15/12/2017

1

New AEDs in Uncontrolled seizures

Dr. Suthida Yenjun

“Basic knowledge in Epilepsy”@ PMK15 December 17

• Intractable epilepsy, Refractory epilepsy, Pharmacoresistant epilepsy

Uncontrolled seizures/epilepsy

• Traditionally, referred to therapeutic failure of three antiseizure drugs

• A task force of ILAE proposed that

“drug-resistant” be defined as the failure of adequate trials of two tolerated appropriately

Drug-resistant Epilepsy (DRE)

adequate trials of two tolerated, appropriately chosen and administered antiseizure drugs (whether as monotherapy or in combination) to achieve seizure freedom

Epilepsia 2010;41:51:1069-1077

Reasons for uncontrolled seizures

• Wrong diagnosis

• Wrong treatment

• Triggers or lifestyle factors

• Properly diagnosed seizures do not respond to the best medical treatment

15

20

iFosphenytoine

OxcarbazepineTiagabine

LevetiracetamPregabalin

RufinamideLacosamide

Eslicarbazepine

GanaxolonePerampanelBrivaracetam

25

Available antiepileptic drugs (AEDs)http://www .accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. Accessed16th March 2015.

1840 1860 1880 1900 1920 1940 1960 1980 20000

5

10

BromidePhenobarbital

PhenytoinPrimidone

Ethosuximide

Valproate

BenzodiazepineCarbamazepine

VigabatrinZonisamide Lamotrigine

FelbamateGabapentin

Topiramatep y

2020

15/12/2017

2

Mechanisms of action of antiepileptic drugs. Clinically approved antiepileptic drugs such as perampanel display a spectrum of mechanisms of action, with effects on both inhibitory (left-hand side) and excitatory (right-hand side) nerve terminals.

Reprinted with permission from Macmillan Publishers Ltd, Bialer M, White HS. Nat Rev Drug Discov. 2010;9:68–82.9Abbreviations: AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid; GABA, γ-aminobutyric acid;

GAT-1, sodium- and chloride-depended GABA transporter 1; SV2A, synaptic vesicle glycoprotein 2A.

Therapeutics and Clinical Risk Management. 2013:9 285–293.

Lacosamide

• US FDA accepted UCB's New Drug Application for lacosamide (Vimpat) in 2007

• the adjunctive treatment of partial-onset seizures and diabetic neuropathic paindiabetic neuropathic pain

• Also approved as monotherapy in treating partial-onset seizures in epilepsy patients aged 17 years or older.

15/12/2017

3

Lacosamide

• Enhances the slow inactivation of voltage-gated Na+

channels : prevent the channel from opening, helping end the action potential but not produce complete blockage of channels….does not affect physiologic function 1

• Modulates collapsin response mediator protein 2 (CRMP-2), preventing the formation of abnormal neuronal connections in the brain 2

1.Doty et al Ann N Y Acad Sci2013;1291:56-68.2. Wilson et al Mol Neurobil.2015;51(2):599-609

Lacosamide• Linear kinetics

• Absolute bioavailability nearly 100%

• Half-life ~ 13 hours

• Partially metabolized by CYP2C19

R ll t d (95%)• Renally excreted (95%)

• Low protein binding(15%)

• No major pharmacokinetic drug-drug interaction or interaction with food

• Oral solution, Tablet and IV formKrauss et al. Annals of Medicine,2012;44:674-679.

Lacosamide

• Initially prescribed in oral doses of 50 mg twice per day, with a total dose of 100 mg/day. increased by 100 mg/day following a twice-daily dose up to a total dose of 200–400 mg/day. g y

• Dose of 600 mg/day was not more effective than a dose of 400 mg/day, but resulted in more adverse reactions

Lacosamide

The most common AEs were

• dizziness (31%)• headache (13%)• nausea (11%)• diplopia (11%)

All appeared to be dose related with the exception of headache

15/12/2017

4

Lacosamide Lacosamide IV injection in SE

• a systematic literature search of electronic databases using a combined search strategy from 2008 until October 2016

• In total 522 SE episodes (51 7% female) in 486• In total, 522 SE episodes (51.7% female) in 486 adults and 36 children and adolescents were evaluated with an overall LCM efficacy of 57%

• Efficacy was comparable between use in nonconvulsive (57%; 82/145) and generalized-convulsive (61%; 30/49; p = 0.68) SE

Lacosamide IV injection in SE

• whereas overall success rate was better in focal motor SE (92%; 34/39, p = 0.013; p < 0.001)

• The main adverse events during treatment of SE are dizziness abnormal vision diplopia and ataxiadizziness, abnormal vision, diplopia, and ataxia

• Overall, lacosamide is well tolerated and has no clinically relevant drug–drug interactions

Effect of lacosamide in combination with other AEDs in an animal model for pharmaco-resistant epilepsy

Ratio AED:LCM 1:3 1:1 3:1

LTG + LCM synergism tendency synergism synergism

VPA + LCM additivity synergism tendency synergism tendency

CBZ + LCM synergism synergism synergism

22

PHT + LCM additivity additivity synergism tendency

LEV + LCM synergism synergism synergism

TPM + LCM synergism tendency synergism synergism

GBP + LCM additivity synergism synergism

AED=antiepileptic drug; CBZ=carbamazepine; GBP=gabapentinLCM=lacosamide; LEV=levetiracetam; LTG=lamotriginePHT=phenytoin; TPM=topiramate; VPA=valproate

Adapted from Shandra et al. Poster presented at AES, 2007.

Results in animal models should not be extrapolated to situations in humans

Perampanel

• Perampanel (Fycompa, Eisai) was first approved in 2012

• used in addition to other drugs to treat partial seizures and generalized tonic-clonic seizures for people older than 12 yearspeople older than 12 years,

• As of August 2016 Perampanel had been studied and development discontinued in migraine, multiple sclerosis, neuropathic pain, and Parkinson's disease.

Perampanel• It was the first antiepileptic drug in the class of selective non-competitive antagonist of AMPA receptors

15/12/2017

5

Perampanel

• black box warning : serious psychiatric and behavioral changes

• The psychiatric changes included mood changes like euphoric mood, anger, irritability, aggression, belligerence agitation anxiety psychosis (acutebelligerence, agitation, anxiety , psychosis (acute psychosis, hallucinations, delusions, paranoia) and delirium

• Behavioral changes included physical assault and homicidal ideation and/or threats.

Rufinamide

• came to the US market in 2008

• primarily indicated for use as adjunctive treatment of seizures in Lennox–Gastaut syndrome

Rufinamide

• Children: Initial: 10 mg/kg/day in 2 equally divided doses; increase dose by ~10 mg/kg every other day to a target dose of 45 mg/kg/day or 3200 mg/day (whichever is lower) in 2 equally divided doses

• Adults: Initial: 400-800 mg/day in 2 equally divided doses; increase dose by 400-800 mg/day every other day to a maximum dose of 3200 mg/day in 2 equally divided doses.

Rufinamide

• the most frequently occurring AEs were fatigue (18.3%), vomiting (15.0%), and loss of appetite (10.0%), somnolence (17.0%), and headache (16.0%) : mild to moderate in severity

• AED hypersensitivity syndrome (rash & fever) has occurred 1-4 weeks after therapy & more likely in children

• No significant effects on working memory, psychomotor speed, or attention

(Wheles et al. 2010)

Rufinamide

Drug interaction

• Mild increased clearance of oral contraceptives (CYP3A4 induction)

• Phenobarbital, primidone, phenytoin, carbamazepine induce carboxyesterase & significantly increase rufinamide clearance

• Valproate significantly increases rufinamide levels by 60-70%

15/12/2017

6

Clobazam

• CLB is a benzodiazepine that has been marketed as an anxiolytic since 1975 and an anticonvulsant since 1984

• Used for add-on use in tonic-clonic, complex partial, and myoclonic seizures, certain types of status epilepticus, specifically the myoclonic, myoclonic-absent, simple partial, complex partial, and tonic varieties and non-status absence seizures

• Recommended for catamenial epilepsy

Clobazam

Clobazam

• Clobazam (Onfi®), approved October 2011, is indicated for the adjunctive treatment of Lennox-Gastaut syndrome (LGS) in adults and children 2 years of age and older

• Two recent double-blinded, placebo controlled trials A total of 306 patients were enrolled in the studies, with ages ranging from 2–54 years

• Clobazam was adjunctive therapy, added to treatment with valproate, lamotrigine, levetiracetam, or topiramate

Clobazam

• The primary efficacy measure was the percentage reduction in weekly drop seizures (which could include tonic, atonic, or myoclonic)

• The results have also shown that high-dosage CLB (1.0 mg/kg/day) was the most effective vs placebo, whereas medium-dosage CLB (0.5 mg/kg/day) and rufinamide had moderate effects

• Each dose of clobazam statistically significantly decreased the number of drop seizures (p<0.01–0.05).

Ng YT , et al. Neurology. 2011;77(15):1473–81. Cramer JA, et al. Acta Neurol Scand 2013;128:91-9.

Eslicarbazepine acetate

• The drug was approved in the European Union in April 2009 under the trade names Zebinix and Exalief and in the US in 2013 as monotherapy or adjunctive therapy in partial epilepsy in adults

• structurally linked to carbamazepine and oxcarbazepine• structurally linked to carbamazepine and oxcarbazepine. It is converted into the major active metabolite S-licarbazepine which is the active metabolite of oxcarbazepine

• S-licarbazepine stabilizes the inactive state of voltage-gated sodium channels

Eslicarbazepine acetate

• Started at a dose of 400 mg/d for 1–2 weeks before reaching the maintenance dose. Based on the individual clinical response, the dose can be increased to 1200 mg/d.

• Studies for the use of ESL as an anticonvulsant for children are under way as of 2016

• Like oxcarbazepine, ESL has potential uses for the treatment of trigeminal neuralgia and bipolar disorder

15/12/2017

7

Eslicarbazepine acetate

• ESL has a favorable drug-drug interaction profile due to its low protein binding and minimal effect on the hepatic cytochrome P450

• The most common AEs reported to include dizziness• The most common AEs reported to include dizziness, headache, and somnolence. Hyponatremia and rash were rare.

Brivaracetam

• a pyrrolidone derivative in the same class as levetiracetam that continues to undergo clinical trials

• Like levetiracetam, brivaracetam binds to the synaptic vesicle protein 2A but with higher affinity;synaptic vesicle protein 2A, but with higher affinity; brivaracetam also inhibits sodium channels

Brivaracetam Brivaracetam

• Approved in Europe and the US under the trade name Briviact in 2016

• Brivaracetam (BRV) is used to treat as adjunctive therapy for partial onset seizures with or withouttherapy for partial-onset seizures with or without secondary generalisation

• No data are available for its effectiveness and safety in patients younger than 16 years

Brivaracetam

• An exploratory, phase IIb, double-blind, randomized, parallel-group, placebo-controlled study using brivaracetam doses of 5, 20, or 50 mg/day was performed; tolerability was good

• Dose: 50 mg PO q12hr initially; based on individual patient tolerability and therapeutic response, adjust dose down to 25 mg q12hr (50 mg/day) or up to 100 mg q12hr (200 mg/day)

Brivaracetam

• IV injection may be used when PO administration is temporarily not feasible; injection should be administered at the same dosage and same frequency as tablets or oral solution; clinical trials limited IV administration to 4 consecutive daysy

• The most common AEs were mild to moderate in intensity, and included headache, somnolence, influenza, dizziness, neutropenia, and fatigue

15/12/2017

8

Retigabine

• Acts by opening the KCNQ potassium channel, leading to neuronal hyperpolarization

• License application for add-on treatment for drug-resistant partial onset seizures with or without secondary generalisation in people aged 18 or oldersecondary generalisation in people aged 18 or older in 2011

• In 2013 GSK announced that there were safety issues around the drug as it could cause a blue discolouration of the skin and eye abnormalities and production has been discontinued in June 2017