Transcript Title of Presentation Date - American Society for Experimental

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 Toxicology
University of Utah
Salt Lake City, UT
American Society for Experimental NeuroTherapeutics | 15th Annual Meeting
Disclosure
Upsher-Smith Laboratories
Insero Health
Janssen Pharmaceuticals
NeuroAdjuvants, Inc.
UCB Pharma
Citizen’s United for Research in Epilepsy
Scientific Advisory Board
Consultant
Sponsored research & consultant
Scientific co-founder
Vimpat Speakers Bureau
Senior Research Advisor
American Society for Experimental NeuroTherapeutics | 15th Annual Meeting
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
IND Objectives: Pharmacology
• 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
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
Tonicextension
seizure
Generalized tonicclonic 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
Maximal
electroshock
Existing Rodent Seizure and Epilepsy
Models Find Drugs
Felbamate
Fosphenytoin
Gabapentin
Importantly, many new drugs
Lamotrigine
have been introduced for the
Lacosamide
treatment of epilepsy that have
Levetiracetam
Oxcarbazepine
benefited adult and pediatric
Perampanel
patients!
Pregabalin
Rufinamide (Lennox-Gastaut Syndrome)
Stiripentol (Dravet Syndrome)
Tiagabine
Topiramate
Vigabatrin (Infantile Spasms)
Zonisamide
Further,
More AEDs in the Pipeline*
• Brivaracetam (binds SV2A & blocks voltagegated 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)
http://boston.com/travel/getaways/us/
hawaii/articles/ 2007/12/02/shooting_the_tube/
• Also:
http://www.epilepsy.com/etp/pipeline_new_therapies
Image kindly provided by Professor Harold Wolf
*Presented at Eleventh Eilat Conference (April 6-10, 2012)
Perceived Efficacy of AEDs
Drug
Phenytoin
Carbamazepine
Valproic Acid
Ethosuximide
Phenobarbital
Zonisamide
Gabapentin
Lamotrigine
Topiramate
Tiagabine
Oxcarbazepine
Levetiracetam
Felbamate
Pregabalin
partial
seizures
Absence
seizures
tonic/ atonic
seizures
Myoclonus
GTCC
2.5
-0.2
0.8
-0.2
2.0
2.9
-0.8
0.6
-0.8
1.5
2.0
2.9
1.9
2.6
2.8
0.1
2.9
0.1
0.5
0.4
2.4
0.1
1.0
0.8
2.4
2.3
1.0
0.9
1.4
1.6
1.1
-0.6
-0.1
-0.8
0.8
2.4
2.0
1.6
1.1
2.1
2.4
1.3
1.8
1.3
2.1
1.3
-0.9
-0.1
-0.4
0.5
2.8
-0.9
0.4
-0.8
1.6
2.6
1.1
1.0
1.8
2.1
2.1
0.8
1.8
0.9
1.5
1.8
-0.7
-0.1
-0.8
0.8
Slide courtesy of Jacqueline French, MD
Pharmacology of Valproic Acid (VPA)
Animal Model
Maximal
electroshock
Pharmacology
Tonic-extension
seizure
Generalized tonicclonic seizures
Effective
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
generalized
Limbic seizures
Effective
sc Metrazol
;
Seizure phenotype Human correlate
Relationship between human AED plasma
(Css) and rat MES ED50 values
Bialer et al., Epilepsy & Behavior, 5: 866-872, 2004.
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
Drug
Ataxia/
Incoordination Dizziness
Irritability Cognitive Depression/
Mood
Cognitive
Sedation / Agitation Disturbance mood issues stabilizing activation
Phenytoin
1.8
1.4
1.1
0.5
1.1
1.0
0.3
0.0
Carbamazepine
Valproic Acid
Ethosuximide
Phenobarbital
Zonisamide
Gabapentin
Lamotrigine
Topiramate
Tiagabine
Oxcarbazepine
Levetiracetam
Felbamate
Pregabalin
1.6
1.8
1.1
0.5
1.4
0.4
1.5
0.0
0.8
0.9
1.0
0.1
1.0
0.1
1.9
0.1
0.8
0.9
1.0
0.8
0.6
0.6
0.0
0.0
1.4
1.1
2.6
1.3
2.0
1.6
0.0
0.3
0.6
1.0
1.3
1.5
1.4
0.6
0.0
0.0
0.5
0.8
1.1
0.1
0.8
0.3
0.5
0.1
0.9
1.3
0.4
0.6
0.3
0.0
1.9
0.6
0.9
0.9
1.0
1.0
2.5
1.3
0.5
0.0
0.6
1.5
1.5
0.8
1.3
1.4
0.0
0.0
1.5
1.6
1.1
0.5
0.8
0.3
1.0
0.1
0.3
0.6
1.1
1.9
0.3
1.4
0.1
0.1
1.0
0.8
0.8
1.0
0.6
0.6
0.1
0.4
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
Activity
Monitor
Stance
Gait
Ataxia
Placing
response
Muscle tone
Rotarod
Food intake
Ataxia/
Activation/ Weight Weight
Dizziness Sedation
Incoordination
agitation loss
Gain
x
X
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Animal Models of Hyperlocomotion:
AccuScan SuperFlex (IITC, Inc.)
(Smith et al., unpublished)
Predicting human AEs using rodent
testing: anxiety, depression, mood
Human/Animals
Activation/
agitation
x
x
x
x
x
x
x
x
x
x
x
Forced Swim Test
Light/Dark Box
Dominant-submissive
behavior
Tail Suspension
Chlordiazepoxide/
amphetamine
Mood
Mood
destabilizing stabilizing
x
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)
AccuScan SuperFlex (IITC, Inc.)
Elevated plus maze
(rats)
Novelty Induced
Hypophagia
(rats or mice)
(Dulawa & Hen, 2005)
Predicting human AEs using
rodent testing: Cognition
Human/ Animals
Activation/ Cognitive
agitation disturbance
x
Morris Water Maze
Novel Object
Recognition
Long Term
Potentiation
x
Passive Avoidance
Elevated Plus Maze
Radial and T-maze
Mood
destabilizing
x
x
x
x
x
x
x
x
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.
• 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.
Jensen. Epilepsy as a spectrum disorder: Implications from novel clinical and basic neuroscience. Epilepsia (2011) vol. 52 Suppl 1 pp. 1-6
Neuropsychiatric Comorbidities of
Epilepsy:
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%).
How comparable are the drug evaluation
studies: human vs. rodent?
Adult Patient with Epilepsy
Mice and Rats
 Long-term epilepsy (altered
 Neurologically intact
neuronal substrate)
 Often taking multiple AEDs
 Treatment is chronic
 Hepatically induced
 Often displays co-morbidities
 Pharmacologically naïve
 Treatment is acute
 Non-induced
 No 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.
Funding
NINDS, NIH Contract HHSN271201100029C
Animal Model
Maximal electroshock
Pharmacology
Na+ channel blockers
K + channel activators
NMDA and AMPA receptor antagonists
a2d ligands
sc Metrazol
T-type Ca2+ channel blockers
Benzodiazepines
Barbiturates
GABA transport blockers
GABA transaminase inhibitors
a2d ligands
6 Hz (44 mA)
Benzodiazepines
K+ channel activators
SV2A ligands
VPA analogs
Galanin agonists
GAERS, Lethargic mouse, and
Wistar rat
T-type Ca2+ channel blockers
GABAB receptor antagonists
SV2A ligands
Kindled rat
Na+ channel blockers
K + channel activators
AMPA receptor antagonists
GABA receptor modulators
SV2A ligands
a2d ligands
Animal Model
Maximal
electroshock
Seizure phenotype Human correlate
Pharmacology
Tonic-extension
seizure
Generalized tonicclonic seizures
PHT, CBZ, OxCBZ, VPA,
PB, FBM, GBP, LTG,
LCM, TPM, ZNS, EZG
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
generalized
Limbic seizures
CBZ, OxCBZ, PHT, VPA,
PB, BZD, FBM, GBP,
PGB, LTG, TPM, TGB,
ZNS, LVT, VGB, EZG
sc Metrazol
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