Lecture 6 - Drug Discovery Flashcards
Preclinical development
Ensure you are developing a drug that has a suitable target for the disease
Why is it necessary to have appropriate formulation of a drug?
Aid it’s absorption
Drug discovery
Target selection Lead finding Lead optimisation Pharmacological profiling (2-5 years)
Preclinical development
Pharmacokinetics Short term toxicology Formulation Synthesis scale up (1.5 years)
Clinical Development: Phase I
Pharmacokinetics Tolerability Side-efffects in healthy volunteer
Clinical Development: Phase II
Small-scale rials in patients to assess efficacy and dosage Long-term toxicology studies
Clinical Development: Phase III
Large scale controlled clinical trials
Regulatory Approval
Submission of full date and review by regulatory agencies (1-2 years)
Phase IV
Post marketing surveillance
Main aims of pre-clinical
Pharmacology Toxicology
Subjects of pre-clinical
In vitro, laboratory, animals
Main aims of Phase I
Clinical pharmacology and toxicology Drug metabolism and bioavailability Evaluate safety
Subjects of Phase I
Healthy individuals and/or patients
What is the main aim of phase II?
Initial treatment studies Evaluate efficacy
Subjects for phase II ?
Small number of patients
What is main aim of Phase III?
Large randomised controlled trials Comparing new to old treatments Evaluate safety and efficacy
Subjects for phase III?
Large number of patients
What is the main aim of Phase IV?
Post-marketing surveillance Long term safety and rare events Yellow card scheme
Subjects of Phase IV?
All patients prescribed the drug
Drugs acting on GPCR have what percentage of market value?
50%
what do current drugs interact with?
Only a fraction of the available receptors
What do other functional proteins include?
Other receptors, enzymes, transport proteins
What are targets?
Proteins in the patient body associated with disease Identify which proteins are relevant
What are the methods utilised to identify lead compounds?
Synthetic or medicinal chemistry
How to identify lead compound?
Put them through high-throughout screening (HTS) Purified proteins are target
Fluorescence-based assay
Preferred in terms of how quickly they can give results on time scale basis
A lot of high-throughout screening is what?
Automated
What does HTS allow researchers to do?
Identify active compounds, antibodies or genes that modulate a biomolecular pathway
Filter down compounds
See which one produces a desired effect Look at the affinity of a compound for a receptor that generate a dose response curve
Lead compound
Prototype chemical with biological activity May not have all desired qualities of target drug Might have undesired properties
How do you narrow down 1000s of compound into a single molecule?
High-throughout screening Silicon profiling (computer modelling)
Efficacy in disease model
Cell culture model Use cells that are cultured to express receptor of interest Certain strains of laboratory rats are bred because they are spontaneously hypertensive As they age: develop hypertensive profile
What is the hypertensive profile used for?
To investigate the potential efficacy of drugs used for the treatment of high blood pr sure or hypertension
What can high dosage of drug be?
Poisonous
Maximal response EC50
Desired effect
How does undesirable effect emerge?
As the drug concentration increases
Therapeutic index
Measurement of drug safety
Therapeutic index
Indication of separation between 2 EC50
Low therapeutic index
Little separation
What does non life-threatening disorder often demand?
High therapeutic index
What may life-threatening disorder be able to tolerate?
Side effects
What are the preclinical development?
Safety pharmacology Preliminary toxicology Pharmacokinetic testing Chemical and pharmaceutical development
Where does toxicology start?
Non-GLP (non-good laboratory practice)
What is GLP used for?
New drug application
Who does the toxic exploratory toxicology inform?
Regulatory toxicology
Which toxicology is more intensive?
regulatory
What is the Ames test used to screen?
Chemicals that may be mutagens
What does Ames test use?
Bacteria to identify potential carcinogen
What is the first steps of Ames Test?
Selection of the suspected mutagens
Second step of Ames test
The selected mutagens is mixed with rat liver extract (stimulate body chemisry)
Third step of Ames Test
Expose bacteria to mutagen-rat liver mix
When is the first submission to the regularity authorities madeV
Before a drug is taken into preclinical studies phase of the drug developmental process
Where are regulatory authorities found?
Different countries/ different regions
Phase I Trial Design
Small group of volunteers (20-80) Subjects intensively monitored for signs of toxicity: ECG/blood pressure/heart rate/Liver and Renal function/ Blood/ Urinalysis Tolerability Pharmacokinetic properties Pharmacodynamic effect “proof of concepts”
What lead compound was developed an anti-inflammatory found in pre-clinical settings?
TGN1412
What compound is used in analgesics?
BIA 10-2474
Phase II / initial patient studies
Study patients with the disease (100-300) Typically performed in hospital clinic setting with experienced clinic investigator Determine pharmacodynamic effect, establish dose regimen to use in definitive Phase III studies Completion allows determination of whether initial hypothesis was correct (drug will treat condition X)
Phase III - large scale Efficacy Trials
Multi-centred trials involving upwards of 1000 patients Usually double blind, randomised trials comparing with existing standard drugs. Pharmacoeconmic analysis undertaken
Phase IV - post marketing surveillance
Long term monitoring of value of drug
