Role of Toxicology Data in Drug

Development

K.S. Rao, M.V.Sc., Ph.D., DABT

Senior Scientific Officer

Syngene International

Bangalore

ks.rao@syngeneintl.com

20th April 2012

1

WHAT IS A POISON or TOXICANT?

“All substances are poisons, there is none which is not a poison. The right dose differentiates a poison and a remedy.” Paracelsus (1493-1541)

DEFINITIONS

• Toxicity: Refers to the inherent adverse effects of a material

• Toxicology: Refers to the study of adverse effects of chemicals on living organisms

• Toxicologist: Is one who is trained to examine the nature of those effects and assess the probability of their occurrence

• HAZARD: Refers to the potential of an inherently adverse

material to cause damage under conditions of a proposed use

situation

• RISK: is a measure of the probability that harm will occur under

defined conditions of exposure to a chemical

– – If there can be no exposure to a chemical, no matter how

– dangerous (hazardous) it may be, there is no risk of harm

Pathology

TOXICOLOGY

Physiology

Biochemistr

y Pharmacolog

y

Chemistry

Contributing Sciences to Toxicology

ROLE OF TOXICOLOGY

Determines the short-term and long-term

effects of exposure to the compound on

mammals

Predicts the effects of exposure to the

compound on humans

Provides information regarding safe

handling

Identifies any issues that could inhibit

regulatory success 5

Toxicity and Dose

• The toxicity (poisonous nature) of any substance is

inversely related to the amount (dose) required to

cause harm

– The more that is required, the lower the toxicity

• Substances which can cause harm following exposure

to very small amounts, sometimes no more than a few

molecules, are said to be extremely toxic

• Substances which require exposure to many grams

before harm results are said to have low toxicity

• Even essential nutrients become toxic if the amount

ingested is above a certain acceptable dose

Dose and Dose-Response

• The dose is the actual amount of a chemical

that enters the body

• Dose-response suggests that a dose, or a

time of exposure (to a chemical, drug or

toxic substance), will cause an effect

(response) on the exposed organism

What is the Threshold Dose

• Threshold dose suggests that there should

be a dose or exposure level below which

harmful or adverse effects are not seen in a

population

Dose-Response Curve

(for Ability To Cause Death)

BASIC APPROACH

• Fundamental principle in toxicological study

design is to characterize the full range of potential

toxicity of a drug • To determine the dose or exposure at which effects first occur

• A dose or exposure which is without adverse effects – NOAEL

• Thus, toxicology studies are designed to

maximize the potential for identifying adverse

effects.

• Employing high doses is part of the strategy for

fully maximizing that potential 10

EFFECTS

• The toxicologist is charged with determining if the effects are real, drug-

related effects between control and drug treatment groups

• If they are drug related, are these considered adverse effects

• Following considerations need to be used:

• Dose responsiveness – adverse effects will emerge with increasing dose

• Relevancy of effect to humans

• Transience of the effect

• Adaptation or tolerance to the response

• Functionality of the organism despite the effect

• Professional judgment.

Examples:

• Pharmacodynamic effect of insulin in therapeutic use, can hardly be

considered toxic, but hypoglycemia is clearly a dose-limiting effect

• This should not drive the determination of NOAEL 11

NONCLINICAL DEVELOPMENT

• Choosing species

• 1 rodent (rat/mouse), 1 non-rodent (dog/NHP/mini-pig)

• Metabolite id in animal species vs human

• Choose most sensitive species

• Duration of studies

• Must cover duration of clinical trials

• Biologics

– Target/protein sequence homology

– Cell based assays for binding affinities

– Functional in vivo activity

– Single species may be acceptable for large molecules

– For biologics with long T½ consider once per week dosing

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MINIMUM TOXICOLOGY STUDY

REQUIREMENTS FOR IND

− Safety Pharmacology studies

− Cardiovascular

− Respiratory

− CNS

• At least two mutagenicity studies

− Ames

− Chromosomal aberration

• Acute study in Rats and Dogs

• Sub chronic (14-28 days) studies in Rats and Dogs

• Basic ADME study

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Genetic Toxicology

• Core battery of three tests:

• Microbial mutation test (Ames)

• In vitro mammalian chromosomal aberration

or mouse lymphoma tk test

• In vivo micronucleus test

• First two submitted with initial IND

• Last test submitted prior to Phase 2

• Positive signal may lead to additional

testing

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General Toxicology Dose Selection (1)

• Dosing should be up to the Maximum

Tolerated Dose (MTD)

• Dosing should include a No Adverse Effect

Level (NOAEL)

• Doses should be spaced so as to allow a dose-

response assessment

• Generally three dose groups and a control

group

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General Toxicology Endpoints

• Mortality

• Clinical signs

• Body weight, Food consumption

• Hematology, Clinical chemistry

• Eye (Ophthalmic exam.)

• ECG, Blood pressure (non-rodent)

• Necropsy, organ/tissue weight

• Toxicokinetics

• Pathology (complete battery of tissues)

• Recovery for toxicological findings

PRECLINICAL SAFETY TESTING:

SOME CONCEPTS AND BASIC IDEAS

• Repeat Dose toxicology studies must:

• Establish MTD, NOAEL and Safety Margin

• Determine target organ (s)

• Assess Gender difference, if any

• Assess reversibility

• Go – No Go decision

In most toxicology studies over 100 parameters are monitored. It is the duty of Toxicologist/pathologist to give best explanation in the report to arrive at the NOAEL.

Look at target organ effects: • Growth stimulation (Liver tumors from enzyme induction)

• Exaggerated pharmacology (Insulin type, CNS etc)

• Hormonal perturbation (pituitary, thyroid, and mammary tumors)

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Problems Most Faced in

Toxicology • Choosing the wrong doses

• Must conduct Dose Range Finding studies to chose the

most appropriate doses for the definitive GLP repeat dose

regulatory toxicity studies

• Failing to understand what the effects mean?

• Interpreting the effects observed in particular poor

pathology training

• Toxicologists working in Silos in their own company, in

particular in CRO’s

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Problems Unique to India

• Lack of quality suppliers of lab animals

• Bulk of domestic lab animals are infected

• Lack of quality lab animal diets, and

bedding

• Lack of broad training of toxicologists and

lack of depth in understanding of various

therapeutic areas, in particular

cardiovascular, endocrine and CNS

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Issues involved in Drug Development

Pertaining to Toxicology

• Not enough preliminary toxicology screens conducted

during Discovery/Lead Identification.

• Most drug development programs are headed by highly

opinionated individuals who lack the breadth of drug

development.

• Interdisciplinary approach is not practiced, in particular

small to medium size companies.

• Toxicological issues that come up during early drug

development, are ignored by management

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Top Four Reasons for Discontinuation of Drug

Development in Safety Assessment

• Positive in genotoxicity tests Ames mutation assay, in vivo positive genotoxicity

Direct acting DNA damage

• Cardiovascular safety related problems In vitro hERG channel assay

In vivo ECG-QT prolongation

• Target organ toxicity Poor understanding of toxicity mechanisms

Lack of good biomarkers to monitor adverse effects non-invasively

Poor safety margins

• Potential to cause multiple organ tumors in multiple species

Integrated Drug Development ACCELERATED DEVELOPMENT INTO MAN

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Conclusions - IND

• Were the non-clinical studies adequate in

terms of dose, duration etc.?

• Are there sufficient safety margins for

identified toxicities to support the

proposed clinical trial?

• If yes, recommend safe to proceed.

If no, recommend clinical hold.

Any

Questions