Basic and Clinical Pharmacology of Newer Anti-Seizure Drugs

SATURDAY, OCTOBER 14th

BREAKOUT SESSION 2-AHarbourfront Ballroom 1

Löscher et al, Nat Rev Drug Discov 2014

Brivaracetam (Brivlera)Stiripentol (Diacomit)

NEWER ASDsSince 1993

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

Jong M. Rho, MD

Mechanistic Overview ofAnti-Seizure Drugs

40th Annual Meeting of the Canadian League Against EpilepsyVancouver, British Columbia

October 14, 2017

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

Newer Anti-Seizure Drugs

•Rufinamide

•Lacosamide

•Stiripentol

•Perampanel

•Eslicarbazepine

•Brivaracetam

The ParoxysmalDepolarization Shift(PDS)

Classification of ASD Mechanisms

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

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

Voltage-Gated Sodium Channels

Eslicarbazepine

Rufinamide

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.

Glutamate Receptors

CentralExcitatory

Synapse

Ionotropic Glutamate Receptor Blockers

Perampanel

Pre-synaptic NeurotransmitterRelease

Synaptic Vesicle Proteins

Singh & Brashier, Muller J Med Sci Res 2014

LevetiracetamBrivaracetam

Metabolism at theNeurovascular Unit

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)

Science 2015

Noebels, Nat Neurosci 2015

Single and Multigenic Biological Complexityin Epileptic Brain

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