Relationship between lamotrigine oral dose, serum level and its inhibitory effect on CNS: insights from transcranial magnetic stimulation

doi:10.1016/j.eplepsyres.2003.08.006

Epilepsy Research

Volume 56, Issue 1, September 2003, Pages 67-77

https://doi.org/10.1016/j.eplepsyres.2003.08.006 Get rights and content

Abstract

The antiepileptic drug lamotrigine (LTG) is known to reduce cortical excitability evaluated by transcranial magnetic stimulation (TMS). We investigated the relationship between LTG oral dosages, serum levels and inhibitory effects on resting motor threshold (RMT), a parameter of motor system excitability assessed by TMS. In a randomized, placebo-controlled crossover study 16 male volunteers received 325 mg LTG as a single dose, as bi-hourly graded cumulative dose, or placebo. RMT and serum levels were measured before and after 2–8 h. With single dose, RMT elevation showed a poor but significant correlation to serum levels. With graded dose, serum levels as well as RMT increased dose-dependently with significant (P<0.0001) linear correlation. However, detailed comparison showed a high inter-individual variability in the relationship resembling a sigmoid correlation. Different mechanisms besides the sodium-channel blockage as the main mode of action of LTG are discussed to explain the diversity of individual dose–response relationships. Provided that the RMT elevation reflects the antiepileptic potential of LTG, TMS may be developed as a tool to monitor interindividual response of epilepsy patients to LTG treatment as well as to explore efficacy of other antiepileptic drugs with similar mode of action.

Introduction

Transcranial magnetic stimulation (TMS) uses focused magnetic fields to directly induce and investigate activity in neuronal tissue. The motor threshold in the relaxed muscle (resting motor threshold, RMT) is a basal parameter of TMS to measure neuronal excitability. After Mavroudakis et al. (1994) were the first to show that a single oral dose of an antiepileptic drug is capable of elevating motor thresholds, Ziemann et al. (1996) concluded that lamotrigine (LTG; 3-5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine) and similar drugs reversibly elevate the RMT presumably by blocking voltage-dependent sodium-channels, thus stabilizing neuronal membranes and consecutively reducing the release of excitatory neurotransmitters, particularly glutamate and aspartate (Leach et al., 1986, Lees and Leach, 1993). It was hence concluded that RMT reflects neuronal membrane excitability which mainly depends on ion-channel conductivity. The effect seems to be rather specific inasmuch as other TMS parameters are not affected by ion-channel blockers although it is known that RMT also depends on synaptic excitability, for example, non-NMDA glutamatergic neurotransmission (Di Lazzaro et al., 2003).

LTG has a wide range of efficacy in focal as well as generalized epilepsies (Goa et al., 1993, Fitton and Goa, 1995) and for epilepsies, in turn, the cortical excitability hypothesis suggests that a lowered RMT can be observed in patients with focal as well as generalized epilepsy (for overview, see Ziemann et al., 1998). However, only little is known about the individual dose–response relationships of RMT elevation under LTG or other channel blockers. While from one study on five subjects a positive correlation between RMT elevation and phenytoin serum level was assumed (Chen et al., 1997) another study described increasing RMT during continuous treatment with increasing LTG oral dosages (Manganotti et al., 1999). Currently it is unclear whether RMT elevation is related to LTG serum level and, if so, what type of relationship this would be. Answering this question is essential as the first step towards estimation whether RMT could be used as a quantitative measure of channel blocker efficacy on the central nervous system and, moreover, whether RMT could be used as a parameter of efficiency in antiepileptic therapy control. In the present study we systematically investigated in detail the relationship between various oral dosages of LTG, serum level and the RMT in order to evaluate RMT as a quantitative measure of neuronal excitability.

Section snippets

Methods

Sixteen healthy male volunteers (aged 28.1±2.8 years; body mass index: 24.3±2.4 kg/m²) participated in the study. The protocol was approved by the local ethics committee and informed consent was obtained from all participants according to the Declaration of Helsinki. We performed a double-blind, randomized, placebo-controlled, three-way crossover study.

Dose–response relationships

As shown in Fig. 1A, a single dose of 325 mg LTG led to an average (±S.D.) serum level of 2667±1159 ng/ml after 2 h which slightly decreased to 2383±848 ng/ml after 8 h. For divided doses only 15 subjects could be analyzed. LTG serum level increased stepwise up to a maximum of 2497±717 ng/ml. Similarly, LTG single dose lead to an increase in mean RMT from 51.5±6.9% (maximal stimulator output) at baseline to 55.6±6.8% after 2 h and remained elevated at 56.1±6.8%, 55.8±6.4% and 55.0±6% after 4, 6 and 8

Discussion

Although it is well-known already for a long time that the RMT elevates under LTG, this is the first study to investigate in detail the relationship between oral dose serum level and motor threshold. From our data we are able to demonstrate that LTG serum level as well as RMT increase show a similar dependency from the oral dose suggesting a positive correlation between both parameters (cf. Fig. 1). Maximal LTG serum levels after oral administration of up to 325 mg LTG were in a therapeutic

Acknowledgements

This study was supported by Glaxo Wellcome Research & Development, Medical Department, Greenford, Middlesex, UK.

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Lamotrigine and retigabine increase motor threshold in transcranial magnetic stimulation at the dose required to produce an antiepileptic effect against maximal electroshock-induced seizure in rats
2022, Neuroscience Letters
Transcranial magnetic stimulation (TMS) is a neurophysiological technique that enables noninvasive evaluation of neuronal excitability in the brain. In the past, a large number of antiepileptic drugs were shown to increase the motor threshold (MT) in clinical TMS studies, suggesting the inhibition of excessive neuronal excitability. To facilitate drug development, the confirmation of similar changes in neurophysiological biomarkers in both preclinical and clinical studies is crucial; however, until now, there have been no data showing the drug efficacies on neuronal excitabilities as measured using TMS in rodents. In this study, we found that the antiepileptic drugs, lamotrigine (10 mg/kg) and retigabine (5 mg/kg), significantly increased the MT in rats using TMS, which is similar to clinical study findings. In addition, we demonstrated that these drugs could inhibit maximal electroshock (MES)-induced seizures in rats when given at the same dose required to be effective in the TMS experiment. These findings suggest that the effects of antiepileptic drugs in our rat TMS system have a similar sensitivity to that of the antiepileptic effects in rats with MES-induced seizures. The measurement of MT in a TMS study may be a noninvasive translational approach for predicting antiepileptic efficacy in drug development.
Redefining the age-specific therapeutic ranges of lamotrigine for patients with epilepsy: A step towards optimizing treatment and increasing cost-effectiveness
2021, Epilepsy Research
The 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.
This 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.
The 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.
The 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.
Review of Transcranial Magnetic Stimulation in Epilepsy
2020, Clinical Therapeutics
Citation Excerpt :
Escalating lamotrigine dosage in 10 healthy volunteers over a 5-week period also was reported to correspond to a linear increase in rMT, with a drop in serum lamotrigine levels coinciding with an abrupt return to baseline rMT.11 Tergau et al (2003)17 found similar dose-dependent results in healthy subjects taking lamotrigine, with aggregate data but high interindividual variability. In a comparison of rMT at 2 and 12 h after the administration of 100 versus 200 mg BID of lacosamide in 15 healthy volunteers, a trend toward a dose-responsive effect was found (p = 0.07); corresponding serum drug levels were not measured.10
Despite the availability of numerous pharmacologic and nonpharmacologic antiseizure therapies, a fraction of patients with epilepsy remain refractory to current treatment options, underscoring the need for novel drugs and neuromodulatory therapies. Transcranial magnetic stimulation (TMS), coupled with either electromyography or electroencephalography, enables rapid measurement of the cortical excitation/inhibition ratio, which is pathologically shifted toward excess excitability in patients with epilepsy. In this review, we summarize: (1) TMS protocols that have been deployed to identify promising compounds in the antiepilepsy drug (AED)-development pipeline, and (2) the therapeutic potential of TMS in the treatment of drug-resistant seizures.
A focused literature review of the use of TMS in epilepsy, using a PubMed search, was performed. Over 70 articles were included that pertained to: (1) the use of TMS-EMG and TMS-EEG in elucidating the mechanisms of action of AEDs and in discovering potential new AEDs; and (2) the use of repetitive TMS in the treatment of seizures.
Studies from the literature have reported that AEDs alter TMS-derived metrics, typically by leading to a net increase in cortical inhibition with successful therapy. Preclinical TMS work in rodent models of epilepsy has led to the development of novel antiseizure drug compounds. Clinical translational studies of TMS have been used to determine guidelines on the dosages of other agents in the AED pipeline in preparation for clinical trials. Several studies have described the use of therapeutic repetitive TMS in both the ictal and interictal states of epilepsy, with inconsistent results.
TMS has diagnostic and therapeutic potential in epilepsy. TMS-derived markers can enable early-stage measures of AED target engagement, and can facilitate studies of the pharmacokinetic and pharmacodynamic properties of AEDs. TMS may also be used in the early prediction of the efficacy of different AEDs in treating patients, and in direct neuromodulation of epileptic networks. From the therapeutics perspective, despite favorable results in some trials, the optimization of treatment paradigms and the determination of ideal candidates for TMS are still needed. Finally, preclinical experiments of TMS have provided mechanistic insight into its effects on the excitation/inhibition ratio, and may facilitate rational drug–device coupling paradigms. Overall, the capacity of TMS in both the modulation and measurement of changes in cortical excitability highlights its unique role in advancing antiepilepsy therapeutics
The effect of psychotropic drugs on cortical excitability and plasticity measured with transcranial magnetic stimulation: Implications for psychiatric treatment
2019, Journal of Affective Disorders
Repetitive transcranial magnetic stimulation (rTMS) is an emerging treatment for neuropsychiatric disorders. Patients in rTMS treatment typically receive concomitant psychotropic medications, which affect neuronal excitability and plasticity and may interact to affect rTMS treatment outcomes. A greater understanding of these drug effects may have considerable implications for optimizing multi-modal treatment of psychiatric patients, and elucidating the mechanism(s) of action (MOA) of rTMS.
We summarized the empirical literature that tests how psychotropic drugs affect cortical excitability and plasticity, using varied experimental TMS paradigms.
Glutamate antagonists robustly attenuate plasticity, largely without changes in excitability per se; antiepileptic drugs show the opposite pattern of effects, while calcium channel blockers attenuate plasticity. Benzodiazepines have moderate and variable effects on plasticity, and negligible effects on excitability. Antidepressants with potent 5HT transporter inhibition reduce both excitability and alter plasticity, while antidepressants with other MOAs generally lack either effect. Catecholaminergic drugs, cholinergic agents and lithium have minimal effects on excitability but exhibit robust and complex, non-linear effects in TMS plasticity paradigms.
These effects remain largely untested in sustained treatment protocols, nor in clinical populations. In addition, how these medications impact clinical response to rTMS remains largely unknown.
Psychotropic medications exert robust and varied effects on cortical excitability and plasticity. We encourage the field to more directly and fully investigate clinical pharmaco-TMS studies to improve outcomes.
Early TMS evoked potentials in epilepsy: A pilot study
2016, Clinical Neurophysiology
To explore if the TMS evoked potential is different in patients with epilepsy compared to healthy subjects.
Eighteen healthy subjects and thirteen epilepsy patients participated in this study. Single TMS pulses were applied to the left and right motor cortex. For each target we applied 75 pulses at 110% of the resting motor threshold (RMT), and continuously measured the EEG. Resting motor threshold and the TMS evoked potential (TEP) were compared between patients and healthy subjects.
Epilepsy patients had a higher left RMT than healthy subjects (88.5% vs. 81.8%, p = 0.048). For left motor cortex stimulation, the N100 was larger in amplitude in epilepsy patients than in healthy subjects (p = 0.0073). For right motor cortex stimulation, the P180 was larger in amplitude in epilepsy patients than in healthy subjects (p = 0.006). The differences in these late TEP components were localized in the centro-parietal areas. No significant differences were found for other TEP components.
In this pilot study, we found a significant higher MT and higher TEP amplitudes in epilepsy patients compared to healthy subjects.
Changes in cortical excitability may assist in epilepsy diagnostics or evaluation of the efficacy of anti-epileptic drugs.

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Relationship between lamotrigine oral dose, serum level and its inhibitory effect on CNS: insights from transcranial magnetic stimulation

Abstract

Introduction

Section snippets

Methods

Dose–response relationships

Discussion

Acknowledgements

J. Biol. Chem.

Epilepsy Res.

Epilepsy Res.

Brain Res.

Epilepsy Res.

Electroencephalogr. Clin. Neurophysiol.

Neurosci. Lett.

Neurosci. Lett.

Epilepsy Res.

Epilepsy Res.

Epilepsy Res.

Therapeutic drug monitoring of lamotrigine in patients suffering from resistant partial seizures

Eur. Neurol.

Optimal focal transcranial magnetic activation of the human motor cortex: effects of coil orientation, shape of the induced current pulse, and stimulus intensity

J. Clin. Neurophysiol.