Using Toxicology and Toxicokinetics to Better Predict Therapeutic Index (of Anti-seizure Drugs)

March 1, 2013

H. Steve White, Ph.D., D. Sci.Anticonvulsant Drug Development Program

Dept. Pharmacology and ToxicologyUniversity of UtahSalt Lake City, UT

American Society for Experimental NeuroTherapeutics | 15th Annual Meeting

Disclosure

Upsher-Smith Laboratories Insero HealthJanssen PharmaceuticalsNeuroAdjuvants, Inc.UCB PharmaCitizen’s United for Research in Epilepsy

American Society for Experimental NeuroTherapeutics | 15th Annual Meeting

Scientific Advisory Board

Consultant

Sponsored research & consultant

Scientific co-founder

Vimpat Speakers Bureau

Senior Research Advisor

Disclosure

I’m NOT a Toxicologist!

American Society for Experimental NeuroTherapeutics | 15th Annual Meeting

Learning Objectives• Discuss the approach used in the early

identification of anti-seizure drug activity and toxicity.

• Gain a greater understanding of the tolerability issues associated with chronic use of anti-seizure drugs

• Discuss the utility and limitations of standard rodent behavioral tests in predicting human tolerability to anti-seizure drugs

American Society for Experimental NeuroTherapeutics | 15th Annual Meeting

• Provide rationale for human benefit• Employ animal data to extrapolate projected

doses or blood concentrations that will be efficacious in humans

• Identification of unintended actions that may impact safety

• Estimate THERAPEUTIC INDEX from Pharmacology/Toxicology data

IND Objectives: Pharmacology

Therapeutic Index

• The ratio of the dose that produces the desired therapeutic effect (ED50) to the dose that produces a toxic effect (TD50).

Current Era of AED Discovery

• Ushered in by Merritt and Putnam in 1938 with the discovery of phenytoin

• Employs well-characterized animal seizure models

• Goal is to provide sufficient Proof-of-Concept efficacy data to support an Investigational New Drug Application

Animal Model

Seizure phenotype

Human correlate

Predictive validity

Maximal electroshock

Tonic-extension

seizure

Generalized tonic-clonic seizures

Yes

sc Metrazol Minimal clonic seizure

Generalized myoclonic seizure

Yes (for the most part;

e.g. Keppra)

6 Hz (44 mA) Limbic seizures 2o generalized

Pharmacoresistant partial seizures

Unknown

GAERS, Lethargic mouse, and Wistar rat

Spike-wave discharges

Generalized absence

Yes

Kindled rat Limbic seizures 2o

generalized

Partial seizures Yes

Existing Rodent Seizure and Epilepsy Models Find Drugs

FelbamateFosphenytoinGabapentinLamotrigineLacosamide

LevetiracetamOxcarbazepine

PerampanelPregabalin

Rufinamide (Lennox-Gastaut Syndrome)Stiripentol (Dravet Syndrome)

TiagabineTopiramate

Vigabatrin (Infantile Spasms)Zonisamide

Further,

Importantly, many new drugs have been introduced for the treatment of epilepsy that have benefited adult and pediatric patients!

More AEDs in the Pipeline*

• Brivaracetam (binds SV2A & blocks voltage-gated Na+ channels)

• 2-deoxy-glucose (inhibits glycolysis)• Ganaxolone (neurosteroid)• Huperzine A (NMDA antagonist)

• ICA-105665 (Kv7.2/7.3 activator)• NAX 810-2 (galanin-based neuropeptide)• Propylisopropylacetamide (VPA analog)• Tonabersat (presumed gap junction inhibitor)• YKP-3089 (broad-spectrum AED)

• Also: http://www.epilepsy.com/etp/pipeline_new_therapies

Image kindly provided by Professor Harold Wolf

http://boston.com/travel/getaways/us/ hawaii/articles/ 2007/12/02/shooting_the_tube/

*Presented at Eleventh Eilat Conference (April 6-10, 2012)

Perceived Efficacy of AEDs

Drug partial seizures

Absence seizures

tonic/ atonic seizures Myoclonus GTCC

Phenytoin 2.5 -0.2 0.8 -0.2 2.0

Carbamazepine 2.9 -0.8 0.6 -0.8 1.5Valproic Acid 2.0 2.9 1.9 2.6 2.8Ethosuximide 0.1 2.9 0.1 0.5 0.4Phenobarbital 2.4 0.1 1.0 0.8 2.4

Zonisamide 2.3 1.0 0.9 1.4 1.6Gabapentin 1.1 -0.6 -0.1 -0.8 0.8Lamotrigine 2.4 2.0 1.6 1.1 2.1Topiramate 2.4 1.3 1.8 1.3 2.1Tiagabine 1.3 -0.9 -0.1 -0.4 0.5

Oxcarbazepine 2.8 -0.9 0.4 -0.8 1.6Levetiracetam 2.6 1.1 1.0 1.8 2.1

Felbamate 2.1 0.8 1.8 0.9 1.5Pregabalin 1.8 -0.7 -0.1 -0.8 0.8

Slide courtesy of Jacqueline French, MD

Animal Model Seizure phenotype Human correlate Pharmacology

Maximal electroshock

Tonic-extension seizure

Generalized tonic-clonic seizures

Effective

sc Metrazol Minimal clonic seizure

Generalized myoclonic seizure

Effective

6 Hz (32/44 mA) Limbic seizures 2o generalized

Pharmacoresistant limbic seizures

Effective

GAERS, Lethargic mouse, and Wistar rat

Spike-wave discharges (SWD)a

Primary Generalized

Epilepsy

Effective

Kindled rodent Limbic seizures 2o

generalizedLimbic seizures Effective

;

Pharmacology of Valproic Acid (VPA)

Bialer et al., Epilepsy & Behavior, 5: 866-872, 2004.

Relationship between human AED plasma (Css) and rat MES ED50 values

So what’s the PROBLEM??

• There are still many patients with uncontrolled epilepsy!!

Mohanraj & Brodie, 2005

• Many patients can only achieve seizure control at a substantial cost to their quality of life!

Perceived Adverse Events of AEDs

DrugAtaxia/

Incoordination Dizziness SedationIrritability/ Agitation

Cognitive Disturbance

Depression/ mood issues

Mood stabilizing

Cognitive activation

Phenytoin 1.8 1.4 1.1 0.5 1.1 1.0 0.3 0.0

Carbamazepine 1.6 1.8 1.1 0.5 1.4 0.4 1.5 0.0

Valproic Acid 0.8 0.9 1.0 0.1 1.0 0.1 1.9 0.1

Ethosuximide 0.8 0.9 1.0 0.8 0.6 0.6 0.0 0.0

Phenobarbital 1.4 1.1 2.6 1.3 2.0 1.6 0.0 0.3

Zonisamide 0.6 1.0 1.3 1.5 1.4 0.6 0.0 0.0

Gabapentin 0.5 0.8 1.1 0.1 0.8 0.3 0.5 0.1

Lamotrigine 0.9 1.3 0.4 0.6 0.3 0.0 1.9 0.6

Topiramate 0.9 0.9 1.0 1.0 2.5 1.3 0.5 0.0

Tiagabine 0.6 1.5 1.5 0.8 1.3 1.4 0.0 0.0

Oxcarbazepine 1.5 1.6 1.1 0.5 0.8 0.3 1.0 0.1

Levetiracetam 0.3 0.6 1.1 1.9 0.3 1.4 0.1 0.1

Felbamate 1.0 0.8 0.8 1.0 0.6 0.6 0.1 0.4

Pregabalin 1.0 1.5 1.5 0.4 1.1 0.6 0.3 0.1

Slide courtesy of Jacqueline French, MD

Could these adverse events be predicted from animal studies ??

Predicting human AEs using rodent testing: General behavior

Human/ Animals

Ataxia/ Incoordination Dizziness Sedation Activation/

agitationWeight

lossWeight

GainActivity Monitor x x xStance X x xGait x x xAtaxia x x xPlacing response xMuscle tone xRotarod xFood intake x x

Animal Models of Hyperlocomotion:

(Smith et al., unpublished)

AccuScan SuperFlex (IITC, Inc.)

Human/Animals

Activation/ agitation

Mood destabilizing

Mood stabilizing

Forced Swim Test x xLight/Dark Box x xDominant-submissive behavior x x x

Tail Suspension x xChlordiazepoxide/ amphetamine x x x

Predicting human AEs using rodent testing: anxiety, depression, mood

Animal Models of Depression

Porsolt Forced Swim Test(rats or mice)

Tail Suspension Test(mice)

Animal Models of Anxiety Disorders

Light-Dark Box(mice or rats)

Elevated plus maze(rats)

Novelty Induced Hypophagia

(rats or mice)

(Dulawa & Hen, 2005)

AccuScan SuperFlex (IITC, Inc.)

Human/ Animals Activation/ agitation

Cognitive disturbance

Mood destabilizing

Morris Water Maze xNovel Object Recognition xLong Term Potentiation xPassive Avoidance x xElevated Plus Maze x x xRadial and T-maze x x

Predicting human AEs using rodent testing: Cognition

Assessing Cognitive Decline

In-vitro: Long-Term Potentiation In-vivo: Morris Water Maze

Phenytoin and Carbamazepine, but not Valproate, attenuate TBS-induced LTP in area CA1

Valproic Acid Displays Cognitive Impairment in Morris Water Maze

Single Dose Phenytoin and Valproic Acid Produce Impairment in Morris Water Maze

* p<0.05

Given all of the available behavioral and cognitive tests why are we not better at

predicting CNS tolerability issues?

Issues associated with rodent behavior and cognitive testing

• Extensive behavioral and cognitive testing not routinely conducted.

• The degree to which results from rodent testing translates to humans is not known.

• Behavioral and cognitive testing is often done after acute dosing in neurologically intact animals.

• Rodent testing is conducted following mono-therapy; patients with refractory epilepsy are often taking multiple anti-seizure drugs.

• Naïve, neurologically intact rodents don’t display comorbidities.

Epilepsy as a spectrum disorder• Up to half of all epilepsy patients have some form of cognitive or

psychiatric condition. • The cognitive symptoms often include impairments in attention,

executive function, and memory.

Jensen. Epilepsy as a spectrum disorder: Implications from novel clinical and basic neuroscience. Epilepsia (2011) vol. 52 Suppl 1 pp. 1-6

• Cognitive symptoms do not universally disappear once seizures are well controlled.

• Pharmacology: the double-edged sword:

• Anticonvulsants may exacerbate cognitive dysfunction.

• Nootropics may lower seizure thresholds.

Major Depressive Disorder: Most frequent psychiatric comorbidity (35-55%) in people with epilepsy (PWE).

Anxiety Disorder: Second most frequent (10-35%) psychiatric comorbidity in PWE.

Bipolar Disorder: Intermittant episodes of mania and depression (12%).

Neuropsychiatric Comorbidities of Epilepsy:

How comparable are the drug evaluation studies: human vs. rodent?

Adult Patient with Epilepsy Long-term epilepsy (altered

neuronal substrate)Often taking multiple AEDsTreatment is chronicHepatically inducedOften displays co-morbidities

Mice and RatsNeurologically intact

Pharmacologically naïveTreatment is acuteNon-inducedNo known co-morbidities

Summary

• There are animal models that could aid in the assessment of drug-induced ataxia, incoordination, sedation and cognitive impairment.

• Perceived adverse events may be the result of the therapy and/or the attendant comorbidity.

• Modification of current approach may yield more informative data for predicting chronic adverse events in the person with epilepsy.

Acknowledgements

University of Utah

• Karen Wilcox, Ph.D.• Peter West, Ph.D.• Gerald Saunders• Anitha Alex, Ph.D.• Misty Smith, Ph.D.

Anticonvulsant Screening Project, NINDS, NIH

• John Kehne, Ph.D.• Jeff Jiang, Ph.D.• Tracy Chen, Ph.D.• Taek Oh, Ph.D.

FundingNINDS, NIH Contract HHSN271201100029C

Animal Model Pharmacology

Maximal electroshock Na+ channel blockersK + channel activators

NMDA and AMPA receptor antagonistsa2d ligands

sc Metrazol T-type Ca2+ channel blockersBenzodiazepines

BarbituratesGABA transport blockers

GABA transaminase inhibitorsa2d ligands

6 Hz (44 mA) BenzodiazepinesK+ channel activators

SV2A ligandsVPA analogs

Galanin agonists

GAERS, Lethargic mouse, and Wistar rat

T-type Ca2+ channel blockers

GABAB receptor antagonists

SV2A ligands

Kindled rat Na+ channel blockersK + channel activators

AMPA receptor antagonistsGABA receptor modulators

SV2A ligandsa2d ligands

Animal Model Seizure phenotype Human correlate Pharmacology

Maximal electroshock

Tonic-extension seizure

Generalized tonic-clonic seizures

PHT, CBZ, OxCBZ, VPA, PB, FBM, GBP, LTG,

LCM, TPM, ZNS, EZG

sc Metrazol Minimal clonic seizure

Generalized myoclonic seizure

ESM, VPA, BZD, EZG, FBM, GBP, PB*, TGB,*,

VGB*

6 Hz (32/44 mA) Limbic seizures 2o generalized

Pharmacoresistant limbic seizures

CLZ, FBM, LCM, LEV, EZG, VPA

GAERS, Lethargic mouse, and Wistar rat

Spike-wave discharges (SWD)a

Primary Generalized

Epilepsy

 ESM, VPA, BZD, LTG, TPM, LVT [SWD

worsened by PHT, CBZ, OxCBZ, and

GABAmimetics]

Kindled rodent Limbic seizures 2o

generalizedLimbic seizures CBZ, OxCBZ, PHT, VPA,

PB, BZD, FBM, GBP, PGB, LTG, TPM, TGB, ZNS, LVT, VGB, EZG

;

BDZ, benzodiazepines; CBZ, carbamazepine; ESM, ethosuximide; EZG, ezogabine; FBM, felbamate; GBP, gabapentin; LCM, lacosamide; LTG, lamotrigine; LVT, levetiracetam; OxCBZ, oxcarbazepine; PB, phenobarbital; PGB, pregabalin; TGB, tiagabine; TPM, topiramate; VPA, valproic acid; VGB, vigabatrin; ZNS, zonisamide

*PB, TGB, and VGB block clonic seizures induced by sc PTZ but are inactive against generalized absence seizures and may exacerbate spike wave seizures.amodels of spike-wave seizures not routinely employed in initial evaluation of investigational drugs