Lecture 14 - Cardiovascular Safety Assessment Flashcards
(17 cards)
What is the general process of drug development?
Discovery phase:
* Find a target
* Find hits (>10,000 compounds per project)
* Hit to lead (~500 compounds per project)
* Lead opt (~1,000 compounds per project)
* Pre-clinical (1-3 compounds per project
Development phase:
* Phase 1 (1 compound per project)
* Phase 2
* Phase 3
* Enter market (0.08 compounds per project)
Why is it better to assess cardiovascular safety early into drug development?
It is cheaper to stop drug development in the early stages ($0.85 billion in discovery phase) rather than the late stages ($1.75 billion in development phase) - cheaper to fail
Why is cardiovascular safety so important?
WHO (2021):
* ~32% of deaths worldwide are due to cardiovascular issues
* ~31% of deaths worldwide are due to other non-communicable diseases ‘’
In a large number of cases, treatment will be given to a person who suffers from or also suffers from cardiovascular issues - we do not want to make this worse
Candidate drug regulatory studies: what are the steps to approving a drug for the development phase and why?
- Investigational New Drug (IND) application filed with the regulatory agency covering the country where the trial will be conducted
- Conducted safety studies should be presented including a minimum package of safety data that the agency expects to see - effect on function/structure on the cardiovascular system (function is assessed using dogs, structure is assessed using rats/dogs)
This is to protect the first group of people taking the candidate drug (healthy volunteers)
Regulatory studies on the candidate drug - assessment of cardiovascular function: what are the parameters that are monitored?
What effect does the CD have on the following parameters in dog*:
Blood pressure (BP)
Heart rate (HR)
Electrocardiogram (ECG)
Left ventricular pressure (LVP)
- Note: rat data not valid (human cardiac electrophysiology significantly different from that of rats)
Regulatory studies on the candidate drug - assessment of cardiovascular function: what is the mechanism of monitoring cardiovascular function?
- Conscious dogs, previously implanted with a telemetry device that records and transmits parameters (BP;HR;ECG;LVP)
- Four dogs given vehicle or low/medium/high dose of CD
- Clinical route of administration used (oral administration most common)
- Data recorded for 24 hours
- Blood samples taken to measure concentration of drug in plasma
- After a recovery period, same dogs get a different dose or vehicle and cycle repeats
- Enables plot of effect versus plasma drug concentration
- Dogs re-used after a suitable “washout” period
Regulatory studies on the candidate drug - assessment of cardiovascular function results: how are results used?
EC50 compared with the cardioovascular function results - drug should only be used if the intended dose is relatively far from the dose that disrupts cardiovascular function
Regulatory studies on the candidate drug - assessment of cardiovascular structure: what is the mechanism of monitoring cardiovascular structure?
- Five dogs given vehicle or low/medium/high/high dose of CD
- Clinical route of administration used (oral administration most common) once a day for 28 days
- After the period, the first four are euthanised and their hearts are analysed to determine any CV structure changes
- The fifth dog undergoes a recovery period for a month and then it is also euthanised to see if not taking the drug causes a recovery of any changes to CV structure
Prior to this, rats will be used with the same design
Candidate drug regulatory studies results: what determines whether a drug is acceptable for use, and are there any instances where the risks can be ignored?
The balance between risk and benefit is taken into account
A CV risk may be acceptable for an end-stage cancer patient but not for someone with rheumatoid arthritis - progression of drug manufacturing, even when there are CV effects may only occur if the effects are SMART
SMART: what does it stand for?
NonSerious - would it be acutely life-threatening
Monitorable - can it be measured in man
Anticipatable - is there a clear dose-response relationship
Reversible - does the effect go away once dosing is stopped
Treatable - can it be managed by known, safe interventions
Grepafloxacin: what is it, what is the mechanism behind its function, and what safety issue was found with its use?
Bacterial infections - bacterial topoisomerase inhibitor
Cardiac arrhythmia - blockage of hERG K+ channel in heart, prolongs ventricular cell action potentials, subsequent QT interval prolongation has the potential to lead to a fatal cardiac arrhythmia (Torsades de Pointes)
Norfenfluramine: what is it, what is the mechanism behind its function, and what safety issue was found with its use?
Obesity - promoting serotonin release
Valvular heart disease - damages heart valves, dangerous for survival:
* 5HT2(subscript B) receptor on vavlular interstitial cells
* These cells bind NFEN and undergo GPCR activation of PKC and changes in gene transcription, resulting in stiffened valves that function improperly
Rofecoxib: what is it, what is the mechanism behind its function, and what safety issue was found with its use?
Treat Arthiritis pain - cyclooxygenase 2 (COX2) inhibitor
Increased risk of myocardial infarction and stroke - assessment of various studies discovered, on average, a massively higher CV risk when taking the drug:
* COX2 has a cardioprotective effect
* Inhibiting it removes that cardioprotective effect
Drugs targeting cancer kinases: what is it, what is the mechanism behind its function, and what safety issue was found with its use?
Treat cancer - inhibiting kinases known to progress cancerous growth
Cardiac output became diminshed during use of these drugs:
* Same kinases targeted in cancers are also required for the health of cardiac myocytes
Early discovery studies: why are they beneficial, what types are used, and why do they work?
stopping manufacturing of a drug early into the discovery phase (during the synthesis-screening cycle) is cheaper and safer for life
- Cardiac ion channel screening - seeing the effect of drugs on known channels to see any disruptions
- Cell-based assays
Cardiac ion channel screening: why does it work, how does this process work, and what is an example?
Ion channels underlying action potentials is known - drug-induced modulation of these channels is a known safety risk
Cell lines expressing key ion channels are available - testing any disruption to these cells can be done
hERG channel
Cell-based assays: why are they useful, how do they work, what improvements are there for them nowadays, and what must be considered with their usage?
Allow a “black box” screen to be done by monitoring one or more activities in a cell-based system and measuring whether they are changed by the compound - only a fraction of the molecular mechanisms of CV safety issues are known
Commercially available human stem cell-derived cardiac myocytes - better than animal cells since they had ethical issues and low throughput
Stem-cell-derived cardiomyocytes do not fully recapitulate native cell biology
