Emerging drugs for EpilepsyDr. Priyanka Kumawat

Introduction

• Clinical phenomenon rather than a single disease entity.

• Seizure- A paroxysmal event due to abnormal, excessive, hypersynchronous, rhythmic discharges from an aggregate of central nervous system (CNS) neurons.

• Epilepsy- Disorder characterized by recurrent seizures (also known as “seizure disorder”) due to chronic underlying process.

• Epilepsy syndrome- Disorders in which epilepsy is a predominant feature and clinical and pathologic characteristics are distinctive and suggest a specific underlying etiology eg: Benign familial neonatal convulsions, lissencephaly.

• Status epilepticus- Continuous or repetitive, discrete seizures with impaired consciousness in the interictal period with duration of seizure activity 15 – 30 min

Epidemiology

• The incidence of epilepsy is ~0.3–0.5% in different populations throughout the world.

• The prevalence of epilepsy has been estimated as 5–10 persons per 1000.

• 5% of the population suffer a single seizure at some time.• Chance of having a second seizure after an initial unprovoked

episode is 30%.• 70% well controlled with drugs (prolonged remissions)• 30% epilepsy at least partially resistant to drug treatments =

INTRACTABLE (PHARMACORESISTANT) EPILEPSY.• Recurrence rate after the withdrawal of drugs is about 30%.

Seizure triggers

• Missed medication (#1 reason)• Stress, anxiety• Hormonal changes, Menses• Dehydration• Lack of sleep, extreme fatigue• Photosensitivity• Alcohol use • Certain Medications-

(chloroquine,penicillins,quinolones,INH,acyclovir,tramadol, TCA,Li,theophylline,amphetamine, cocaine,flumazenil)

• Fever in Some Children

Pathophysiology of seizures

• Due to shift in normal balance of excitement and inhibition in CNS.

• Central role for the excitatory neurotransmiter glutamate (increased) and inhibitory gamma amino butyric acid (GABA) (decreased)

• Excitability is affected by-– Alteration in ion channel functioning– Neurotransmitter level– Receptor functioning(NMDA & non NMDA)– Energy metabolism

Symptoms that may indicate seizure disorder

• Periods of blackout or confused memory• Occasional “fainting spells”• Episodes of blank staring• Sudden falls for no apparent reason• Episodes of blinking or chewing at inappropriate times• A convulsion, with or without fever• Clusters of swift jerking movements in babies

What if not treated

• Seizures can be potentially life threatening with: – Brain failure– Heart failure– Lung failure– Trauma– Accidents

• Sudden Unexpected Death in Epilepsy (SUDEP)• Even subtle seizures can cause small damage in brain• Long Term problems:

– Fall in IQ– Depression– Suicide– Social problems– Quality of life

Diagnosis

• Clinical examination and history

• Routine investigation: Haematology, biochemistry, chest X-ray, electroencephalogram (EEG).

• Neuroimaging :CT/MRI- in all persons aged 25 or more presenting with first seizure

• Advanced investigations (in pts. with intractable focal epilepsy where surgery is considered): Neuropsychology, Semiinvasive or invasive EEG recordings, MR Spectroscopy, Positron emission tomography (PET) and ictal Single photon emission computed tomography (SPECT)

Classification

Current treatment

Medical treatment• Hydantoin- Phenytoin• Barbiturates- Phenobarbital, Mephobarbital, primidone• Iminostilbenes- Carbamazepine,Oxcarbazepine• Succinimides- Ethosuximide, Methsuximide• Valproic acid• Benzodiazepines- Clonazepam,Clorazepate,Midazolam,Diazepam,

Lorazepam• Other drugs-

Gabapentin,Pregabalin,Vigabatrin,Tiagiban,Levetiracetam, Topiramate,Felbamate,Zonisamide,Lacosamide,Rufinamide, Acetazolamide

Surgical treatment-• Curative (resective) procedures:

– Anteromesial temporal resection– Hemispherectomy.

• Palliative procedures(seizure-related risk decrease and improvement of the QOL): – Vagal nerve stimulation (VNS)– Adenosine releasing implants

Nonpharmacologic treatment-- Ketogenic diet- Lifestyle modifications- Deep brain stimulation- Brain cooling

Basic rules for drug treatment:

• Started in pt with recurrent seizure( and cause is not reversed)• Single seizure with epileptogenic lesion in the brain• Drug treatment should be simple, preferably using one

anticonvulsant (monotherapy). “Start low, increase slow“.• Add-on therapy is necessary in some patients (multiple drugs) • Withdrawal of drugs-If pt is seizure-free for 2 years with normal

EEG and CNS examination.• Dose is gradually reduced over 2-3 months

MECHANISM OF ACTION OF ANTI-EPILEPTICS

• Na channel inactivation- Inability of neurons to fire at high frequency eg: phenytoin, carbamazepine, lamotrigine,felbamate, topiramate, valproic acid, lacosamide

• Ca+2 channel blockers- Ethosuximide,valproic acid,lamotrigine• Enhanced GABAergic synaptic transmission – BZD, phenobarbital,

felbamate, topiramate, carbamazepine, Oxcarbazepine• GABA uptake inhibitors/GABA transaminase inhibitors e.g. Tiagabine,

Vigabatrin• Promotion of GABA release e.g. Gabapentin• NMDA receptor antagonist- Felbamate• AMPA/kianate receptor antagonist- Phenobarbital, topiramate, lamotrigine• SV2A(synaptic vesicular protein) ligands- Levetiracetam• Brain carbonic anhydrase inhibitors- acetazolamide, topiramate,

zonisamaide

Specific treatments

Newer anti-epileptic drugs

• Brivaracetam• Carisbamate • Eslicarbazepine acetate • Retigabine • Perampanel• Ganaxolone• Clobazam• Ezogabine • Stiripentol

BRIVARACETAM

• Derivative of levetiracetam• SV2A ligand-selectively bind to synaptic vesicles in

glutaminergic and GABAergic neurons, glutamate and GABA release.

• Also inhibits voltage gated Na-channels.• More potent and efficacious than levetiracetam• Trial done in Partial onset seizures,uncontrolled with one or 2

AEDs(anti epileptic drugs)• Dose 50 mg/day

Pharmacokinetics• Rapidly and almost completely absorbed after oral administration.• Elimination half life is 7 to 8 hours.• Weakly bound to plasma protein (<20%)• Metabolised by non-cytochrome P450 dependent hydrolysis and

hydroxylation.• Excretion via renal route.• No dose adjustment is needed when giving concomitantly with other AEDs.

Adverse effects-– Headache– Dizziness– Somnolence– Fatigue

• Do not change PK of OCPs when used together• No effects on fertility, pregnancy or early embryonic development in

rat or rabbits in a dose upto 600mg and 120mg/kg respectively.• Under phase III trial

CARISBAMATE• Derivative of felbamate• New derivative of this compound, carisbamate, is designed to avoid toxic

metabolites.• It is a novel neuromodulator.• Mechanism of action still unknown• Exhibits disease modifying effects as demonstrated by reduction in neuron

loss and prevention of recurrent seizures in a rodent model of status epilepticus.

• Dose- 300-1600mg/day.

Pharmacokinetics• Completely absorbed after oral administration, not affected by food.• Half life is 10.6 to 12.8 hours.• Protein binding 44%.• Extensively metabolised, metabolism pathways are O-glucuronidation and

hydrolysis followed by oxidation.• 1.7% of the dose excreted unchanged in urine.

Adverse effects-• Most common adverse events are dose dependent(>1000mg) and includes headache dizziness somnolence , and nausea• safe in elderly patients.• Under phase III trial

ESLICARBAZEPINE• Derivative of carbamazepine • Does not undergo autoinduction.• Inhibitor of voltage gated Na channels• Fewer drug interactions• Less tendency to raised blood cholesterol and lipids• Dose- 800- 1200 mg/day

Pharmacokinetics• Protein binding is 30%.• Half life is 20 -24 hours and is consistent with first order kinetics.• No relevant effect on the activity of the major cytochrome enzymes.• Can lead to activation of UGT1A1-mediated glucuronidation of

ethinylestradiol.• Primarily excreted renally.

Tolerability

• Most common adverse effects :– Headache– Dizziness– Nausea – Sleepiness – Double vision – incoordination

• Less neurotoxic than both carbamazepine and oxacarbazepine in animals studies.

• No abnormal vital signs were seen in clinical laboratory tests.

RETIGABINE• Affect a new target in the synapse,enhance the activity of KCNQ(kv7)

potassium channels.• Anticonvulsant activity in generalized seizures, partial seizures and

status epilepticus as adjunctive therapy.• Also have neuroprotective effect.• Dose- 200-400 mg t.i.d

Pharmacokinetics• Oral bioavailability : 60%• Half life : 6- 10 hours• Protein binding <80%• Metabolized via N-glucuronidation and N-acetylation/hydrolysis to

inactive metabolite.• Drug and metabolites are renally excreted.

Adverse effects-• CNS effects

– Dizziness– Cognitive impairment– Sedation– Hyperexcitability– Headache

• others– Vertigo – Diplopia– Hypothermia

• Low potential of PK drug interactions with concomitant AEDs• No Pk interaction with OCPs• Phase III study is ongoing.

STIRIPENTOL• Aromatic allylic alcohols.• Broad spectrum antiseizure activity• Cause enhancement of GABAergic neurotransmission by increasing

GABA release, inhibiting GABA reuptake and activation of GABAA receptors in a barbiturate like manner.

• Approved in 2007 for dravet syndrome in europe

Pharmacokinetics-• Rapidly absorbed orally with a Cmax 1.5 hours after oral intake.• 99% bound to plasma protein.• Clearance increases with increasing dose as it has non-linear

kinetics.• Potent inhibitor of CYP3A4, CYP1A2, CYP2C19 and thereby affects

numerous other drugs including other AEDs.

Adverse effect

• Most commonly reported adverse effect includes: Loss of appetite, Drowsiness, Cognitive impairment, Diplopia, Nause and abdominal pain.

• There is a tendency for liver hypertrophy on long term use, possibly because of its intense drug metabolizing capacity.

Ezogabine

• Approved in June 2011 as add-on therapy for the treatment of partial epilepsy in adults.

• Reduction in seizure rate of 24% to 27%• Dosage- 200mg to 400mg tds

Adverse effects-– dizziness– confusion– fatigue– somnolence

Perampanel

• Approved in October 2012 as add-on therapy for the treatment of partial epilepsy in patients 12 years old and older

• Reduction in seizure rate was 28.5%, 35.3%, and 35.0% for 4, 8, and 12 mg, respectively.

• MOA-Highly selective AMPA type glutamate receptor antagonist

Pharmacokinetics-• Rapid oral absorption• Vd-77 L• PPB-95%• T1/2 ≈ 70 hr(once daily dosing strategy)• Metabolize by CYP3A4• Excreted 70% in feces in urine and 30%

Adverse effects– Dizziness– Fatigue– Irritability– Clumsiness– Weight gain

• Does not affect the plasma concentrations of other AEDs

Ganaxolone

• Analog of neurosteroid allopregnanolone(a metabolite of progesterone)

• Significantly reduce seizure frequency in adults with POSs• Positive allosteric modulator of GABA• Useful for absence seizures, Infantile spasms and catamenial

epilepsy• Dose- 1500 mg/day as adjunctive therapy

Pharmacokinetics• Lipophilic• Absorption is higher in fed state• T1/2- 7-10 hr• Plasma level rapidly decline due to metabolism and tissue

distribution

• No significant drug interactions• CYP3A4 inhibitor(ketoconazole) blocks its metabolism.

Adverse effects– Dizziness– Fatigue– Somnolence

• Safe and well tolerated in infants at dose up to 54 mg/kg

• Drug is under phase III trial

summaryBrivaracetam

Carisbamate

Eslicarbazepine acetate

Retigabine

Stiripentol Ganaxolone

Perampanel

1.Synaptic vesicle protein 2A (SV2A) ligand2. inhibits voltage gated Na-channels.

1.neuromodulator.

2. still unknown

Inhibitor of voltage gated Na channels (Same way as of carbamazepine )

Open voltage-gated potassium channel. & Neuroprotector

Enhancement of GABAergic neurotransmission by increasing GABA release, inhibiting GABA reuptake and activation of GABAA receptors

Positive allosteric modulator of GABA

Highly selective AMPA type glutamate receptor antagonist

Phase III Phase III Phase III Under review for approval

Approved Phase III Approved

Drugs at early stage of development

• 2 Deoxy-glucose-chemical analog of sugar but can not undergo metabolism after being taken up into brain cells and finally reduce the epileptogenesis.under phase II trial

• Huperazine A-in early phase II studies,derived from a club moss,used in china to treat Alzheimers,fever,swelling, scheizophrenia

• Galanin NAX 5055- Neuropeptide found in brain,its increased activity is related with decreased brain activity

• MPP-021-congnitive enhancer• NTP-2014-phase I trial,enhances inhibition in brain by a unique

mechanism that may not produce sedation• ICA-105665-Highly selective Kv7 potassium channel opener

• Vigabatrin analog,CPP-115-increase levels of GABA without loss of vision effects.

• P529,palomid-helpful to treat epilepsy in tuberous sclerosis(it also has tumour decreasing property)

• Dynamin inhibitors- block dynamin and leads to excitation run down

• YKP-3089-possible use are epilepsy,nerve pain,anxiety and bipolar depression

Conclusion

• There is a ray of hope for refractory patients with epilepsy either as monotherapy or add on therapy

• Many of the drugs have advantage over older one of having less toxicity and lesser drug interactions with concomitant medications

• Newer drugs are more safe with liver and renal derangement pts.

• More safer drugs are coming for children,elderly and pregnant pts.

References

• Harrison’s practice 18th edition• Goodman & Gilman’s 12th edition• Seizures: Medical Causes and Management Carl J. Vaughan, MD, MRCPI and

Norman Delanty, MB, FRCPI• Perampanel: newly approved,novel antiepileptic medication for partial-

onset seizures Expert Rev. Neurother. 13(2), 131–134 (2013)• Basic Mechanisms Underlying Seizures and Epilepsy• New developments in the treatment of partial-onset

epilepsy.Neuropsychiatric Disease and treatment 2012:8 455-64.• Biolink.Dynamin inhibitors for epilepsy• Progress report on new antiepileptic drugs: A summary of the Tenth

Eilat Conference (EILAT X). M. Bialer et al.2010.Elsevier

THANK YOU

LACOSAMIDE (SPM 927)

• Formerly known as harkoseride (ADD 2304037).• Approved in June 2009 as add-on therapy for the treatment of partial

epilepsy in adults. • Selectively enhances slow inactivation of voltage-gated Na channel

without affecting the fast inactivation current.• 100mg twice daily- reduce the median seizure rate by 26%• 200mg twice daily- reduced the median seizure rate by 39%.• Synergistic anticonvulsant activity with the AEDs like topiramate,

gabapentin, lamotrigine, levetiracetam, and carbamazepine and less profound with phenytoin and valproate.

Pharmacokinetics• Rapidly and completely absorbed after oral administration.• Negligible first pass effect.• 95% of the oral dose was excreted in urine.

40% - in unchanged form

40% - converted to O-desmethyl

metabolite• Tmax reached 0.5-4 hours after oral dose.• t1/2 -13 hours

• Plasma protein binding < 15%

Adverse effects dizziness

diplopia and blurred vision

nausea and vomiting

headache

tremor

RUFINAMIDE

• Triazol derivative• Mechanisms of action are still under investigation.• Invitro studies suggest- prolongation of inactivation state of voltage-

gated Na channels like many other AEDs.

Pharmacokinetics• Oral bioavailability > 85%• Low protein binding 34%• Metabolized by enzymatic hydrolysis, independent of CYP

isoenzymes to an inactive metabolite.• Primarily excreted by renal route.• Half life : 6 – 10 hours• It may increase the serum concentration of phenytoin , no interaction

with other AEDs.

• Dose - 45mg/kg/d in children (1600mg twice daily in adults) ,resulted in a 32% reduction in median seizure rate.

• It was approved inapproved in November 2008 as add-on therapy for the treatment of Lennox-Gastaut Syndrome in patients four years of age and older

• Adverse effects-– Dizziness– Fatigue– Nausea– Diplopia– Vision blurred– Headache– Balance difficulties.

Need for further advancement

• Treatment resistant seizures remain a problem for 1/3rd of patients despite advancement

• Still requirement to Improving lives of patients with epilepsy through: – Improved seizure control– Improved side effect profiles– Safer treatment

• Requires a robust pipeline of drugs and devices in clinical development

Summary

• Brivaracetam : Phase III• Carisbamate : Phase III• Eslicarbazepine acetate : Phase III• Retigabine : Under review for FDA approval• Perampanel : Phase III• Ganaxolone : Phase III• Clobazam : Approved• Ezogabine : Approved in 2011• Stiripentol : Approved in 2007