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Preclinical safety assessment of topical drugs and associated pathologyFlandre TIATP and STP-I WebinarJanuary 2020
TM – PCS
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Agenda
Topical/wound healing drug safety assessment Formulation Pathology associated with topical drug Pathology associated with wound healing drug
IATP and STP-I Webinar – preclinical safety of topical drugs2
Important Reminder: Please send any questions you may have to Satish Panchal: [email protected]
Questions will be addressed at the end of the presentation
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Why safety assessment of topical/wound healing drug ? Hazard identification: Characterize hazard Risk assessment Fulfilling regulatory expectations
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Hazard identification
Characterize hazard/safety findings– Qualitative and quantitative assessment effects (latency; reversibility)– Species specificity – translatability to humans?– Clinical monitorability (at EARLY stage)– Threshold value– Molecular mechanism – target-related?
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Hazards
Genetic toxicity– Proliferative changes are expected, but is it uncontrolled or mutagenic?
Local toxicity– Is it tolerated by skin and exposed tissue?– Is the vehicle tolerated?
Is the toxicity identified relevant for humans?– Is it species-specific?– Related to mechanism of action?– Monitorable? Reversible?
Phototoxicity is a special consideration given skin is the target organ
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Risk assessment
Risk assessment– Determine and describe exposure– Quantify possible exposure in man and estimate likelihood for hazard to occur
Assess risk – Human relevance of hazard Translatability to human– Safety factors (consider populations particularly sensitive to the toxicity)– Differs depending on the indication, dose, treatment route and duration
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Risk management
Is there a therapeutic window?– What should the therapeutic index (TI) be? 10, 30, or some other number?– What is being used to estimate the TI?– The longer you treat, the more toxicity you expect to see which reduces the TI
Is the hazard species-specific or translatable to humans? Is there extensive systemic exposure?
– Evaluate absorption from skin (intact or wounded), compare this to a systemically available dose (iv or po administration)
– If topical delivery yields high systemic exposure, your risk is much greater for target organ toxicity and DDIs
Is there phototoxicity?– Phototoxicity guidances give special consideration for dermal treatments; both UVA and UVB must
be considered in the safety testing– Threshold will be different (lower) with topical drug as skin is the target organ
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Regulatory requirements/expectations
No dedicated guidance for preclinical safety assessment for topical/wound healing products– Principles and procedures for evaluating toxicity of household substances, NAS, 1977
(acute dermal toxicity)– OECD 410, Repeat dose dermal toxicity study, 1981 (21 or 28-day repeat dose dermal
toxicity)– EPA health effects test guidelines OPPTS 870.3200, 1998, (21 or 28-day repeat dose
dermal toxicity)– Guidance for Industry Chronic Cutaneous Ulcer and Burn Wounds — Developing
Products for Treatment, 2006
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Regulatory requirements/expectations
General guidelines for small molecules/biologics apply – ICH M3R2: guidance on non-clinical safety studies for FIH and marketing– ICH S2: Genotoxocity testing– ICH S3: Toxicokinetic– ICH S4: Chronic toxicity testing – ICH S6: Biotechnology derived pharmaceuticals– ICH S5: Reprotox testing– ICH S7: Safety pharmacology– ICH S10: Phototoxicity testing
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Regulatory expectations – general considerations Route of administration
– Intended clinical route needs to be used– Topical application yields low systemic exposure, limiting systemic tox assessment – Systemic dosing will provide target organ toxicity
Species selection– Small molecules are evaluated in two (or more) species: rodent + non-rodent– If for oral programs, rat and dog are default species unless scientific reason for an alternative,
for topical programs, minipig is well accepted as pig and human skin are similar– For biologics, nonhuman primate is typically the appropriate species if antibody specificity is limited
Duration and frequency of treatment in general toxicology studies– Day-for-day coverage up to chronic (>6 months) treatment – Treatment frequency also needs to cover or exceed clinical plan (qod would be covered with qod,
but given the high chance for misdose, qd would be added)
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Regulatory expectations – considerations for topical drugs In general, the preclinical safety program is targeted for the type of compound, application route, and
duration of treatment FDA and ICH Guidances for preclinical studies supporting human pharmaceutical development
(general guidances)– Content and Format of INDs (11/95)– Exploratory INDs (1/06)– M3-Nonclinical safety studies to perform clinical trials (7/97, updated 1/10)– S6-Preclinical testing of biologics (7/97)
Topical administration (cutaneous ulcers and burn applications, FDA June 2006)– Guidance includes toxicology guidance proposing vehicle and sham control groups, treatment multiples over
intended clinical dose, and administration to reflect the clinical route– Immunogenicity evaluation to be included for biologic agents– Carcinogenicity studies for “chronic wound” indication for small molecules. For others, tumor promotion models and
scientific assessment of tumor risk (including scar carcinomas) given the compounds are typically growth factors
Aerosol products require pulmonary toxicity testing
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Preclinical safety program – Key considerations for topical drugs Preclinical assessment to be performed in two species: a rodent and a non-
rodent Topical as well as systemic exposure and toxicity are measured Studies typically run in minipig (topical and systemic) and rat (systemic) Systemic rat studies in support of wound healing projects are accepted by the
regulatory agencies Testing the clinical concentrations in the topical arm (intact skin) will be
sufficient
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Preclinical safety program – Key consideration for wound healing drugs Study designs can be inspired from topical programs, and modified as
appropriate for wound healing, as there is no dedicated guidance for preclinical safety assessment for wound healing products
Lack of translatable chronic animal model Preclinical assessment to be performed in two species:
– Rodent for systemic exposure and toxicity– Non-rodent (minipig) for:
– Systemic exposure and toxicity– Topical exposure and toxicity (Intact + wounded skin) at same concentration as
clinic
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Pig as preferred non-rodent species for topical/wound healing drug – why ?
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Human NHP Pig Dog Rodent
Epidermal pattern Epidermal Epidermal Epidermal Infundibular Infundibular
Epidermal thickness (µm)
86.2 ± 6.8 26.9 ± 3.1 51.9 ± 1.5 21.2 ± 2.5 Rat 13.3 ± 2.2Mouse 21.7 ± 1.2
Sweat gland Eccrine glandsover entire body; apocrine in genitals, underarms
Eccrine glands over entire body; apocrine in genitals, underarms
Eccrine glands in carpal glands;apocrine glandsassociated with allfollicles
Eccrine glands in footpad, nose; apocrine glands associated with all follicles (andperianal region
Eccrine glands in footpads; no apocrine glands
Sebaceousglands
Associated withall follicles
Associated withall follicles
Associated withall follicles
Associated withall follicles
Associated withall follicles
Superficial vascular plexus
Yes Yes Yes Yes Yes (no in mouse)
Also metabolism and physiology (i.e. skin permeability) of the skin minipig is closer to human compared to dog or NHP
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Pig as preferred non-rodent species for topical/wound healing drug – why ?
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Mouse Cyno Minipig Human
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Minipig wound healing toxicity study
Wound
Topical
Wound from punch biopsy in rat
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Typical preclinical toxicity package for IND/CTA (GLP studies) 2- (or 4-)week rodent and nonrodent studies with 4-week recovery by the intended clinical
route of administration Safety pharmacology studies (rat CNS/respiratory, in vitro hERG, and non-rodent telemetry) for
small molecules (LMW) Genotoxicity (Ames and in vitro chromosome aberration) (for LMW) Photosafety (in vitro 3T3 NRU or in vivo study, based on UV/VIS spectra) (for LMW) Tissue cross-reactivity for biologicsNotes: Additional studies could be needed (eg to identify target organ toxicity in the absence of
significant exposure by the intended route). Shorter duration general tox studies may be employed under special circumstances.
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Preclinical safety program
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4/13-wk topical minipig
4/13-wk oral/iv minipig
4/13-wk oral/iv rat
topi
cal
syst
emic
geno
tox
othe
rs
topical UV-LLNA
Ames Test
Chromosomal Aberr.Micronucleus in vivo
hERG in vitro ECG telem. minipig
CNS + Resp in rat
39-wk topical minipig
26-wk oral/iv rat
Reprotox battery rat
Carcinogenicity dermal rat
Carcinogenicity mouse
2-wk oral/iv minipig
2-wk oral/iv rat
LLNA
Ames screen
MNT in vitro
Sec. safety pharm
4-d screening rat
hERG screen
2-wk minipig*3T3 screen
3T3
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Therapeutic window
Therapeutic Index (also called safety margin or exposure multiple) is calculated for AUC and Cmax:– Animal AUC0-24h/Predicted human AUC0-24h
and/or – Animal Cmax/predicted human Cmax
Calculated for each route of exposure and each species Calculating human predictions are made based on the proposed clinical
dosing concentration and projected average treated area to be covered Safety margin generally shrinks the longer the animals are dosed
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Therapeutic window - consideration for wound healing drugs Wound size would impact exposure, limited size for preclinical studies relying
on TI for extrapolation to clinical studies:– Ratio of systemic exposure in the most sensitive animal species and the projected
human systemic exposure– Calculated human predictions are made based on the proposed highest clinical dosing
concentration and projected average wound area to be covered
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Formulation – general consideration
Topical formulation (cream, ointment, solution, gel, ...)– drives pharmacokinetic properties– might be the reason for clinical failure – might be the cause of species-specific dermal reactions
Systemic formulation– Exposure and safety– Identify target organs and reversibility– Used for establishing safety margin
Safety of the clinical formulation (CSF) should be tested in the GLP studies. Programs typically require a bridging study between DRF and GLP studies if the
former are run with an experimental formulation
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Formulation – tolerability of topical CSF
Choice of CSF for topical formulation– Aims on human use (cream, ointment, solution, gel, ...):– Will drive pharmacokinetic properties of compound – Might have neutral effects on wound healing for clinical trial (PoC)
Translation of local tolerability to human vs tox species not easy as sometimes tox species is/are oversensitive to a certain vehicle requesting a contingency plan
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Formulation tolerability
Here is an example of assessment of formulation tolerability in wound healing model for which re-epithelialization, granulation tissue and inflammation are benchmarked again control hydrogel formulation.
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HPMC
HPMC+HPbCD
Carbopol
Anhydrous G
elLiposo
mes
Occlusiv
e Ointm
ent
Simple
Cream
Complex Crea
m
0
50
100
150
HPMC
HPMC+HPbCD
Carbopol
Anhydrous G
elLiposo
mes
Occlusiv
e Ointm
ent
Simple
Cream
Complex Crea
m
0
1
2
3
4
5
HPMC
HPMC+HPbCD
Carbopol
Anhydrous G
elLiposo
mes
Occlusiv
e Ointm
ent
Simple
Cream
Complex Crea
m
0
1
2
3
4
5
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Pathology associated with formulation
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Hydrogel (control)
Granulation tissue
Re-epithelialization
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Pathology associated with formulation
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CarbopolFormulation
visible
Poor granulation
tissue
Poor re-epithelialization
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Pathology associated with formulation
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Liposome
Inflammatory cells
Poor re-epithelialization
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Pathology associated with topical drug
Potential microscopic findings associated with topical drug should be compared with untreated and formulation treated control skin.
Different mechanisms involved in skin damage:– direct toxicity (e.g., chemical burns from strong acids or alkalis)– immune-mediated reactions (i.e., allergic reactions)– phototoxic or photoallergic reactions– genotoxicity
In the following slides, few pictures of most common findings associated with topical drug administration.
Further description of microscopic finding terminology could be found on– goReni: https://www.goreni.org/– NTP: https://ntp.niehs.nih.gov/nnl/
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Single cell necrosis, epidermal (and vacuolation, epidermal)
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Hyperplasia, epidermal
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Hyperkeratosis (orthokeratotic)
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Infiltration, inflammatory cells, dermal to epidermal
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Vagina (topical): erosion/ulceration with inflammation
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Vehicle controlFormulation 1 + drug Formulation 2 + drug
Mucosa
Erosion/Ulceration
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Prepuce (topical): erosion/ulceration with inflammation
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Vehicle controlFormulation 1 + drug Formulation 2 + drug
Mucosa
Erosion/Ulceration
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Pathology associated with wound healing drug
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Re-epithelialization
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Anti-Keratin 5 (purple staining)Epidermis expressing K5in basal layer
Wound bed with no K5 expression
Wound border expressing K5
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Delay in wound healing (decreased re-epithelialization, granulation tissue progression and collagen deposition)
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Control
Treated
Granulation tissue
Re-epithelialization
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Inflammation (and bacterial colony )
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Granulomatous inflammation
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Pathology associated with UV-LLNA phototoxicity model Few examples of ear skin findings associated with phototoxicity model.
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Hyperplasia, epidermal (and edema)
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Infiltration, mononuclear cell, dermal (with hyperplasia and hyperkeratosis (crust))
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Acknowledgement
Boisclair J.Saravan C.Sukhdeep S.
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Important Reminder
Please send any questions you may have to Satish Panchal [email protected]
Questions will be addressed at the end of the presentation.