Intravenous lacosamide in status epilepticus: Correlation between loading dose, serum levels, and clinical response
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
Author’s 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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Management of status epilepticus in adults. Position paper of the Italian League against Epilepsy
2020, Epilepsy and BehaviorCitation Excerpt :Finally, in a recent RCT, Misra et al. [25] found no significant difference in efficacy between valproate and lacosamide (1-hour seizure cessation rate 63.6% with lacosamide vs. 69.7% with valproate); however, the study was underpowered to detect a statistically significant and a clinically relevant difference between the two drugs. The correct loading dose proposed for lacosamide is still debated, as higher doses have not always been reported to be more effective [30–32]. In conclusion, phenytoin, phenobarbital, valproate, levetiracetam, and lacosamide appear to be effective in the treatment of definite SE, with no clear indication for the preferred use of one drug over another.
Intravenous brivaracetam in status epilepticus: Correlation between loading dose, plasma levels and clinical response
2019, Epilepsy ResearchCitation Excerpt :Previous studies on newer generation AEDs in SE suggested a ceiling effect in terms of response. Regarding lacosamide, a loading dose greater than 5 mg/kg (Santamarina et al., 2018) was useful whereas no benefits were found when increasing higher than 9 mg/kg (Perrenoud et al., 2017). These data suggest that there may not be a benefit of increasing indiscriminately loading dose in SE even if the treatment is well tolerated.
Levetiracetam circulating concentrations and response in status epilepticus
2018, Epilepsy and BehaviorCitation Excerpt :Plasma levels may potentially thus be of limited help to predict the availability of treatment at its biological target. Thirdly, LEV exposure studied here might be beyond maximum efficacy doses (ceiling effect); a similar observation was done for lacosamide in SE with benefit using loading doses above 5 mg/kg [23] but not more than 9 mg/kg [24]. Making a parallel with chronic epilepsy in an outpatient setting, most of the medication effects in responders are usually obtained at low dosage, and increasing doses seem to bring little additional benefit in terms of remission [25,26].
Intravenous lacosamide (LCM) in status epilepticus (SE): Weight-adjusted dose and efficacy
2018, Epilepsy and BehaviorCitation Excerpt :In addition, the proposed reference plasma levels (10–20 mg/l) [24] are based on outpatients under the standard prescribed doses, and it is unclear whether the same range is applicable for SE. In a recent study evaluating plasma levels of LCM, no association was found between higher serum levels and greater efficacy, although there was a smaller number of patients, which means that there was little ability to detect a small effect brought about by treatment [25]. On the other hand, this is a retrospective analysis, and we have not been able to define the upper limit of the loading dose.
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2023, European Journal of Neurology