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Therapeutic drug monitoring of new generation antiepileptic drugs: concrete benefit, correlation with clinical effects and usefulness of saliva samples

English title Therapeutic drug monitoring of new generation antiepileptic drugs: concrete benefit, correlation with clinical effects and usefulness of saliva samples
Applicant Novy Jan
Number 163430
Funding scheme Project funding
Research institution Service de Neurologie Département des Neurosciences Cliniques CHUV
Institution of higher education University of Lausanne - LA
Main discipline Neurology, Psychiatry
Start/End 01.06.2016 - 30.06.2019
Approved amount 320'918.00
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All Disciplines (2)

Discipline
Neurology, Psychiatry
Clinical Pharmacology

Keywords (6)

Ultra-performance liquid chromatography coupled to; Saliva; Epilepsy; Newer generation antiepileptic drugs; Outcome; Therapeutic drug monitoring

Lay Summary (French)

Lead
L’épilepsie est la maladie neurologique sérieuse la plus fréquente (>3% de la population général a souffre d’épilepsie dans sa vie). Septante pourcents des gens souffrant d’épilepsie sont traité par une médication antiépileptique. La surveillance des taux médicamenteux est une pratique bien établie pour les vieux médicaments antiépileptiques, mais ces médicaments sont supplantés de manière croissante par les médicaments antiépileptique de nouvelle génération. Les médicaments antiépileptiques de nouvelle génération montrent également des concentrations qui varient entre individus. Les bénéfices d’un traitement sur-mesure guidé par la surveillance des taux médicament n’ont jamais été examinés.
Lay summary

Nous avons développé le dosage des taux médicaments antiépileptiques utilisant la chromatographie couplé à une spectrométrie de masse en tandem pour les principaux médicaments antiépileptique de nouvelle génération : la lamotrigine, le lacosamide, le levetiracetam, le topiramate, et le zonisamide. Nos objectifs sont :

- évaluer si la mise en place d’un traitement sur mesure par la surveillance des taux médicamenteux peut apporter un bénéfice concret aux patients en termes de contrôle sur la maladie et sur la survenue d’effets secondaires.

- explorer la relation entre la concentration médicamenteuse et le contrôle de la maladie en termes d’arrêt complet des crises d’épilepsie.

-évaluer la fiabilité et la valeur ajoutée d’une surveillance des taux médicamenteux dans la salive, un liquide moins difficile à obtenir qu’une prise sang.

Ces objectifs seront atteints par deux études conduites en parallèle. Une étude randomisé chez des patients nécessitant un ajustement de leur médication, évaluera de manière prospective l’effet de la surveillance systématique ou uniquement « secours » des taux médicamenteux sur l’activité de maladie et les effets secondaires en utilisant une analyse de survie. Une autre étude observationnelle chez des patients sous médication stable soit libre de crise (défini de manière statistique) ou continuant à avoir des crises comparera les taux médicamenteux et identifiera les taux auxquels l’effet maximal du médicament est atteint. Pour tous les échantillons de sang prélevés, des prélèvements de salive seront collectés et la fiabilité des taux dans la salive sera évaluée rétrospectivement. 

 

Direct link to Lay Summary Last update: 05.10.2015

Responsible applicant and co-applicants

Employees

Publications

Publication
Therapeutic Drug Monitoring of Newer Antiepileptic Drugs: A Randomized Trial for Dosage Adjustment.
Aícua-Rapún Irene, André Pascal, Rossetti Andrea O, Ryvlin Philippe, Hottinger Andreas F, Decosterd Laurent A, Buclin Thierry, Novy Jan (2020), Therapeutic Drug Monitoring of Newer Antiepileptic Drugs: A Randomized Trial for Dosage Adjustment., in Annals of neurology, 87(1), 22-29.
Closed-loop Neuropharmacology for Epilepsy: Distant Dream or Future Reality?
Aicua-Rapun Irene, André Pascal, Novy Jan (2019), Closed-loop Neuropharmacology for Epilepsy: Distant Dream or Future Reality?, in Current Neuropharmacology, 17(5), 447-458.
Intravenous brivaracetam in status epilepticus: Correlation between loading dose, plasma levels and clinical response
Aicua-Rapun Irene, André Pascal, Rossetti Andrea O., Decosterd Laurent A., Buclin Thierry, Novy Jan (2019), Intravenous brivaracetam in status epilepticus: Correlation between loading dose, plasma levels and clinical response, in Epilepsy Research, 149, 88-91.
Levetiracetam circulating concentrations and response in status epilepticus
Perrenoud Matthieu, André Pascal, Buclin Thierry, Decosterd Laurent A., Rossetti Andrea O., Novy Jan (2018), Levetiracetam circulating concentrations and response in status epilepticus, in Epilepsy & Behavior, 88, 61-65.
Intravenous lacosamide in status epilepticus: Correlation between loading dose, serum levels, and clinical response
Perrenoud Matthieu, André Pascal, Alvarez Vincent, Stähli Christine, Decosterd Laurent A., Rossetti Andrea O., Novy Jan (2017), Intravenous lacosamide in status epilepticus: Correlation between loading dose, serum levels, and clinical response, in Epilepsy Research, 135, 38-42.
Early Lance–Adams syndrome after cardiac arrest: Prevalence, time to return to awareness, and outcome in a large cohort
Aicua Rapun Irene, Novy Jan, Solari Daria, Oddo Mauro, Rossetti Andrea O. (2017), Early Lance–Adams syndrome after cardiac arrest: Prevalence, time to return to awareness, and outcome in a large cohort, in Resuscitation, 115, 169-172.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
30th International Epilepsy Congress Poster Newer generation antiepileptic drugs efficacy correlation with plasma levels 26.08.2018 Vienne, Austria Aicua Rapun Irene;
13th European Congress on Epileptology Poster Benefit of therapeutic drug monitoring of newer generation antiepileptic drugs in epilepsy: a randomised controlled trial. 26.08.2018 Vienne, Austria Aicua Rapun Irene;


Abstract

Epilepsy is the most common serious neurologic condition (>3% lifelong prevalence) that requires long term medication in 70% of affected patients. Therapeutic drug monitoring (TDM) is well established for older antiepileptic drugs (AEDs) such as phenytoin, phenobarbital, valproate and carbamazepine, but these agents are decreasingly used as newer generation compounds gain pre-eminence. There is evidence that these newer AEDs show inter-individual concentration variability as well. The benefit of TDM-based individualisation of their prescription has not been assessed.We have developed state of the art ultra-performance liquid chromatography coupled to tandem mass spectrometry for the measurement of five newer generation AEDs: lamotrigine, lacosamide, levetiracetam, topiramate and zonisamide. We aim at studying the clinical relevance of TDM for these agents in the treatment of epilepsy. Our concrete objectives are:-to assess whether individualising therapy through TDM brings a tangible benefit to patients in term of clinical response and adverse events;-to unravel the relationship between serum concentration and clinical response in terms of seizure remission;-to assess the reliability and added value of salivary TDM, less invasive than the reference plasma TDM.These objectives will be reached through two concomitant studies: on the one side, a randomised trial of either systematic TDM or rescue TDM in consenting patients requiring treatment adjustment; outcome will be assessed in terms of tolerance and treatment response in a survival analysis. On the other side, an observational study on patients ineligible for the trial, either in remission (defined as the longer of 3 pre-treatment interseizure intervals or 1 year) or continuing to experience seizures, to compare the distribution of drug levels and identify ceiling levels correlating with remission. For all blood samples taken in those studies, saliva probes will be collected and their reliability for TDM ascertained retrospectively. The samples will also be used for further collaborative, interdisciplinary efforts in population pharmacokinetic modelling, pharmacogenomics and biomedical engineering (development of micromethods for drug measurement at the point of care).
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