Drug Discovery and Development Flashcards
What is the rough drug development time-line spanning over 10-12 years?
Discovery and basic research (a couple of years)- working out the physical and chemical properties,
pharmacology in vitro.
Pre-clinical studies in animals (a couple of years).
Regulatory review (e.g. FDA)
Clinical testing (about 5-7 years)- phases 1, 2 and 3.
Regulatory review
Pre-launch activities (a couple of years)- scale up synthetic processes.
Launch
Post-marketing studies (phase 4)- adverse drug reactions being reported.
This process costs more than US $800 million (NZ $1 billion).
Name two recent examples of drug-drug interactions which lead to drugs being withdrawn from the market after successful clinical trials:
- Sorivudine- anti-viral, inhibition of 5-fluorouracil metabolism, lead to 15 fatalities in Japan.
- Terfenidine- anti-histamine when coadministered with ketoconazole (also grapefruit juice) leading to cardiotoxicity and a couple of fatalities.
Name two recent examples of unexpected toxicity which lead to drugs being withdrawn from the market after successful clinical trials:
- Troglitazone- for non-insulin dependent diabetes, lead to severe hepatoxicity (liver).
- Rofecoxib- selective inhibitor of COX-2 for chronic pain relief, withdrawn in 2004 due to increased risk of heart attack/stroke.
Name the properties crucial for the ultimate clinical success of a drug:
- ADME
2. Toxicity/toxicology
Name the 6 main reasons for failure during drug development, from the most frequent to least:
Inappropriate pharmacokinetics (39%) Lack of efficacy (30%) Animal toxicity (11%) Adverse effects in man (10%) Commercial reasons and misc (5% each)
Describe the first legislation recorded of drug regulation:
Apothecary Wares, Drugs and Stuffs ACT, UK 1540.
What drug contributed to the establishment of regulatory authorities for drug regulation worldwide?
Thalidomide in the early 1960s. Given to pregnant women to help with sleep and depression but lead to 10,000 babies being born with deformities. This may have been due to insufficient testing.
What are the six steps from regulatory authority to markets?
- Regulatory authority
- Regulatory guidelines
- Review of drug data
- Chemistry, pharmacology, toxicology, pharmacokinetics and clinical trials
- Decision to grant or refuse a product licence
- Marketing
Name three examples of drugs discovered from herbal/traditional remedies:
Morphine from opium poppy.
Digoxin/digitoxin from foxgloves.
Salicyclic acid (aspirin) from willow bark.
Name two drugs discovered from empirical approach (use of model in vitro):
Development of models felt to be predictive of activity, leading to screening of large numbers of compounds.
Anticancer drugs
Cyclosporin (immunosupressant)
How are drugs discovered through rational drug design, and what are two examples of drugs designed this way?
Understanding the cellular/molecular basis of diseases such as receptors allows the use of computational technology to create a 3D structure of receptor to design agonist drug.
E.g. propanolol (B blocker) and cimetidine (H2 antagonist)
Prodrugs/analogs/metabolites of existing drugs are used in drug discovery. Name two examples of drugs in this class:
Aspirin (salicyclic acid) is irritating to the gut, but acetyl salicyclic acid is better.
Paracetamol (phenacetin) is toxic to the kidney.
Name three drugs discovered by serendipity (chance observation):
Penicillin, valpoate and sildenafil (Viagra).
How can genomics be used in drug discover?
Information of genes can be used to identify drug targets e.g. gene therapy and siRNA.
What are preclinical studies?
In vitro/in vivo animal studies. They focus on the biological activity, toxicity and safety evaluation, PK/PD and ADME studies.
