Summary
- Safety pharmacology became a thing after the emergence of rare cardiac adverse effects from terfenadine (an antihistamine used to treat hay fever) in the 1990s
- IND applications either get approved or put “on hold” (with a request for more data); seems like there is no “reject” option
- Extent of safety pharmacology studies depends on disease: more severe diseases (or those w/o existing treatments) can get away with less safety studies
- Example: life-threatening disease w/o existing treatments requires only a single study (n=4 dogs) with integrated telemetry recording (i.e. continuous monitoring with various sensors) of cardiovascular parameters, CNS neurological examination, and respiratory profile using a pneumotachometer (device used to measure flow of air into and out of lungs)
- Non-life-threatening disease may require full functional observation battery (FOB), including 30 parameters
- Safety pharmacology depends on drug
- Biologics don’t need to be investigated for hERG binding (leading to torsades de pointes)
- First-in-class small molecules needs to be tested for everything
- Depends on subjective risk/benefit profile of drug
- Timing of core battery studies and which non-core-battery studies to do depend on judgement of drug sponsor
- Sometimes drug discovery teams will run non-GLP safety studies prior to core battery based on results from discovery teams (depending on drug)
- For example: CV adverse effects are higher for multi-target tyrosine tyrosine kinase inhibitors. Repeat-dose safety pharmacology studies in conscious animals measuring systemic arterial pressure and chronotropic (changing heart rate) effects are justified here
- If drug is bioavailable and has adequate PK in different species, it will be tested in a range of species (is this required?)
- Biologics usually don’t require extra safety studies
- First step: dose range finding (or tolerance studies)
- DRF studies include cage side observations (for physical and behavioural effects), drug exposure analysis, blood chemistry, haematology, pathology and histopathology
- Typical “core battery” safety pharmacology studies
- Usually GLP compliant (but not necessarily?)
- Usually conducted with a single drug dose (in same administration route of tox and matching clinical route)
- Cardiovascular (CV) safety is usually assessed in a conscious telemetry study in large animals from tox studies (n=4) using Latin square or dose-escalation design with sufficient drug wash-out times between dosing
- Why are there multiple doses here?
- Respiratory safety assessed in conscious rats (n=8) and sometimes dogs/monkeys when rats aren’t suitable
- CNS safety evaluated using modified Irwin test in rats (n=10) or other animals when appropriate
- Sometimes EEG monitoring, respiration, animal activity by jacketed external telemetry is done