This presentation provides insight about different toxicity studies

1. Different types of Toxicity studies
-Mohana Thakkar
Date: 13/12/2023

2. What is Toxicology?
The study of the adverse effects of chemicals or physical agents on living organisms.
Toxic agent: anything that can produce an adverse biological effect.
Toxic agents may be:
Chemical (such as cyanide)
Physical (such as radiation)
Biological (such as snake venom)
Toxic substance is simply a material which has toxic properties.

3. Non-clinical
development
Objectives:
After a lead molecule (candidate compound) is identified,
non-clinical development begins.
Non-Clinical studies are required to answer the following
questions:
Does it work?
How can it be delivered and how does the body react?
(ADME profiling)
Is it safe? (Toxicology/safety, pharmacology assessment)
Is the manufacturing process viable & controllable? (CMC
activities)

4. Why are non-clinical studies needed?
For decisions:
 On Clinical trials
On Marketing authorization applications (New Drugs Submissions)
On Post-Marketing or monitoring studies
To determine first-in-human doses of the compound (based on pharmacology &
toxicology data)
Need to prove new drugs are safe:
- Before first administration to humans
- Before later clinical trials

5. What does Nonclinical toxicology really do?
– Hazard identification – Risk assessment

6. Where does
Toxicology fit in
Drug
Development?
Toxicology in every Phase = Nonclinical

7. Types of
Toxicology
studies:
Toxicology studies aim to address the toxicity of the
compound in different scenarios:
Single-dose toxicity
Repeated-dose toxicity
Genotoxicity (will the product alter the genetic profile,
interfering with DNA or chromosomes?)
Carcinogenicity (will the product cause cancer?)
Development and reproductive toxicity (DART)

8. TOXICOLOGY PROGRAMME
Study type and
duration
Route of
administration
Species Compound administered (This
column required only if
metabolite(s) are investigated)
Single-dose
toxicity
po and iv Rat and mouse Parent drug
Metabolite X
Single-dose
toxicity
po and iv Rat and mouse
Repeat-dose
toxicity
1 month
6 months
9 months, etc
po
po
po
Rat & Dog
Rat
Dog
Parent drug
“ “
“ “

9. What is Toxicokinetics?
The application of pharmacokinetics principles to the
design, conduct & Interpretation of drug safety evaluation
studies.
Deals with absorption, distribution, biotransformation &
excretion of toxic chemicals.

10. Brief summary
of the studies
conducted:
Single-Dose Toxicity: The single-dose data should be very
briefly summarized, in order by species, by route. It may be
provided as a table.
Repeat-Dose Toxicity (including supportive toxicokinetics
evaluation): Should be summarized in order by species, by
route & by duration, giving brief details of the methodology.
Important findings should be highlighted:
Nature & severity of target organ toxicity
Dose exposure/response relationships
No observed adverse effect levels
Non-pivotal studies can be summarized in less detail

11. Genotoxicity:
Definition: Genotoxicity is the property of chemical agents
that damage the genetic information within a cell causing
mutations, which may lead to cancer.
These studies involves:
Assessment of gene mutation
Assessment for chromosomal damage in mammalian
systems
If positive findings observed, additional testing must be
considered.
Studies should be briefly summarized in the following order:
in vitro non-mammalian cell system
in vitro mammalian cell system
in vivo mammalian system (including supportive
toxicokinetic evaluation)
 other systems

12. Carcinogenicity
(including
supportive
toxicokinetics
evaluations)
A brief rationale should explain why the studies were chosen
and the basis for high-dose selection.
Studies should be briefly summarized in the following order:
 Long-term studies: in order by species; including range-
finding studies that cannot appropriately be included under
repeat-dose toxicity or pharmacokinetics.
Short- or medium-term studies: including range-finding
studies that cannot appropriately be included under repeat-
dose toxicity or pharmacokinetics.
Other studies

13. Reproductive and Developmental Toxicity
Studies should be summarized in the following order, giving brief details of the
methodology and highlighting important findings:
Fertility and early embryonic development
Embryo-fetal development
Prenatal and postnatal development, including maternal function
Studies in which the offspring (juvenile animals) are dosed and/or further evaluated, if such
studies have been conducted.
If modified study designs are used, the sub-headings should be modified accordingly.

14. Other Toxicity Studies (if available)
The rationale for conducting the studies should be provided, if other studies
performed:
Antigenicity
Immunotoxicity
Mechanistic studies (if not reported elsewhere)
Dependence
Studies on metabolites
Studies on impurities
Other studies

15. Chemistry, Manufacturing, Control (CMC)
Key CMC steps during non-clinical development:
Formulation for non-clinical development studies
 Determining the dosing system and method of application of the active ingredient based on
product properties and type of animal model.
Detailed physico-chemical characterisation
Stability testing and impurity analysis
Development and validation of methods to quantify the active substance in body fluids (e.g.
blood, plasma, urine) in pharmacokinetic and toxicokinetic studies
Development of a prototype for the clinical formulation.

16. Non-clinical outcomes that can terminate
development
Discovery of target organ toxicity
For example, if a compound is hepatotoxic (toxic for the liver) in an animal
Identification of poor pharmacokinetic properties
For example, if a product is poorly absorbed, if it accumulates, or if it generates toxic
metabolites.
ADME studies are performed to optimize selection of successful product candidates

17. Use of animals in medicines research & development
On ethical grounds, the Declaration of Helsinki states the acceptability of using animals as
models of risk assessment for man when these models can mimic human diseases.
Questions that should be addressed:
 How relevant are non-clinical (animal) models for the human situation?
 Were the non-clinical signs and pathologies sufficiently studied within the context of the
proposed human use of the novel medicine?
 How to align expectations from animal information to the information provided by clinical
studies in healthy volunteers and patients?
 Can alternative tests be used?

18. How to choose the first-in-human dose?
No Observed Adverse Effect Level (NOAEL) is most important: NOAEL level is the level
of exposure at which there is no significant increase in the frequency or severity of any adverse
effects.
In the case of many biotechnology-derived medicines (biological medicines), and when risk
factors have been identified, the first human dose is established using the Minimal-Anticipated-
Biological-Effect-Level (MABEL).

19. References:
 ICH M4S (R2): NONCLINICAL OVERVIEW AND NONCLINICAL SUMMARIES OF MODULE 2
ORGANISATION OF MODULE 4
The GCC Data Requirements for Human Drugs Submission
General toxicity studies: General toxicity studies - EUPATI Toolbox
Non-Clinical testing: Non-clinical testing - EUPATI Toolbox
Systemic toxicology: Systemic toxicology - EUPATI Toolbox
Reproductive toxicology: Reproductive Toxicology - EUPATI Toolbox