Week 4 Flashcards
(12 cards)
Variation in Toxic Responses
Individual differences (genetic), Species differences, Selective toxicity
Risk Assessment considerations
The toxicity of the compound;
How it is to be used;
How much of it is going to be used;
Likelihood of exposure;
How persistent the chemical is;
Perception of risk.
Acceptable Risk
Benefits gained through use of substance. Adequacy and availability of alternative
substances
Extent of public use/exposure
Employment considerations
Effects on environmental quality
Conservation of natural resources
Four stage RA process
- Hazard identification
- Determination of the dose-response relationship
- Exposure assessment
- Integration of all data into a final assessment; risk characterisation
Framework for Human Health Risk Assessment
Hazard identification (human data, animal data, in vitro data) + Dose-response relationship + Exposure assessment (modelling & monitering) —> extrapolation to risk prediction and characterisation
Dose-response
dose-response relationship of a new drug determines/sets:
- the starting dose in initial human trials, and guidelines for the post-marketing use
finding a compromise
between a dose that is safe yet therapeutically efficient
Exposure assessment
◦ exact dose of drug in most cases can be determined in the milligram range; and
◦ exposure route (e.g. oral, dermal, inhalation or injection) is clearly defined
Factors contributing to actual exposure
ADME (Toxicology)
End result
The overall safety of the drug, and An estimate of the potential patient burden
Factors to be considered:
- A need to balance cost with benefits of the drug
- Type of drug and the disease it is intended to treat
- There is a certain degree of flexibility for diseases with
un-met needs
Precautionary principle
‘better safe than sorry’ approach:
In the context of drug safety, it would be a recommendation not to approve a drug based on the
potential for harm, even if it is not certain to occur
Suggestive, but uncertain evidence, is enough to take action against a pharmaceutical compound
Weight-of-evidence approach
Evaluation process involves looking at all the data available, including but not limited to:
- Mode of action (molecular biology and biochemistry)
- Epidemiological
- In vitro tests
- Clinical experience
- Literature on similar compounds
- QSAR
Scientific judgment is used to evaluate the strengths and weaknesses of each method when determining the total risk of a new compound. eg reliability and strength of scientific method. size of the measured endpoint, do multiple end point results point in one direction?
Lipinski’s Rule of 5
Not >5 hydrogen bond donors
◦ expressed as the sum of -OH and -NH groups
- Not >10 hydrogen bond acceptors
◦ expressed as the sum of Ns and Os
- A molecular mass not >500 daltons (500g/mol)
- Octanol-water partition coefficient log P not >5
