Lecture 13 Non-clinical (non-human) toxicology Flashcards
Why are regulatory authorities important?
Local regulatory authorities control national level risk assessments of drugs and chemicals, this signifies governing sovereignty and international differences. However International Conference on Harmonisation brings tighter regulatory authorities and pharmaceutical companies to discuss safety and guidelines, for which the Common Technical Document is important for.
What are the experimental rules for acute toxicity (singled dose)? [species, route, dose level]
Species: 2 mammalian species including 1 non-rodent.
Route: the proposed clinical route, and another that is parenteral (other than oral)
Dose level: exceed anticipated clinical exposure to inform overdose pharmacology
What are the experimental rules for repeat dose toxicity? [species, route, dose level, length of study]
Species: 2 mammalian species including 1 non-rodent
Route: proposed clinical route
Dose level: up to maximum tolerated dose, or 50x anticipated exposure dose
Length of study: dependent on how long drug is prescribed for clinically, usually at least 2 times longer. Time different for rodent and non-rodent
What are the two options for standard testing in genotoxicity?
#1 A bacterial mutation test (Ames), use bacteria to see if chemical causes mutation. A cytogenetic test to test for structural abnormalities in chromosome. And an in vivo test for genotoxicity using rodent haemopoietic cells. #2 A bacterial mutation test (Ames). And an in vivo test for genotoxicity with two different tissues.
What is standard testing for carcinogenicity?
A long-term study in rodent species, at least two years. And another long-term study in second rodent species or mid-term in-vivo study in rodent. Organs examined for tumours, followed up by extrapolation of mechanism to humans.
What is standard testing for reproductive toxicity?
Exposure to mature adults and to all developmental stages from conception to sexual maturity.
Safety pharmacology: what are primary and secondary adverse pharmacodynamic effects?
Primary: mechanism of action and effects in relation to desired therapeutic target.
Secondary: mechanism of action and effects not related to desired therapeutic target.
What are the key measures for cardiovascular system?
Heart rate, blood pressure
ECG changes
Conductance abnormalities
What are the key measures for CNS?
Motor activity, coordination
Behavioural changes
Sensory/motor reflex
What are the key measures for respiratory system?
Respiratory rate, tidal volume
Peak inspiration / expiration
If trial finds occurrence of no events, does this still contribute to risk estimation?
Yes
What is the rule of three?
If there was no occurrence in n events, we can be 95% confident that the long run risk < 3/n
So the greater the n the lower the long run risk.
How does the long-run risk calculated from the rule of three compare to the exact measurement?
Excellent estimate!
The greater the n the closer the estimate by rule of three is to the exact measurement.
How can we use the rule of three to estimate the number of subjects required?
The number of subjects required is 3x estimated frequency of event for 95% likelihood of detection
