TBL 8 - SAFETY, PHARMACOLOGY AND TOXICOLOGY Flashcards
What does safety pharmacology employs?
Safety pharmacology is a rapidly developing disciple that employs the basic principles of pharmacology in a regulatory-driven process to generate data to inform risk/benefit assessment
What is the aim of safety pharmacology?
Aim of safety pharmacology is to characterize the pharmacodynamics/pharmacokinetic (PK/PD) relationship of a drugs adverse effects evolving methodology.
What is safety pharmacology include unlike toxicology?
Unlike toxicology, safety pharmacology includes a regulatory requirement to predict the risk of rare lethal events.
What are the 3 key issues for SP?
Key issues for SP are:
1) detection of an adverse effect liability 2) projection of the data into safety margin calculation
3) finally clinical safety monitoring
What does SP predict about a drug?
SP sets out to predict whether a drug, if administered to human (or animal) populations, is likely to be found unsafe, and its professional mandate is to prevent such an occurrence.
Prior to 1990s what type of test did pharmaceutical companies conduct?
Prior 1990, pharmaceutical companies conducted toxicological testing of lead compounds as part of preclinical drug discovery.
What phase does rare and lethal adverse effects of drug become apparent?
Over decades, drugs progress as far as phase 3 clinical trials (i.e. intended patient population) before rare and potentially lethal adverse effects become apparent.
Why was the post marketing surveillance (PMS) necessary?
Vigilant post-marketing surveillance (PMS) efforts by regulatory authorities necessary to confirm the existence of a rare adverse event occur after approval for human use.
What type of tools do regulatory authority use (4 things)?
Regulatory authorizes use tools such as drug experience reports, medical literature (clinical trial data) and multiple agency data sources and spontaneous reporting system (SRS) to monitor adverse drug effect patterns potentially indicative of public health concern.
Where does spontaneous report system (SRS) receive info about ADR’s ?
- SRS receives adverse drug reaction derived from health care providers and hospitals.
What is an example of a drug that showed a rare adverse effect?
When adverse effect is very rare, may require millions of prescriptions before an awareness of its existence emerges. Example: terfenadine
Why was the antihistamine terfenadine withdrawn?
Mid-1990s antihistamine terfenadine was withdrawn following a growing awareness that drug could evoke the life-threatening cardiac syndrome, torsade’s de pointes (TdP) in healthy patients.
Perception only cardiac/cardiovascular compounds were considered to possess such tendency.
What was the problem with terfenadine?
Problem was terfenadine, a non-cardiovascular drug, had a low efficacy to induce TdP making it so rare an event that it required several mil prescriptions before its liability became suspected.
What was an indication for terfenadine?
Indication for which terfenadine was used (hay fever) is far from life threatening.
Risk (death) outweighs benefit (the amelioration of a runny nose, rosen 1996)
- Preclinical toxicology testing, as an approach involved determining the high-dose adverse event profile of a compound given at chronic toxic doses but wouldn’t have detected a rare lethal event liability at therapeutic dosage.
- Screening for TdP risk in animals or in phase 1/2 clinical investigations was not recognized as relevant or necessary in late 1980s and early 1990s.
- Magnitude of effect of terfenadine on QT interval is small and peak effects may exhibit a delayed onset.
- Problem could be avoided if , instead of routine toxicology a programmed of specific high throughput screening (HTS) for TdP liability had been utilized in every drug discovery at the time, but consideration of biomarkers for rare adverse event liability was no part of toxicology agenda in early 1990s.
