First Time in Human Trials Flashcards
Acute toxicity profile?
Required for acute and chronic administration.
Less info from preclincial studies.
Chronic toxicity profile?
For chronic indication.
What is required before testing a drug in man?
Minimum 14 day toxicity test in one rodent and one non-rodent species.
Should test 3 dose levels: below, around the expected dose and well above human dose.
May include longer term studies (12/24 months).
Repeated dose toxicity?
Required if an acute drug can be taken for x number of days.
The longer the drug can be used in humans, the longer the preclincial testing needs to be.
NOAEL
No Observable Adverse Effect Level
- Highest dose that does not produce a significant increase in adverse effects (compared to control).
- Dose immediately before unacceptable side effects.
- Biologically significant not statistically significant.
HED
Human Equivalent Dose
- Calculated from NOAEL in most appropriate species (usually most sensitive).
- Converted using a body surface area factor.
- Be conservative for safety.
- A safety factor should then be applied
Why apply a safety factor?
- Human bioavailability/metabolism may differ significantly from animals
- Toxicity mechanisms may be unknown
- Toxicity may be due to unidentified metabolite
- Toxicity may be difficult to detect in animals
What studies can be used to determine NOAEL?
- Overt toxicity -> clinical signs, lesions
- Surrogate markers of toxicity -> serum liver enzyme levels
- Exaggerated pharmacodynamic effects
MRSD
Maximum Recommended Starting Dose
- HED divided by safety factor
- Always start at a very low dose before escalating
Why would you increase the safety factor?
Steep dose-response curve
Severe toxicity
Non-monitorable toxicity
No pre-monitory signs of toxicity
Variable bioavailability
Irreversible toxicity
Unexplained mortality
Large variability in doses/plasma levels causing effect
Nonlinear pharmacokinetics
Inadequate dose-response data
Novel therapeutic targets
