Safety Pharmacology & Toxicology

Question 1

Pharmacodynamics

Answer 1

The study of ‘what the drug/chemical does to the body’
-Efficacy
-Toxicity

It is the study of a drug’s molecular, biochemical and physiologic effects or action.

Question 2

Importance of pharmacodynamics/toxicodynamics

Answer 2

Important in order to establish the lowest dose that produces the maximum therapeutic effect while minimizing adverse effects (toxicity)

Question 3

What does pharmacodynamics/toxicodynamics do?

Question 4

What is the therapeutic window

Answer 4

window where drug is most effective

Question 5

Therapeutic index

Answer 5

Measure between therapeutic and toxic effects of a drug

Question 6

What are most failures in preclinical studies due to

Answer 6

Safety issues (80%)

Question 7

What are the four major causes of drug toxicity

Answer 7

Pertubation of ADME - poor metabolisation leads to build up - high concentrations in the body - toxicity

The metabolisation of a non-toxic chemical?

The chemical disrupts the physiology of the cell via non specific pathways e.g. oxidative stress, apoptosis, necrosis etc)

The chemical interact specifically with biological targets, leading to specific target-mediated toxicity

Question 8

What is an adverse reaction?

Answer 8

A response to a drug that is noxious, unintended at occurs at doses normally used in man for the prohylaxis, diagnosis or therapy of disease or for modification of the physiological function

Question 9

Types of adverse reactions

Answer 9

Type-A reactions
Type-B (bizzare or idiosyncratic) adverse reactions

Question 10

Type-B reactions

Answer 10

Unrelated to known drug pharmacology
Don’t occur in most patients (for a specific population e.g. age, genetic risk factors)
Very rare - often not detected until the drug has gained broad exposure in a large patient group population

Question 11

Type-A reactions

Answer 11

associated with the primary or secondary pharmacology of the drug
responsible for 80% of all side effects
can be detected in animal models of pharmacology/toxicology

Question 12

What do safety pharmacology studies investigate?

Answer 12

Potential undesirable pharmacodynamic effects of a substance on physiological functions

Question 13

Objectives of safety pharmacology studies

Answer 13

1) To identify undesirable pharmacodynamic properties of a substance that may have relevance to its human safety.

2) To evaluate adverse pharmacodynamic and/or pathophysiological effects of a substance observed in toxicology and/or clinical studies.

3) To investigate the mechanism of the adverse effects observed and/or suspected.

Question 14

What are the safety pharmacology regulatory guidelines?

Answer 14

Good Laboratory Practice (GLP)
Harmonised and validated tests - everything must be transparent and reproducible
Have clear guidance on:
The test system
The doses and administration of drugs
Exposure times
Data collected
Data Analysis and interpretation
Data reporting

Question 15

Who are the governing regulators that ensure pharmaceuticals are fit for purpose?

Answer 15

ICH

Question 16

What guidelines must toxicology study follow?

Answer 16

OECD

Question 17

What do safety pharmacology studies involve?

Answer 17

A combination of… tests.

1) in silico - performed on computer or via computer simulation (e.g. Prediction of drug-enzyme interaction; PK-PD modelling).
e.g, AI
The ability to predict potential events

2) in vitro – performed or taking place in a test tube, culture dish, or elsewhere outside a living organism (e.g. micronucleus test).

3) in vivo - performed or taking place in a living organism (e.g. rodent).

Question 18

Example of in silico test

Answer 18

QSAR models - mathematical models used to predict the physicochemical, biological and environmental fate properties of compounds from the knowledge of their chemical structure

Question 19

Example of in vitro test

Answer 19

Irwin test - behavioural test

Question 20

Three main categories of studies

Answer 20

1. Core battery studies
   Investigate the effects of the test substance on vital functions
2. Follow-up studies
   Provide greater depth of understanding than, or additional knowledge to, that provided by the core battery on vital functions (gastrointestinal, renal)
3. Supplemental studies
   Evaluate potential adverse pharmacodynamic effects on organ system function not addressed by the core battery or repeated dose toxicity studies (genotoxicity and carcinogenicity)

Question 21

What is typically measured as the Core Battery?

Answer 21

cardiovascular
- BP, HR, ECG

respiratory
- respiratory rate and tidal volume or heamaglobin oxygen saturation

central nervous system
- motor activity, behavioural changes, coordination, motor/sensory reflex responses, body temp

Question 22

What is typically done as the Core Battery?

Answer 22

Central nervous system
- In-vivo rodent Irwin test or Functional Observational Battery (FOB)

Cardiovascular system
- In-vitro hERG (IKr) study or In-vivo non-rodent (usually telemetry)

Respiratory system
- In-vivo rodent generally using plethysmography

Question 23

Investigating: mutagenicity/genotoxicity/carcinogenicity

Answer 23

Ames assay
- Detects mutations

Mammalian in-vitro micronucleus test
- Detects chromosomal abnormalities

Question 24

The 3Rs

Answer 24

guiding principles for more ethical use of animals in testing
All animal use in bioscience research funded by research councils and charities is expected to implement the 3Rs principles of Replacement, Reduction and Refinement; and demonstrate high standards in the design and conduct of animal research.