Toxicology in Drug Development
Michael Watson
Vice President
Program Management
Ricerca Biosciences, LLC
May 23, 2007

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”

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

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

Traditional Toxicology
• In vitro toxicology
– Screening
– Aids design of better studies
• Mechanistic toxicology
– Guides discovery
– Explains relevance
• Safety assessment
– Dose/response relationship

In Vitro Toxicology
• Screening
– Cytotoxicity
– Protein binding
– CYP inhibition/induction
– Membrane permeability
– Metabolic stability
• Improve subsequent study design
– Interspecies comparison

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

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

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?

Prior to “First in Man”
• Safety Pharmacology
– Cardiovascular
– CNS
– Respiratory
• Toxicokinetic and Pharmacokinetic Studies
– Exposure data in animals needed prior to human
clinical trials

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)

Route of Administration
• Mimic clinical route
– Oral, subcutaneous, intramuscular, intravenous
– “Specialized” routes
• Inhalation
• Infusion
– Topically applied drugs (dermal)
• Toxicology studies in miniature swine

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

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

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

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

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

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

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

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

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

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
•