Toxicology in Drug Development

Michael Watson

Vice President

Program Management

Ricerca Biosciences, LLC

May 23, 2007

Toxicology

• Science to address potential harmful effectsof chemicals

– Medicine, hunting, warfare, suicide, homicide

• Paracelsus – Swiss medical practitioner,1493 – 1541, Father of Toxicology

– “The dose makes the poison”

Drug Development Process

NCEapproval

Target ID &Validation

Phase III

Phase II

Phase I

LeadDevelopment

Hits

HTSLead ID

Chemistry & Biology

LeadOptimization

ADME/Tox

IND

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 pharmaceuticalsfor human use

– ICH “M3 (M)”

Non-clinical safety studies for the conduct of humanclinical 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 humanclinical 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 doseclinical trial

– 14 or 28 days to support equal duration of clinicaltrial

– 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 chromosomaldamage

– Consider adding mouse micronucleus to completethe 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 tocompare 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 inanimals and assess risk in humans

• Required if drug to be administered forsubstantial part of patient’s lifetime

• Review all data to determine if testingwarranted

• Data overview and protocols reviewed byregulators 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