Drug Discovery Flashcards
How do you make a drug candidate
- High throughput screening
- Structure activity relationships
Which properties does the drug need to have
- Type of activity
- Selectivity of action
- Bioavailability
- Safety
what is a receptor
- A cellular macromolecule or assembly of macromolecules that are concerned directly and specifically in chemical signalling between and within cells
what do most drugs interact with
G protein coupled receptors
describe the overview of drug discovery process
- Failure usually happens at the front end
- Spend £100s of millions, 1/13 compounds entering preclinical development makes it
- Takes about 15 years – most likely end up in failure
1. Target selection
2. Target validation
3. Lead discovery
4. Lead optimisation
5. Preclinical development
6. Clinical development
7. Regulatory approval
How does high throughput screening works
- How to find a new molecule
- Automated robots small sets based on knowledge of target and design, takes about 6 month
- After 3 more moths, there are confirm HTS and pharmacology, creates a new compound
- Takes 9 months in total
How do you develop new drugs
- Straight from known compounds
- DNA encoded library screening
- Fragment based lead generation
- Focused screen
- Structure based design
- Random high throughput screen
describe the process of screening
- Potency – is it potent enough
- Selectivity – what else does the molecule affect, side effects
- Pharmacokinetics – how long does it staying the body, how does it get into the brain, will it get past acid/peptidases in stomach, metabolites
- Pharmacodynamics – efficacy in vivo
- Efficacy in animal disease model
- Safe when given acutely
describe selectivity of action
- defines the ability of a drug to act against a range of receptors, channels and enzymes – activity may be associated with unwanted side effects
- drugs can be poisonous
- risk: benefit analysis – non life threatening disorders often demand a high therapeutic index (want drug to be really safe), life threatening disorders may be able to tolerate side effects (can trade of side effects for helping you survive)
describe the desired pharmacokinetic properties
- this is how the body affects a specific chemical after administration
- routes of drug administration – they all have pharmokinetic advatnages and disadvantages
describe what the drug needs to survive
If orally-administered
• Needs to survive the acid/ peptidase in the stomach
Drugs are metabolised
• Especially by the liver
• Cytochrome P450 enzymes – oxidse and degrade drugs – design molecule to overcome this
• Metabolites can have biological activity
Drugs or their metabolites are excreted
• Urine
• Faeces
Restricted drug distribution
• Blood-Brain Barrier
• Restriction to the gut lumen
what does the toxicology and safety assessment do
this is to determine safe doses of exposure in humans
What does the toxicology and safety assessment include
In vitro includes - Mutagenicity in bacteria (Ames test) - Mammalian microsomal enzyme test In vivo includes - Acute oral - Sub chronic (14-180 days) - Toxicity to reproductive systems (2 generations; birth defects) - Chronic studies, including 90 day sub-chronic study and 2 year chronic study (carcinogensis) - Effects of metabolites
what is phase I about
tolerance and safety
what is phase II about
proof of concept and getting the dose right
what is phase III about
cost of money
Describe Phase I
- Small numbers
- Imeediate response to a new drug
- Small doseases
- Escalated dose until effect seen
- Tolerability assessed
- Pharmackokientics studied
- Short term studies
- Single dose per volunteer usually
describe the accident that happened with phase I
- 90 people tested, one dead, 5 hospitlaised
- Biotrial – French contract research organisation
describe phase II
- Patient groups
- Small numbers studied intensively
- Pharmacological assessment – kinetics
- Efficacy – does it work in the clinical setting
- Tolerability in target group – unwanted effects
describe Phase III
- More patients
- Studied less intensively
- Usually controlled designs
- Compare versus established therapy or placebo
- Identify optimum dose
- Checks methods of administration
- Establish indications for the drug
- Prepare for licensing of the drug
- Must establish a case for the new drug
- Negotiations with regulators
- Additional studies if required
what is the problem with phase III
- 90% of total drug development is greater than 1 billion pounds
how is the authorisation process determined
- Application from pharmaceutical company
- Detailed supporting dossier
- Assessment by toxicologist, pharmacist and physician
- Assessment report reviewed by expert advisory committee
- Decision to grant or refuse made by competent authority
what do they make decisions based on
- Safety
- Quality
- Efficacy
- Cost is not taken in to account
how does patent protection work
- Novel intellectual property protected from patenting
- After a patent is filed it is not published for 18 months
- After a patent is granted the holder has exclusive rights for 20 years
- The invention is usually long before commercialisation so time to recover costs and make profits takes 5-12 years
what is phase 4
this is post marketing surveillance
describe phase 4
- After initial licensing
- Extend indications for drugs
- Refine target group
- Interaction studies – perhaps responding to case reports
- Why do some fail to respond
- Continuous process
what are the bad things that are associated with medicine
- 5% of all hospital admissions are due to ADRS
- 5% of all hospital patietns suffer an ADR
- 5th most common cause of death
- 197,000 deaths in EU from ADR
- Cost of ADRs cost 79 billion euro a year
- This can be reduced by pharmacovigilance
justifying R and D
R&D costs are huge
- Only 3 in 10 are profitable with one of those becoming a blockbuster with $1bn revenue a year
- Many more do not make it to market ]
Wider view needs to be used
- Use drugs, don’t need surgery, can continue to support family
what are the 3 examples of how drugs can go wrong
- sustainability
- choosing the right and wrong indication
- trial design can trip you up
describe sustainability
Sustainability
- Antibiotic resistance is spreading
- Pharmaceuticals companies no longer producing antibiotics
How do we get around this
- Propose a new commercial model
- This means that return on investment is not based on number of prescriptions sold but on lump sum from government or group of governments therefore no need to market or encourage people to use it
describe choosing the right and wrong indication and how that is critical
- 5-HT3 – stopped nausea and vomiting of chemotherapy, but it caused mild constipation
- People started dying causes was not clear
- Introduced later but under severe restrictions
- Positive revolutionized cancer treatment, but people died and funding lost
describe how trial design can trip you up
Trail design can trip you up – neuropathic pain
- Usually poorly treated
- 84 randomised control trials using 92 drugs versus a placebo
- Baseline ratings did not change over 23 years
- Placebo response over time increased and pain baseline decreased so placebo works better than the drugs
- Longer trials, larger trials, greater contrast research organisation caused increase in placebo responses
Cost of drugs
Some drugs cost up to $100,000 for a full course, but cost of manufacturing is a tiny fraction of this
