Part of the MaRS Best Practices Series - Pre-Clinical development workshop
http://www.marsdd.com/bestpractices/
Speaker: Mike Watson. Exec Director Drug Development Services, Ricerca BioSciences
Keppel Ltd. 1Q 2024 Business Update Presentation Slides
Toxicology in Drug Development
1. Toxicology in Drug Development
Michael Watson
Vice President
Program Management
Ricerca Biosciences, LLC
May 23, 2007
2. Toxicology
• Science to address potential harmful effects
of chemicals
– Medicine, hunting, warfare, suicide, homicide
• Paracelsus – Swiss medical practitioner,
1493 – 1541, Father of Toxicology
– “The dose makes the poison”
3. Drug Development Process
Chemistry & Biology
Target ID & Lead
Validation Development
Hits IND Phase I Phase III
NCE
approval
ADME/
HTS
Tox Phase II
Lead ID
Lead
Optimization
4. Why do Toxicology Testing?
• Need to prove new drugs are safe
– First administration to man
• What dose to use?
• What effects to look for?
– Later clinical trials
• Expanded patient population
• Longer duration of treatment
5. Traditional Toxicology
• In vitro toxicology
– Screening
– Aids design of better studies
• Mechanistic toxicology
– Guides discovery
– Explains relevance
• Safety assessment
– Dose/response relationship
6. In Vitro Toxicology
• Screening
– Cytotoxicity
– Protein binding
– CYP inhibition/induction
– Membrane permeability
– Metabolic stability
• Improve subsequent study design
– Interspecies comparison
7. Mechanistic Toxicology
• Guides discovery
– Your lead just died!
– Find out why
– Medicinal chemistry to identify new lead
• Explains relevance
– Poor toxicology profile in rats
– Demonstrate rats not a relevant model
8. Safety Assessment
• Regulatory Guidelines
– International Conference on Harmonization
Tripartite
•
USA, Europe, Japan
•
Technical requirements for registration of pharmaceuticals
•
for human use
– ICH “M3 (M)”
Non-clinical safety studies for the conduct of human
clinical trials for pharmaceuticals
9. Prior to “First in Man”
• Design the testing program
– “Target Product Profile”
• What do you want to see on the product label?
• Sketch out a likely clinical trial program
• Design the required “first in man” clinical study
• Define testing program required
• How much API do I need?
– How long is a piece of string?
10. Prior to “First in Man”
• Safety Pharmacology
– Cardiovascular
– CNS
– Respiratory
• Toxicokinetic and Pharmacokinetic Studies
– Exposure data in animals needed prior to human
clinical trials
11. Prior to “First in Man”
• Single dose toxicity
– Acute toxicity in two mammalian species
• Repeat dose toxicity
– Two mammalian species
– Rodent and non-rodent
– Route of administration to mimic clinical
– Range of dose levels
• Having effect (high dose) to no effect (low dose)
13. Repeat Dose Toxicity
• Duration of studies
– Single dose (in USA) to support single dose
clinical trial
– 14 or 28 days to support equal duration of clinical
trial
– How to decide
• Required duration of clinical trial
• Cost and time
• API material supply
14. Prior to “First in Man”
• Local tolerance
– Relevant to clinical route
– May be part of toxicology study, but…….
• Genotoxicity
– In vitro tests for mutations and chromosomal
damage
– Consider adding mouse micronucleus to complete
the package
15. Interpretation of Results
• Determine “no observed adverse effect level”
– In all species tested
– May be different from “no effect level”
• Convert to “human equivalent dose”
– On basis of body surface area
• Select most appropriate animal species
• Apply safety factor
• Result = Maximum recommended starting dose
16. Early Studies in Patients
• Toxicokinetic and Pharmacokinetic Studies
– Further information on ADME in animals needed to
compare human and animal metabolic pathways
– Studies in animals with radiolabeled API
• Extended duration of repeat dose
• Complete genotoxicity package
17. In Vivo Metabolism Studies
• Synthesis of radiolabeled material
– Which label to use
– Where in the molecule
• Mass balance
• Tissue distribution
– Whole body autoradiography
• Metabolic pathway elucidation
18. Later Studies in Patients
• Extended duration of repeat dose
– 3 months to “chronic” duration
• Reproduction toxicity studies
– Inclusion of women of childbearing potential
• Carcinogenicity studies
– Depending on duration of drug treatment
19. Reproduction Toxicity Studies
• Traditional terminology
– Segment 1, 2 and 3
• Segment 1: Fertility and general reproductive
performance
• Segment 2: Teratogenicity
• Segment 3: Peri-post natal
– Newer ICH guidelines
• Flexibility
• Design studies to cover all stages of reproduction
20. Carcinogenicity Testing
• Objective: identify tumorigenic potential in
animals and assess risk in humans
• Required if drug to be administered for
substantial part of patient’s lifetime
• Review all data to determine if testing
warranted
• Data overview and protocols reviewed by
regulators prior to testing
21. Carcinogenicity Testing
• Lifespan studies in rats and mice (2 years)
• Difficult to design and interpret
– Untreated rodents gets tumors
– Different strains have different common tumors
– Tumors can be benign or malignant
– Tumors earlier in life, incidence unchanged
– Decreased body weight makes healthier animals
22. Keys to Drug Development Success
Anticipate and expect problems
•
It is never too early to plan ahead
•
Maintain flexibility
•
Trade off between $$ and timing
•
Plan for success
•