Canadian League Against Epilepsy - Basic and Clinical Pharmacology of Newer Anti ...... ·...
Transcript of Canadian League Against Epilepsy - Basic and Clinical Pharmacology of Newer Anti ...... ·...
![Page 1: Canadian League Against Epilepsy - Basic and Clinical Pharmacology of Newer Anti ...... · 2017-10-17 · Disclosures Research Grants –Canadian Institutes of Health Research (CIHR)](https://reader033.fdocuments.in/reader033/viewer/2022042303/5ece4dcdb1af104f892b68bb/html5/thumbnails/1.jpg)
Basic and Clinical Pharmacology of Newer Anti-Seizure Drugs
SATURDAY, OCTOBER 14th
BREAKOUT SESSION 2-AHarbourfront Ballroom 1
![Page 2: Canadian League Against Epilepsy - Basic and Clinical Pharmacology of Newer Anti ...... · 2017-10-17 · Disclosures Research Grants –Canadian Institutes of Health Research (CIHR)](https://reader033.fdocuments.in/reader033/viewer/2022042303/5ece4dcdb1af104f892b68bb/html5/thumbnails/2.jpg)
Löscher et al, Nat Rev Drug Discov 2014
![Page 3: Canadian League Against Epilepsy - Basic and Clinical Pharmacology of Newer Anti ...... · 2017-10-17 · Disclosures Research Grants –Canadian Institutes of Health Research (CIHR)](https://reader033.fdocuments.in/reader033/viewer/2022042303/5ece4dcdb1af104f892b68bb/html5/thumbnails/3.jpg)
Brivaracetam (Brivlera)Stiripentol (Diacomit)
NEWER ASDsSince 1993
![Page 4: Canadian League Against Epilepsy - Basic and Clinical Pharmacology of Newer Anti ...... · 2017-10-17 · Disclosures Research Grants –Canadian Institutes of Health Research (CIHR)](https://reader033.fdocuments.in/reader033/viewer/2022042303/5ece4dcdb1af104f892b68bb/html5/thumbnails/4.jpg)
Basic and Clinical Pharmacology ofNewer Anti-Seizure Drugs
• Mechanistic Overview of Anti-Seizure Drugs• Dr. Tara Klassen, University of British Columbia
• Pharmacokinetic Profiles of Newer Anti-Seizure Drugs
• Dr. Jong M. Rho, University of Calgary
• Clinical Efficacy of Newer Anti-Seizure Drugs• Dr. Jorge Burneo, Western University
• Adverse Effect Profiles of Newer Anti-Seizure Drugs• Dr. Lionel Carmant, Université de Montréal
![Page 5: Canadian League Against Epilepsy - Basic and Clinical Pharmacology of Newer Anti ...... · 2017-10-17 · Disclosures Research Grants –Canadian Institutes of Health Research (CIHR)](https://reader033.fdocuments.in/reader033/viewer/2022042303/5ece4dcdb1af104f892b68bb/html5/thumbnails/5.jpg)
Jong M. Rho, MD
Mechanistic Overview ofAnti-Seizure Drugs
40th Annual Meeting of the Canadian League Against EpilepsyVancouver, British Columbia
October 14, 2017
![Page 6: Canadian League Against Epilepsy - Basic and Clinical Pharmacology of Newer Anti ...... · 2017-10-17 · Disclosures Research Grants –Canadian Institutes of Health Research (CIHR)](https://reader033.fdocuments.in/reader033/viewer/2022042303/5ece4dcdb1af104f892b68bb/html5/thumbnails/6.jpg)
Disclosures Research Grants
– Canadian Institutes of Health Research (CIHR)– Alberta Children’s Hospital Research Institute (ACHRI),
University of Calgary; Alberta Children’s Hospital Foundation– Brain Canada Platform Support Grant
Scientific Advisory Boards– Citizens United for Research in Epilepsy (Chicago, IL)– The Charlie Foundation (Santa Monica, CA)– Matthew’s Friends Foundation (Surrey, United Kingdom)
Consultant Activity– Danone Nutricia– Accera, Inc.– Xenon Pharma– Ajinomoto USA
![Page 7: Canadian League Against Epilepsy - Basic and Clinical Pharmacology of Newer Anti ...... · 2017-10-17 · Disclosures Research Grants –Canadian Institutes of Health Research (CIHR)](https://reader033.fdocuments.in/reader033/viewer/2022042303/5ece4dcdb1af104f892b68bb/html5/thumbnails/7.jpg)
Newer Anti-Seizure Drugs
•Rufinamide
•Lacosamide
•Stiripentol
•Perampanel
•Eslicarbazepine
•Brivaracetam
![Page 8: Canadian League Against Epilepsy - Basic and Clinical Pharmacology of Newer Anti ...... · 2017-10-17 · Disclosures Research Grants –Canadian Institutes of Health Research (CIHR)](https://reader033.fdocuments.in/reader033/viewer/2022042303/5ece4dcdb1af104f892b68bb/html5/thumbnails/8.jpg)
![Page 9: Canadian League Against Epilepsy - Basic and Clinical Pharmacology of Newer Anti ...... · 2017-10-17 · Disclosures Research Grants –Canadian Institutes of Health Research (CIHR)](https://reader033.fdocuments.in/reader033/viewer/2022042303/5ece4dcdb1af104f892b68bb/html5/thumbnails/9.jpg)
The ParoxysmalDepolarization Shift(PDS)
![Page 10: Canadian League Against Epilepsy - Basic and Clinical Pharmacology of Newer Anti ...... · 2017-10-17 · Disclosures Research Grants –Canadian Institutes of Health Research (CIHR)](https://reader033.fdocuments.in/reader033/viewer/2022042303/5ece4dcdb1af104f892b68bb/html5/thumbnails/10.jpg)
Classification of ASD Mechanisms
![Page 11: Canadian League Against Epilepsy - Basic and Clinical Pharmacology of Newer Anti ...... · 2017-10-17 · Disclosures Research Grants –Canadian Institutes of Health Research (CIHR)](https://reader033.fdocuments.in/reader033/viewer/2022042303/5ece4dcdb1af104f892b68bb/html5/thumbnails/11.jpg)
K+ K+
HCN channel
NMDA receptorAMPA/kainate receptor
Na+(Ca )2+Na ,
+ K+
Ca2+, Na+
OUTSIDE
INSIDE
Postsynapticmembrane
Propagated actionpotential
Glutamate
Voltage-dependent sodium channel
Na+
Depolarization
Multiple sub-types voltage-dependent calcium channels
Ca2+Vesicular release
SV2A synapticvesicle protein
Felbamate
LamotrigineGabapentin
Topiramate
LamotrigineFelbamate
TopiramateOxcarbazepineLevetiracetam
GabapentinPregabalin
PhenytoinCarbamazepineOxcarbazepineValproic acidLamotrigineFelbamateTopiramateZonisamideRufinamideLacosamide
a
Levetiracetam
Central Excitatory Synapse
![Page 12: Canadian League Against Epilepsy - Basic and Clinical Pharmacology of Newer Anti ...... · 2017-10-17 · Disclosures Research Grants –Canadian Institutes of Health Research (CIHR)](https://reader033.fdocuments.in/reader033/viewer/2022042303/5ece4dcdb1af104f892b68bb/html5/thumbnails/12.jpg)
Central Inhibitory Synapse
GABA transporter
Glutamate
GAD
GABA
GABA-T
semi-aldehyde
GABA
Glial Cell
GABA transporter
GABA-TGABASuccinic
semi-aldehyde Succinic
OUTSIDE
INSIDE
Postsynapticmembrane
Cl–
GABA ReceptorsA
Tiagabine
Vigabatrin
FelbamateTopiramate
Benzodiazepines
Barbiturates
![Page 13: Canadian League Against Epilepsy - Basic and Clinical Pharmacology of Newer Anti ...... · 2017-10-17 · Disclosures Research Grants –Canadian Institutes of Health Research (CIHR)](https://reader033.fdocuments.in/reader033/viewer/2022042303/5ece4dcdb1af104f892b68bb/html5/thumbnails/13.jpg)
Voltage-Gated Sodium Channels
![Page 14: Canadian League Against Epilepsy - Basic and Clinical Pharmacology of Newer Anti ...... · 2017-10-17 · Disclosures Research Grants –Canadian Institutes of Health Research (CIHR)](https://reader033.fdocuments.in/reader033/viewer/2022042303/5ece4dcdb1af104f892b68bb/html5/thumbnails/14.jpg)
Eslicarbazepine
Rufinamide
![Page 15: Canadian League Against Epilepsy - Basic and Clinical Pharmacology of Newer Anti ...... · 2017-10-17 · Disclosures Research Grants –Canadian Institutes of Health Research (CIHR)](https://reader033.fdocuments.in/reader033/viewer/2022042303/5ece4dcdb1af104f892b68bb/html5/thumbnails/15.jpg)
An Overview of Sodium Channel Modulation
Open Channel Block Fast InactivationEnhancement of Slow Inactivation
DrugsLocal anesthetic drugs (eg, lidocaine)
Classical AEDs (eg, DPH, CBZ, LTG)
Lacosamide
Functional implication
Blocks action potential propagation (ie, neuronal activity)
Responsible for use dependence
Governs availability of Na+ channels
Consequence of overdose
Paralysis, death Neuronal slowing Exaggerated CNS effects
Time course ImmediatelyDelay by milliseconds
Delay by secondsto minutes
Molecular mechanism
Open channel (pore) block“Hinged-lid” mechanism
Conformation change of channel pore
Beyreuther BK, et al. CNS Drug Rev. 2007;13:21-42. Cummins TR, et al. Expert Rev Neurotherapeutics. 2007;7:1597-1612. Errington AC, et al. Mol Pharmacol. 2008;73:157-169.
![Page 16: Canadian League Against Epilepsy - Basic and Clinical Pharmacology of Newer Anti ...... · 2017-10-17 · Disclosures Research Grants –Canadian Institutes of Health Research (CIHR)](https://reader033.fdocuments.in/reader033/viewer/2022042303/5ece4dcdb1af104f892b68bb/html5/thumbnails/16.jpg)
Glutamate Receptors
![Page 17: Canadian League Against Epilepsy - Basic and Clinical Pharmacology of Newer Anti ...... · 2017-10-17 · Disclosures Research Grants –Canadian Institutes of Health Research (CIHR)](https://reader033.fdocuments.in/reader033/viewer/2022042303/5ece4dcdb1af104f892b68bb/html5/thumbnails/17.jpg)
CentralExcitatory
Synapse
![Page 18: Canadian League Against Epilepsy - Basic and Clinical Pharmacology of Newer Anti ...... · 2017-10-17 · Disclosures Research Grants –Canadian Institutes of Health Research (CIHR)](https://reader033.fdocuments.in/reader033/viewer/2022042303/5ece4dcdb1af104f892b68bb/html5/thumbnails/18.jpg)
Ionotropic Glutamate Receptor Blockers
Perampanel
![Page 19: Canadian League Against Epilepsy - Basic and Clinical Pharmacology of Newer Anti ...... · 2017-10-17 · Disclosures Research Grants –Canadian Institutes of Health Research (CIHR)](https://reader033.fdocuments.in/reader033/viewer/2022042303/5ece4dcdb1af104f892b68bb/html5/thumbnails/19.jpg)
Pre-synaptic NeurotransmitterRelease
![Page 20: Canadian League Against Epilepsy - Basic and Clinical Pharmacology of Newer Anti ...... · 2017-10-17 · Disclosures Research Grants –Canadian Institutes of Health Research (CIHR)](https://reader033.fdocuments.in/reader033/viewer/2022042303/5ece4dcdb1af104f892b68bb/html5/thumbnails/20.jpg)
Synaptic Vesicle Proteins
![Page 21: Canadian League Against Epilepsy - Basic and Clinical Pharmacology of Newer Anti ...... · 2017-10-17 · Disclosures Research Grants –Canadian Institutes of Health Research (CIHR)](https://reader033.fdocuments.in/reader033/viewer/2022042303/5ece4dcdb1af104f892b68bb/html5/thumbnails/21.jpg)
Singh & Brashier, Muller J Med Sci Res 2014
LevetiracetamBrivaracetam
![Page 22: Canadian League Against Epilepsy - Basic and Clinical Pharmacology of Newer Anti ...... · 2017-10-17 · Disclosures Research Grants –Canadian Institutes of Health Research (CIHR)](https://reader033.fdocuments.in/reader033/viewer/2022042303/5ece4dcdb1af104f892b68bb/html5/thumbnails/22.jpg)
Metabolism at theNeurovascular Unit
![Page 23: Canadian League Against Epilepsy - Basic and Clinical Pharmacology of Newer Anti ...... · 2017-10-17 · Disclosures Research Grants –Canadian Institutes of Health Research (CIHR)](https://reader033.fdocuments.in/reader033/viewer/2022042303/5ece4dcdb1af104f892b68bb/html5/thumbnails/23.jpg)
Stiripentol
• STP reduces synaptosomal GABA uptake (IC50 5x10-5
M)
• STP slightly increases (+22%) brain concentrations of GABA after “in vivo” administration (300 mg/kg i.p.)
• STP is a positive allosteric modulator of GABAA
receptors (those containing 3 subunits)
![Page 24: Canadian League Against Epilepsy - Basic and Clinical Pharmacology of Newer Anti ...... · 2017-10-17 · Disclosures Research Grants –Canadian Institutes of Health Research (CIHR)](https://reader033.fdocuments.in/reader033/viewer/2022042303/5ece4dcdb1af104f892b68bb/html5/thumbnails/24.jpg)
Science 2015
![Page 25: Canadian League Against Epilepsy - Basic and Clinical Pharmacology of Newer Anti ...... · 2017-10-17 · Disclosures Research Grants –Canadian Institutes of Health Research (CIHR)](https://reader033.fdocuments.in/reader033/viewer/2022042303/5ece4dcdb1af104f892b68bb/html5/thumbnails/25.jpg)
Noebels, Nat Neurosci 2015
Single and Multigenic Biological Complexityin Epileptic Brain
![Page 26: Canadian League Against Epilepsy - Basic and Clinical Pharmacology of Newer Anti ...... · 2017-10-17 · Disclosures Research Grants –Canadian Institutes of Health Research (CIHR)](https://reader033.fdocuments.in/reader033/viewer/2022042303/5ece4dcdb1af104f892b68bb/html5/thumbnails/26.jpg)
Summary
• Newer ASDs possess novel mechanisms of action (albeit with some variations on a theme)
• Yet, whether these mechanisms can afford greater clinical efficacy has yet to be demonstrated
• Stiripentol represents an ASD that has a paradigm-altering action (i.e., influencing metabolism at the synapse)
• Epilepsy is inherently a biological system that has many levels of complexity
• Thus, single/narrow mechanistic approaches are less likely to render complete control in all patients