Download How predictive is ocular toxicology?

How predictive is ocular toxicology?
Piotr Szczesny MD PhD
PDS LEAD F. Hoffman La Roche AG
Paris
4th February 2014
Introduction
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The FDA poster (1933) to illustrate
the need for regulations over
cosmetics
A case of a 38-year-old Ohio woman
The first photo was taken an hour
before application of eyelash dye
The second photo was taken within
the following month
The patient developed bilateral
staphylococcal corneal ulcers that
resulted in loss of useful vision (VA=
light perception)
The product contained a coal-tar
derivative, paraphenylenediamine,
which could cause allergic blepharitis,
toxic keratoconjunctivitis, and
secondary bacterial keratitis
Wilhelmus 2001
Topical application: Draize test
• Draize test is the standard eye test
conducted in animals to predict irritability
of substances in humans
– 85% → correct predic on of irritability
– 10% → overes ma on of irritability
– 5% → underes ma on of irritability
• The test is a subject to inter laboratory
variability, subjective scoring of injury
Bartlett 2013 Wilhelmus 2001
Examples of drugs withdrawn from the market
in the UK due to ocular toxicity
Drug
Adverse Reaction
Year
Clioquinol
Subacute myelo-optic neuropathy
1975
Practolol
Oculo-mucocutaneous syndrome
1977
Metipranolol
Anterior uveitis
1991
A. Breckenridge 1996
1992
There are numerous
excellent reviews dealing
with “classical” ocular
toxicity of drugs which have
been on the market for a
some time …
In majority they refer to
small molecules and
established classes of drugs
Ocular toxicities are not uncommon
• Clinical ocular toxicology lists app. 2300
drugs and app 200 ocular AE terms
• Some toxicities can lead to irreversible
ocular damage, blindness or loss of the eye
• The eyes seem to be the second most
frequent body organ to manifest drug
toxicity, after liver (Richa et al 2010)
• Drug induced ocular adverse effects are the
second most frequent reason for claims
against ophthalmologists (Santaella et al 2007)
Translational aspects
• When comparing nonclinical findings with
adverse ocular effects of drugs in humans as
described in the literature, the overall trend
demonstrates translation of nonclinical results
to humans
• Lack of correlation may be due to
– species-specific pharmacology
– effects that require chronic use over years
– low incidence of findings that may only
appear in large populations
Attar et al 2013, Chambers 2008
Ocular toxicity assessment:
Considerations in Drug Development
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The eye has unique structure which facilitates monitoring
The eye must be evaluated for toxicity to determine the
safety of drugs, industrial chemicals, and consumer
products
Changes in the ocular structures and/or function seen in
preclinical studies can delay clinical development or lead
to termination of the project
The ability to detect and characterize ocular toxicity in
preclinical models and to predict risk in patients depends
on
– The knowledge of the target/mechanism of action
– The preclinical testing strategy
– The availability of state-of-the-art ocular safety
assessment tools
– The current regulatory environment
Review by Brock et al 2013
Ocular findings: not in isolation
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Different medications can cause similar
ocular adverse reactions (e.g. uveitis
caused by systemic glucocorticoids,
sulfonamides or anti TNFs …) see review by
London et al 2013
A single medication may affect more than
one ocular structure and cause multiple
clinically ocular disorders (e.g. cataract,
glaucoma or uveitis caused by steroids)
Some medications may cause pathology of
similar nature in the eye and in other
organs (e.g. sulfonamides can cause
vascular leakage in the eye leading to
uveitis and vascular leakage in the kidney
leading to proteinuria …
Based on Greaves 2008 and Li et al 2008
Manifestations of hypersensitivity to
sulfonamides in a dog
Trepanier et al 2008
Drugs associated with uveitis (Naranjo)
Species difference: uveitis or iritis
has been reported in clinical trials
and during postmarketing. Humans
are more sensitive to cidofovir (eye
and kidney showed similar nature of
changes) Freeman et al 1998
Species difference: generally more
severe and more frequent uveitis
observed in pre-clinical and clinical
studies. Attention: Biologics
Moorthy et al 2013
Blood ocular barrier has components of blood brain and
blood CSF barrier
Inner retina like
Outer retina like
NB: CNS drugs are designed to
cross BBB → they have
potential to reach the eye!
inner
outer
Choi et al 2008
and besides there is a secret door…
• It is not uncommon to see some delayed
leakage of the ocular barrier around the optic
nerve head in apparently healthy eyes …
• Drugs and their metabolites can enter vitreous
as a result of passive diffusion, more so if they
are not bound to proteins
• Ethanol concentrations in the vitreous range
from 0.9 to 1.3 times that of blood
concentrations
• Several CNS acting drugs and substances of
abuse are detectable in vitreous samples (e.g.
SSRIs, SNRIs, benzodiazepines, acetylmorphine,
cocaine and cocaine metabolites)
Fernandez et al 2013, Pelander et al 2010, Garside et al 2006, Leikin & Watson 2003, Ziminski et al 1984; Cox et al 2007, Mackey-Bojack et al 2000
3rd eyelid
Bowman’s capsule
Schlem’s canal
Retinal vasculature
Photoreceptors
Tapetum
Optic nerve (myelin)
Visual streak
Size of the globe
Size of the lens
Blinking rate
Harderian gland
Comparative anatomy/physiology to consider
Attar et al 2013
Drug transporters and metabolizing enzymes
identified in the various ocular tissues
Attar and Shen 2008 Ch 20 Ocular Transporters in Ophthalmic Diseases and Drug Delivery
Ocular distribution of known transporter proteins
EAAC: Excitatory amino acid carrier; EAAT: Excitatory amino acid transporter; GLUT: Glucose transporter; LAT: L-type amino acid transporter; MCT: Monocarboxylate
transporter; MRP: Multidrug-resistance protein; NaDC: Na+-coupled dicarboxylate transporter; oatp: Organic anion transporting polypeptide; PepT: Dipeptide transporter.
Melanin and ocular drug toxicity
• Melanin is found widely in the eye
and products which bind to melanin
may cause ocular toxicities
• If a drug product is found to bind to
melanin, it may be important to know
whether the non-clinical studies
demonstrated abnormalities in
electroretinograms (ERGs)
• If a drug product is found to bind to
melanin and demonstrates ERG
abnormalities in animals, it would be
prudent to implement ocular
monitoring in early studies
W. Chambers 2008
Spontaneous lesions
• Spontaneous ocular lesions occur in
animals
• Spontaneous retinal degenerations in
laboratory animals may be similar to
those produced by toxicity
• It is sometimes difficult to separate
drug induced toxicity from agerelated, inherited or light-induced
retinal degenerations
• For some compounds, the only
manifestation of toxicity may be an
increase in the incidence or an earlier
age of onset of spontaneous lesions
Light induced outer retinal
degeneration in an albino rat
→ It is useful to look at the pattern (inner versus outer retinal involvement)
Recognition of the pattern of drug induced retinal
toxicity
Pattern
Compounds
Disruption of the retina
and retinal pigment
epithelium
Phenothiazines, Thioridazine, Chlorpromazine, Chloroquine
derivatives, Chloroquine, Hydroxychloroquine, Quinine sulfate,
Clofazimine, Deferoxamine, Corticosteroid preparations,
Cisplatin and BCNU (carmustine)
Vascular damage
Quinine sulfate, Cisplatin and BCN, Talc, Oral contraceptives
Aminoglycoside antibiotics, Interferon (carmustine), Ergot
alkaloids, Phenylpropanolamine
Cystoid macular edema
Latanoprost, Nicotinic acid, Paclitaxel/docetaxel , Fingolimod
Retinal folds
Acetazolamide, Chlorthalidone, Ethoxyzolamide,
Hydrochlorothiazide, Metronidazole, Sulfa antibiotics,
Triamterene
Crystalline retinopathy
Tamoxifen, Canthaxanthine, Methoxyflurane, Talc,
Nitrofurantoin
Uveitis
Rifabutin, Cidofovir, steroids, biologics
Miscellaneous
Digoxin, Methanol
Mittra & Mieler 2013
Recognition of the pattern of drug induced cataract
Pattern
Compounds
Anterior
Phenothiazines (anterior cortex),
amiodarone
Nuclear
Long acting miotics (anticholinesterases
e.g. echothiophate iodate)
Posterior
Busulfan (posterior cortex)
posterior cortical: drugs diffusing from
posterior chamber
Posterior
subcapsular
glucocorticoids
Equatorial
Systemic drugs that cross blood ocular
barrier
Anterior
central
Topical drugs
Li et al 2008, Chern 2000
Emerging horizon
• Imaging technology,
specifically Optical
Coherence Tomography
(OCT)
• New targets and
molecularly targeted
agents (MTA)
• Biologics and new
constructs
Huillard et al 2014, Agustoni et al 2014, Renouf et al 2012, Brock et al 2013, Attar et al 2013
Ocular Examination Techniques
OCT + fundus photography have big impact on translational safety in ophthalmology in
current decade
Optical Coherence Tomography (OCT) allows noninvasive
assessment of the retinal structure in humans and animals
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B
A) Histology: PR photoreceptors; ELM external limiting membrane; ONL outer nuclear layer; OPL outer plexiform layer; INL inner nuclear layer; IPL inner plexiform
layer; GCL ganglion cell layer; NFL neural (optic) fiber layer; and ILM inner limiting membrane. RPE retinal pigmented epithelium
B) Optical coherence tomography (OCT) image of the same eye. Retinal layers are visualized as alternating light and dark bands, based on differential light reflectivity
from structures with different densities. Retinal layers are labeled as in A. OS outer segments of PR; Ch choriod. In vivo image acquired using a spectral domain OCT
(SDOCT) instrument. Axial resolution is 5 mm.
Attar et al 2013
FAME example
• Fingolimod is an oral agent approved
for the treatment of multiple sclerosis
• It is a sphingosine-1-phosphate (S1P)
receptor modulator
• Reduce the recirculation of
lymphocytes that react against the
central nervous system
• The S1P receptor also plays a role
endothelial barrier integrity and
regulation of vascular permeability
• This function provides a theoretical
basis for Fingolimod Associated
Macular Edema (FAME)
• Macular edema can be monitored in a
noninvasive way (OCT) and
management guidelines are available
http://ophthalmology.stanford.edu/blog/archives/2013/04/neuro-ophthalmo-38.html
Ocular adverse events of molecularly targeted agents
• MTAs are defined as anticancer agents that selectively
target molecular pathways
• There are substantial discrepancies in the incidence
and severity of ocular adverse events reported in
clinical trials and in labels
• Post marke ng experience → 39% of severe adverse
drug reactions associated with MTAs and described in
updated drug labels were not reported in pivotal
randomized control trials
Huillard et al 2014, Seruga et al 2011
Anticancer and MTA drugs associated with ocular
disorders
ALK, anaplastic
lymphoma kinase;
EGFR, epidermal
growth factor
receptor;
mAbs,
monoclonal
antibodies;
MEK, mitogenactivated protein
kinase;
TKIs, tyrosine kinase
inhibitors
Agustoni et al. Cancer Treatment Rev 2014 40 197–203
Comparison of small molecules vs. biologics
Weir & Wilson 2013
Biologics
Small molecules
Trade Name
Macugen
Lucentis
Eylea
Jetrea
Generic
Pegaptanib sodium
Ranibizumab
Aflibercept
Ocriplasmin
MoA
anti-VEGF
anti-VEGF
Description
Aptamer, pegylated
modified
oligonucleotide
Predictive
inhibition of
neovascularization
Predictive?
Well tolerated in
animals and humans.
No induction of
Immunogenicity
antibodies was
observed, but the
accuracy of the
antibody assay is not
clear
Key ocular PD
effect
anti-VEGF
Recombinant fusion
protein portions of
Fab fragment,
human VEGF receptors
humanized
1 and 2 fused to the Fc
of human IgG1
Predictive
Predictive
inhibition of
inhibition of
neovascularization
neovascularization
Not predictive
immunogenicity
→ intra-ocular
inflammation
Key ocular
safety findings
Predictive
Not predictive
intra-ocular
inflammation in
animals > humans
Administration
related
complications
Predictive
Predictive
Predictive?
Low immunogenicity
in monkeys and
humans
Predictive
Predictive
proteolytic activity
Recombinant
truncated form of
human plasmin
Triesence
Triamcinolone
acetonide
steroid
small molecule
Ozurdex
Dexamethasone
steroid
Small molecule.
Biodegradable
implant
Predictive
Predictive
Predictive
separation of the
anti-inflammatory anti-inflammatory
vitreous
Not evaluated
NA
NA
Predictive
Predictive
Predictive
Lens subluxation (3
Cataracts,
Cataracts, increased
species: monkey,
increased IOP,
IOP, glaucoma
rabbit, minipig) glaucoma reported reported in animals
also reported in
in animals and
and humans
humans
humans
Predictive
Predictive
Predictive
Prediction of immunogenicity of biologics
• The significance of animal models for
predicting the probability (as opposed to
consequences) of immunogenicity in
humans is generally questioned
• Animal models may in some cases be of
value for the comparative immunogenicity
assessment of new product candidates
Büttel et al. Biologicals 2011 39 100-109
- The incidence of formation of anti drug antibodies in NHPs
and patients was comparable in only 59% of the cases
- The type of antidrug-antibody response was different in
NHP and humans in 59% of the cases
NHP = non human primate
ADA = anti drug antibody
CDR = complementarity determining region
Van Meer et al. mAbs 2013, 5 (5): 810-816
Ocular findings as manifestations of systemic effects
• At least 90% of the genes in the
human genome are expressed
in eye at some point during the
life (Sheffield et al 2012)
• Front of the eye has
commonalities with skin,
mucous membranes,
connective or glandular tissues
• Back of the eye has
commonalities with CNS and
vascular system
• Ocular tissues reflect the status
of several body systems
Dana Schutz, Ocular, 2010, oil on canvas
Normal gene expression profiles of the ocular tissues
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Gene expression in ten ocular
tissues from human donor eyes
using Affymetrix Human Exon 1.0
ST arrays is available
The tissues include:
retina,
optic nerve head (ONH),
optic nerve (ON),
ciliary body (CB),
trabecular meshwork (TM),
sclera, lens,
cornea,
choroid/retinal pigment epithelium
(RPE)
– Iris
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The estimated gene and exon level
abundances are available online at
the Ocular Tissue Database:
https://genome.uiowa.edu/otdb/
Wagner et al Exp Eye Res 2013 111 105-111
Take home message from Dr Chambers who is a
practicing ophthalmologist
“If there is any pharmacologic activity due to the drug product, there
is also a risk of adverse events from it due to known or unknown
pharmacologic activity”
“While the events observed in non-human studies may not be
duplicated in human studies, there is frequently some overlap. It is
therefore important to assess the potential for these events.”
“There are many potential ocular toxicity tests. Ocular toxicity tests
should be used to investigate potential adverse events that might be
either frequent or serious. There should be a justified reason for the
selection of each test, and each test should be appropriate for the
event in question.”
Wiley A. Chambers, MD, is the Deputy Director of the Division of
Transplant and Ophthalmology Products in the Center for Drug
Evaluation and Research at the Food and Drug Administration (FDA)
Thank you
Second look at old examples of drugs withdrawn from
the market in the UK due to ocular toxicity
Drug
Adverse Reaction
Year
Mechanism
Clioquinol
Subacute myelo-optic neuropathy
1975
Mitochondrial toxin
Practolol*
Oculo-mucocutaneous syndrome
1977
Immune mediated ?
Metipranolol
Anterior uveitis
1991
Unknown mechanism, but
known class effect.
Nephritis reported in rabbits
*beta-blockers have been associated with drug induced lupus erythematosus
Translational aspects
• Target expression in ocular
tissues
• Pre-clinical findings
– anatomical and physiological
considerations
• Clinical findings
• Class effects
Classes of anticancer drugs associated
with external eye toxicity
AKTi, protein kinase B inhibitor; anti–CTLA-4, anti–cytotoxic T-cell lymphocyte antigen-4; BSP, isphosphonate;
EGFR, epidermal growth factor receptor; HSP90i, heat shock protein-90 inhibitor; i, inhibitor; mAb,
monoclonal antibody; MEKi, mitogenactivated protein kinase inhibitor; SERM, selective estrogen receptor
modulator; TKI, tyrosine kinase inhibitor; VDA, vascular disrupting agent; VEGFRi, vascular endothelial growth
factor receptor inhibitor
Renouf et al. J Clin Oncol 2012; 30:3277-3286
Classes of anticancer drugs associated
with ocular toxicity
AKTi, protein kinase B
inhibitor;
anti–CTLA-4, anti–cytotoxic
T-cell lymphocyte antigen-4;
BSP, isphosphonate;
EGFR, epidermal growth
factor receptor;
HSP90i, heat shock protein90 inhibitor;
i, inhibitor;
mAb, monoclonal antibody;
MEKi, mitogenactivated
protein kinase inhibitor;
SERM, selective estrogen
receptor modulator;
TKI, tyrosine kinase inhibitor;
VDA, vascular disrupting
agent;
VEGFRi, vascular endothelial
growth factor receptor
inhibitor
Renouf et al. J Clin Oncol 2012; 30:3277-3286
The Naranjo’s criteria for establishing causation
between a medication and an adverse reaction
after Moorthy et al 2013
Management of common ocular toxicities:
discontinue and refer to ophthalmologist
ALK, anaplastic lymphoma kinase; EGFR, epidermal growth factor receptor; mAbs, monoclonal antibodies; MEK,
mitogen-activated protein kinase; TKIs, tyrosine kinase inhibitors
Agustoni et al. Cancer Treatment Rev 2014 40 197–203
Drug induced uveitis
a-Strong evidence; b-anecdotal evidence; c-uveitis also associated with skin placement of purified protein derivative
London et al 2013
Examples of non-clinical programs from recently
approved ocular drugs
Small molecules
Generally predictive
Attar et al 2013
Biologics
Immunogenicity
is a challenge
Comparison of nonclinical studies designed to support
an ophthalmic vs. systemic drug
Weir & Wilson 2013
ERG
• Electroretinography (ERG) is the
measurement of electrical
potentials generated by the
retina in response to light
• Target organs may include the
eye and any compound that
binds melanin in the retinal
pigment epithelium, including
psychotropic compounds and
antimetabolics for neoplastic
targets
Chloroquine
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Chloroquine is an anti-malarial that is known to cause retinopathy
The analog, hydroxychloroquine, is less toxic and more widely
used
Chloroquine is a cationic amphiphilic drug which may accumulate
in association with increased phospholipids within lysosomes
Patients who had taken oral chloroquine or hydroxychloroquine
for at least 5 years had a pigmentary change of the macula with
sparing of the foveal center (bull’s eye maculopathy) that may be
accompanied by central visual loss, visual field defects, color
vision deficiency, and other symptoms
In later stages of the disease, there is atrophy of the RPE and
neurosensory retina
OCT, fundus photography, and fluorescein angiography
collectively show outer retina disruption in macula and perifoveal
area
monkeys given intramuscular chloroquine for 4 years showed no
ophthalmologic change and no retinal function change by ERG,
but drug was bound to pigmented tissues (choroid/RPE, ciliary
body/iris) and there was long-term degeneration of RGC, PR and
later RPE and choroid
pigmented rats given IP chloroquine for 7 days and pigmented
mice given IP chloroquine , cytoplasmic bodies were reported in
several cell types, including RGC, PR, and RPE. The mechanism of
retinal toxicity is hypothesized to be drug accumulation in
lysosomes causing lysosomal acidification which leads to
cytotoxicity
Amiodarone
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Amiodarone is an anti-arrhythmic for recurrent
ventricular tachycardia or fibrillation
Ocular side effects reported in up to 40% of patients
is the appearance of colored rings around lights with
daily dosing for 1 - 2 years
Amiodarone is also a cationic amphiphilic drug
which can induce phospholipidosis
Corneal epithelial opacities occur in 70 - 100% of
patients and lens opacities in 50 - 60% of patients
One out of 11 Beagle dogs treated daily with oral
amiodarone for 11 weeks develop bilateral corneal
deposits in both eyes, confirmed by histopathology
Possible reasons for the low incidence in dogs were
insufficient duration of dosing and lack of sunlight
exposure which is believed to exacerbate corneal
deposits of amiodarone in humans
Sildenafil
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Sildenafil is an inhibitor of phosphodiesterase5 (PDE-5) that is used to treat erectile
dysfunction
A less common side effect is change in color
perception towards a blue tint along with
increased perception of brightness
In dogs given IV sildenafil, there was a doserelated reduction in the a-wave amplitude and
increases in a- and b-wave implicit times,
though the effects were transient and
reversible
The cause of the changes in retinal function
may be that sildenafil not only inhibits PDE-5,
but also is a weak inhibitor of PDE-6 which is
involved in cGMP mediated
phototransduction in rod and cone PR
Ethambutol
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Ethambutol is a bacteriostatic agent that is used to treat
tuberculosis and has been associated with optic neuropathy
in 2 - 6% of patients
Patients treated with ethambutol may have ERG
abnormalities: double a-wave, indistinct oscillatory
potentials, abnormal flicker and multi-focal responses
Decreased retinal nerve fiber layer thickness can be detected
by OCT after clinical treatment with oral ethambutol
Rats given subcutaneous ethambutol had normal ERG, but
abnormal VEP
When rats were given oral ethambutol there was selective
loss of RGC
The mechanism of ethambutol retinotoxicity is not
completely understood, but may involve chelation and
depletion of zinc and/or copper in RGC mitochondria which
exacerbates RGC death in patients with a pathogenic
mitochondrial mutation
Tamoxifen
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Tamoxifen is a nonsteroidal estrogen
antagonist that is used in the
treatment of breast cancer
Retinopathy was first described among
women treated with more than 180
mg/day for longer than a year
These patients usually had a
symptomatic decrease in vision and
characteristic fundus findings were
small, white, refractile deposits in the
inner retina, particularly in the
perimacular area.
Associated pigmentary irregularity
occurred
Fluorescein angiography demonstrated
macular edema in most cases.
Tamoxifen retinopathy
Thioridazine
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Thioridazine is a phenothiazine antipsychotic drug
that has been used in high doses in the past
At these doses, a subacute, dramatic form of
retinopathy could appear with extensive
geographic areas of depigmentation, loss of
choriocapillaris and optic atrophy
At the lower doses (< 800 mg/d) used today, this
dramatic type of retinopathy is less common
Fluorescein angiography demonstrates loss of
pigment epithelium and choriocapillaris within the
areas of depigmentation
Visual field changes are nonspecific, but most
characteristically show paracentral scotomas or
ring scotomas
The manufacturers’ current recommendation is
that the dose be titrated to a minimal effective
dose of 300 mg/day or less, with an absolute
maximum of 800 mg/day for limited periods of
time
Thioridazine retinopathy associated with chronic
use (nummular retinopathy)
Deferoxamine
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Deferoxamine is a chelating agent used
to reduce iron in transfusion-dependent
anemia and to treat aluminum toxicity
during chronic renal dialysis
The onset of visual symptoms may be
relatively acute or occur after long
exposure
Patients may complain of blurred vision,
nyctalopia, color vision abnormalities, or
visual field restriction
The spectrum of changes varies widely
and may include RPE window defects,
bull’s eye lesions, vitelliform
maculopathy, and late
hyperfluorescence of the macula
Electroretinography may show
decreased amplitude and prolonged
implicit times
Deferoxamine retinopathy