in lamotrigine (LTG) clearance during pregnancy and post-partum (PP).
Single nucleotide polymorphisms UGT1A4 142T > G, L48V (*3), UGT1A4 70C > A, P24T (*2) and UGT2B7 802C > T, H268Y (*2) were determined in 40 women (47 pregnancies) with epilepsy treated with LTG. Retrospectively collected data included LTG dosage and LTG plasma levels before pregnancy (T0), and LTG dosage and LTG plasma level changes in the first (T1), second (T2) and third trimester (T3), and post-partum (PP) as well as the sex of the foetus.
Reductions in the LTG concentration-to-dose ratio (C/D ratio) during pregnancy were seen in all genotype panels and varied between −53% and −74% in T3. Genetic polymorphism of UGT1A4 T142G (*3) and UGT2B7 C802T (*2) had the most pronounced influence on LTG clearance. Women with UGT1A4 142TG had a lower decrease in the C/D ratio in T3 than those with wild type: −53% (95%CI: −68% to −39%) versus −65% (95%CI: −69% to −60%) (p = 0.04).
In homozygous carriers of UGT2B7 802TT the LTG C/D ratio was reduced significantly already in T1 (p = 0.015) as well as in T3 compared to the heterozygous carriers (802CT) (p = 0.04).
Multiple regression analysis demonstrated that women who carried a female foetus had a significantly higher reductions in the LTG C/D ratio from T0 to the end of pregnancy than those with a male foetus (p = 0.003). In the univariate analysis the reductions in LTG C/D ratio were −64% in T2 (95%CI: −69% to −59%) and −67% in T3 (95%CI: −71% to −63%) in women who expected a female child compared to whose with a male child −58% in T2 (p = 0.002, 95%CI: −67% to −48%) and −57% in T3 (p < 0.001, 95%CI: −65% to −48%).
Genetic polymorphism in UGT1A4 and UGT2B7 may play a modest role in LTG clearance changes during pregnancy. In addition, our study indicates that the sex of the foetus influenced significantly the change in LTG clearance.

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Research reportPharmacokinetics and safety of lamotrigine (Lamictal®) in patients with epilepsy

Abstract

J. Pharm. Sci.

Epilepsy Res.

Epilepsy Res.

Epilepsy Res.

Epilepsy Res.

J. Pharmaceut. Sci.

Int. J. Biomed. Comput.

Preliminary single-dose studies of a potential new anti-epileptic drug, lamotrigine (BW430C) in epileptic patients

Br. J. Clin. Pharmacol

Acute effects of lamotrigine (BW340C) in persons with epilepsy

Epilepsia

Effects on human central nervous system of two isomers of ephedrine and triprolidine and their interactions

Br. J. Clin. Pharmacol.

Comparison of a GLC-NPD method with a GLC-MS-SIM procedure for the determination of tilidine and its metabolites in plasma

J. Anal. Toxicol.

BW430c, a new anticonvulsant. Pharmacokinetics in normal man

Epilepsia

Lamotrigine (BW340c), a potential anticonvulsant. Effects on the central nervous system in comparison with phenytoin and diazepam

Br. J. Clin. Pharmacol.

Research report
Pharmacokinetics and safety of lamotrigine (Lamictal®) in patients with epilepsy