lecture 20 - repurposing of medicines Flashcards
what is repurposing?
The act of taking a drug** intended to treat one patient population, and demonstrating its efficacy in the treatment of a completely different group of patients
what are reasons for failure in clinical trials
- efficacy
safety, commercial, operational, strategy
what are the benefits of drug repurposing ?
Opportunity of new indications for existing drugs
Additional revenue on initial capital investment
Accelerated patient access to effective treatments
what is serendipity meaning noun?
The occurrence and development of events by chance in a happy or beneficial way.
describe sildenafil on target effect
Initially investigated by Pfizer as potential antihypertensive drug.
Early studies observed vasodilation and reduce platelet aggregation mediated by inhibition of PDE5
Research focus shifted to treatment of angina
Unexpected side effect emerged during clinical trials - penile erections
describe the physiology of an erection
It starts with sexual stimulation which leads to the production of NO. NO activates guanylate cyclase, an enzyme that converts GTP into cGMP. cGMP plays a key role in relaxing arterial smooth muscle, which results in increased blood flow to the penile tissue.
The enzyme PDE5 normally breaks down into 5’ GMP, which would lead to the loss of smooth muscle relaxation and thus ending the erection. However, the drug Sildenafil, which is a PDE5 inhibitor, blocks the action of PDE5, resulting in sustained levels of cGMP and thereby promoting and maintaining an erection.
describe the repurposing of the drug sildenafil for erectile function vs anti hypertensive
Viagra 25mg tablet core: fro erectile
Microcrystalline cellulose
Calcium hydrogen phosphate (anhydrous)
Croscarmellose sodium
Magnesium stearate
Film coat:
Hypromellose
Titanium dioxide (E171)
Lactose monohydrate
Glycerol triacetate
indigo carmine aluminium lake (E132)
Revatio 20mg tablet core: antihypertensive
Microcrystalline cellulose
Calcium hydrogen phosphate (anhydrous)
Croscarmellose sodium
Magnesium stearate
Film coat:
Hypromellose
Titanium dioxide (E171)
Lactose monohydrate
Glycerol triacetate
give examples of software purpose in drug discovery
Docking
Binding site prediction
Pathway analysis
Drug design
Pharmacokinetic parameters
Genomics
what is data mining
Literature mining is used to extract disease-relevant information from such databases.
The process can range from simple database searches for a disease to the use of artificial intelligence, such as semantics-based networks, to uncover connections between unrelated studies.
describe the ominous approach
Characterization and quantification of pools of biomolecules that define the structure and function of an organism
typical comics approach Identify a drug signature that is the opposite of the disease signature
what are cautions relating to data driven approaches
Databanks have tremendous potential but they are not a panacea
Results depend upon quality of available data and the algorithms that informatic software applies
Can produce a bewildering array of outputs
Still need a robust screening matrix and the input of subject experts
describe high throughput screening
compounds screening, secondary assays and in vivo analysis. Many issues with this type of screening e.g. solubility, prodrugs, chemical stability, allosteric effects; cell selection, species selection (vs toxicity – see previous thalidomide example)
what are drug repurposing outcomes?
Known target – new therapeutic indication
New target – new therapeutic indication
New target – known therapeutic indication
what are drug repurposing conclusions ?
Need to better identify target populations - incorrect subject selection will mislead repurposing activity
problematic for ‘syndromes’ which have complex of symptoms and physical findings but their cause is not understood e.g. Irritable Bowel Syndrome (IBS) is an umbrella term which may have different aetiologies
Repurposing existing drugs for new indication(s) may involve different dosing regimens and routes of administration to realise a benefit. This still remains a significant risk and bottleneck.
Repurposed drug will be used in a different patient group with different pathophysiology therefore the side effect profile or risk/benefit of the drug could change
a need for better integrative platforms for data analysis that can offer more refined interrogation with ‘user friendly’ interfaces
Wider data sharing between industry, healthcare and academia and formalisation of consortia, particularly for phase II – IV trials that have been discontinued so that repurposing can be undertaken at earlier stages
need new mechanisms to incentivise drug repurposing e.g. change in the regulatory and intellectual property environments. This is particularly important when you consider that many of the repurposing activities are directed at finding new treatments for rare diseases where patient populations can be very small.
