Elsevier

Epilepsy Research

Volume 135, September 2017, Pages 38-42
Epilepsy Research

Intravenous lacosamide in status epilepticus: Correlation between loading dose, serum levels, and clinical response

https://doi.org/10.1016/j.eplepsyres.2017.05.007Get rights and content

Highlights

  • LCM lacks a defined target serum levels after loading dose in SE.

  • A loading dose of >9 mg/kg is associated with serum levels above 10 mg/l.

  • Higher serum levels are not correlated with better clinical response in SE.

Abstract

Introduction

Intravenous lacosamide (LCM) is increasingly used in the treatment of status epilepticus (SE), but optimal loading dose and target serum levels are unclear. We analysed the correlation between LCM serum levels after intravenous loading dose and clinical response.

Materials and methods

Retrospective study in two centres from December 2014 to May 2016 including consecutive SE patients treated with LCM, in which trough serum levels after intravenous loading dose were available. Trough levels were correlated with the loading dose and the clinical response, defined as LCM introduction terminating SE without the need of further treatment. Correlations were adjusted for other SE characteristics.

Results

Among 40 patients, 16 (40%) responded to LCM. LCM serum concentrations within the reference interval (10–20 mg/l) were associated with loading doses of >9 mg/kg (p = 0.003; χ2). However, we observed no difference between LCM serum levels in responders (median 10.4 mg/l) versus non-responders (median 9.5 mg/l; p = 0.36; U test), even after adjusting for other predictors of clinical outcome (SE severity, aetiology, and number of previous treatment).

Discussion

High intravenous LCM loading doses ( > 9 mg/kg) were associated with serum levels within the reference interval, there was however no correlation with the clinical response. Prospective studies are needed to evaluate the benefit of increasing the LCM loading dose in SE.

Introduction

Status epilepticus (SE) is a prolonged epileptic activity, secondary to the loss of mechanisms of seizure termination (Trinka et al., 2015); it represents a neurologic emergency with considerable morbidity and mortality (Betjemann and Lowenstein, 2015, Novy et al., 2010). Benzodiazepines constitute the first line of treatment, followed by intravenous (IV) antiepileptic drugs (AEDs) (Brophy et al., 2012, Glauser et al., 2016, Meierkord et al., 2010). IV AEDs are most commonly administered through a weight dependent loading dose to achieve efficient serum levels as quickly as possible.

Lacosamide (LCM) is available since 2008 with an IV formulation. In chronic epilepsy, it is licensed up to 400 mg daily for maintenance treatment; the proposed reference serum interval lies between 10 and 20 mg/l (Patsalos, 2013). Dose adaptation is not required according to gender or comedications (Cawello, 2015). LCM represents a promising option for the treatment of SE: administered as intravenous loading dose it lacks major side effects (Fountain et al., 2013) and relevant pharmacological interactions (Cawello et al., 2014). Consequently, it is increasingly used “off-label” in this setting (Falco-Walter and Bleck, 2016, Kellinghaus et al., 2014), and has been evaluated in randomized control trial with pending results (Husain, 2015). Ideal loading doses remain however uncertain.

Boluses of 200–400 mg are usually administered in SE (Höfler and Trinka, 2013), and a small prospective study suggested that 400 mg could possibly prove more efficacious than 200 mg (Legros et al., 2014). It was recently observed that loading doses of 8 mg/kg (approximately 550 mg for a 70 kg patient) were needed to reach a serum level within the reference interval (Ramsay et al., 2015) and that doses of more than 10–12 mg/kg resulted in levels above 15 mg/l. Measurements of serum levels could represent a useful surrogate marker of exposition to ascertain the clinical response in SE. In this study, we assessed serum levels after IV LCM loading dose to explore their relationship with the clinical response.

Section snippets

Registry and patients selection

We carried out a retrospective analysis in two centres in Western Switzerland: CHUV (the University Hospital of Lausanne) and Sion (a large regional hospital) including all SE episodes treated between December 2014 (first available serum level in SE) and May 2016. All adults with SE in CHUV are registered in a prospective registry (Novy et al., 2010) that was approved by the relevant ethics committee; the Sion hospital started in June 2015 an identical database. Patients with suspected SE at

Patients characteristics

We included 40 SE patients with LCM trough serum levels. Thirty-seven were treated at the CHUV and three in Sion. At the CHUV, the 37 included episodes with serum levels corresponded to 65% of 57 SE episodes treated with LCM during the same period. Among the 20 remaining episodes, seven had no available levels, 11 were excluded because LCM serum levels were collected more than 36 h after the loading dose, and two other because the dosing was performed less than six hours after the last LCM

Relation between loading dose, serum levels and clinical response

This study confirms that, in adult patients with SE, LCM loading doses higher than 9 mg/kg are needed to reach the reference range reported in people with chronic epilepsy. Treatment response was however neither significantly determined by the loading dose of LCM nor by the resulting serum level.

LCM use in SE is off-label and initial doses (200–400 mg) are mostly derived from intravenous replacement for oral therapy; 400 mg being the highest daily dosage approved. Given the LCM volume of

Authors contribution

MP: study concept and design, acquisition of data, analysis and interpretation, redaction of the manuscript.

PA: acquisition of data, critical revision of the manuscript for important intellectual content.

VA: acquisition of data, critical revision of the manuscript for important intellectual content

CS: acquisition of data, critical revision of the manuscript for important intellectual content.

LAD: lacosamide levels measurements, acquisition of data, critical revision of the manuscript for

Disclosures

AOR has received research support from UCB Pharma and SAGE pharmaceuticals.

JN has received personal/institutional honoraria from UCB Pharma and Pfizer.

The remaining authors have no conflicts of interest.

Funding sources

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Acknowledgements

We would like to thank Tamarah Suys, RN, and Dr Laurent Carteron (Lausanne) for their help in data collection. J. Novy was supported by the Swiss National Science Foundation (grant 320030_163430).

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