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