Toxicology in Preclinical Development - 2 part lecture series (watch episode 1) - lecture 2 is another set

Why is safety evaluation an important step in drug discovery?

All substances have the potential to cause toxicity e.g., Thalidomide incident

Only the dose can distinguish harmless effects from toxicity

What does NOAEL stand for?

No observed adverse effect level is the concentration at which no ADR is noted

Why is safety evaluation an important step in drug discovery?

All substances have the potential to cause toxicity e.g., Thalidomide incident

Only the dose can distinguish harmless effects from toxicity

What does NOAEL stand for?

No observed adverse effect level is the concentration at which no ADR is noted

How is Therapeutic Index calculated?

LD50/ED50 or TD50/ED50

TD = toxic dose

LD = lowest toxic dose

ED = effective dose

How is Margin of Safety calculated?

LD1/ED99

What useful information do toxicology studies provide?

- Guidance on dose levels for clinical trials

- Determines margin of safety

- Prevent serious irreversible toxicity: in clinical trials and in clinical use

- Provide data for management of overdoses

- Identification of target organs for clinical surveillance

- Information on toxicity and relationship between blood level, dose and toxicity

How can toxic effects be predicted?

Toxic effects often follow a dose-response curve allowing one specific dose to be predicted from the knowledge of toxic effects at other doses

What are the different testing platforms from which safety evaluation information is derived from?

Animal models

In-vitro experiments

Isolated cell screening

Clinical trials

What are the three types of toxicity?

Biochemical- change in enzyme

Functional- change in system

Structural- gross/microscopic pathological change

What are the three types of study required for safety evaluation?

Acute, sub-chronic, chronic

What is acute safety evaluation?

- defines dose response

- give single doses to rodents

- monitor signs for 7 days- clinical, body weight, food intake

- post-mortem: organ weight, structural toxicity

What is sub-chronic safety evaluation?

- test 3 doses incl. intended dose

- repeat daily dosing in rodent and non-rodent for 1-3 months

- look for clinical signs, body weight, food intake

- post-mortem: organ weight and pathology

What is chronic safety evaluation?

- same as sub-chronic but for 6 months

What are the gross clinical signs of toxicity?

Appearance and body weight changes

What are the gross pathology signs?

organ weight and appearance changes (tumour or atrophy)

How can histopathological changes be detected?

Light microscopy

How can ultrastructural changes be detected?

Electron microscopy

What is clinical chemistry?

Looking for biochemical changes in enzyme or metabolite levels indicating damage or dysfunction

Which tests are repeatedly monitored?

Liver dysfunction and blood

What are the markers of liver dysfunction?

Serum ALT/AST increase

Serum bilirubin increase

Serum albumin and glucose decrease

Clotting time increase

What are the markers of kidney dysfunction?

Increased urine output

Gamma-glutamyl transpeptidase increase

Amino acids and glucose increase

Urea decrease

Why is in-vitro study not used for safety evaluation?

Poor correlation with in-vivo data

Limited availability

Problems of extrapolating to human in-vivo

Only one tissue exposed may not be target organ

What is the importance of preclinical toxicology?

Ethical implications of human exposure

Not all toxic effects display in animals