Unit 3 - Drug Development Flashcards
Outline the four stages of the drug development process (each requires a short definition)
- Disease/target identification – to reveal a suitable target against a drug can be used to treat the disease
- Drug Discovery and development – The development and screening of potential agents using in vitro and in vivo models
- Clinical trials – to determine that a drug is effective against a specific disease with tolerable side-effects
- Manufacturing and marketing – the up-scale of manufacture after clinical trials and associated packaging considerations
What are the 3 factors associated with drug development process:
- It is long – on average 12 years – clinical trials, identifying a pathway if the disease is rare/not-well understood
- It is expensive – on average £1.2bn
- High rate of attrition – high-throughput screening can mean you start with 1000’s of molecules but end up with one drug
What is the longest and most expensive phase of drug development
Clinical trial phase
What does MHRA stand for?
Medicines and health care products regulatory authority
What things are good for a potential drug target be?
- Must be potentially druggable (comes from good knowledge of structure/function usually from X-ray crystallography and modelling using in silico) – some sort of pocket that allows binding
- Validated in disease pathogenesis – that its association with the disease is causative rather than correlative – so inhibition can effectively inhibit disease progression
- Distinction from previously known targets and specificity to the disease – to limit side-effects
Discuss some of the ways in which ‘new drugs’ can be developed/discovered?
Chemical Modification/me-too drugs
This is where an existing drug structure is modified slightly to improve its activity e.g., potency, faster on-set, fewer side-effects, improved selectivity (like regorafenib from sorafenib multi-kinase inhibitor).
Compound libraries
Uses a library of 1000’s of molecules with a similar structure which can be screened using high-throughput screening to select the drugs with the best characteristics (affinity, ability to inhibit a molecule/process, cell death… etc).
Rational Drug Discovery
Designing a drug against a specific molecule/pathway implicated in a disease – like Tratuzumab and pertuzumab in HER2 amplified breast cancer.
Serendipity
Molecules that have been observed to have a specific event by chances, but are then interpreted scientifically – penicillin inhibits the growth of bacteria or vincristine in cancer
What are the advantages and disadvantages of me-too drug discovery
It can potentially improve characteristics of the drug (potency, half-life, side-effects) and is cheap
But this may reduce the incentive for novel drug discovery and sometimes these changes may only be small!
What factors are investigated during development screening?
In vitro – binding, phenotypic changes, drug interactions (CYPs), permeability, mutagenicity, PgP inhibition, interacts with hERG
In vivo – Metabolic/pharmacokinetic prolife, toxicity, drug interactions, BBB
This may be followed by modification cycles
In drug development what is GLP
Good laboratory practice – must be abided by all those working in drug development – ensures data is comparable, reliable and robust
What factors are investigated in clinical trials
- Pharmacokinetics - ADME
- Pharmacodynamics
- Safety and toxicology
- Efficacy – usually compared to standard treatment options
What does ADME stand for?
Adsorption, distribution, metabolism, excretion
Describe the phases of clinical trials
Phase 1 – Safety in healthy individuals
Phase 2- Safety and effectiveness in disease group
Phase 3- Effectiveness in larger disease groups
Phase IV – surveillance in large population after drug approval
Must abide by good clinical practice
What two phases in drug discovery require communication between pharmaceutical companies and regulatory agencies?
- After preclinical (for Phase I) – IND (investigational new drug) or CTA (clinical trial application) based on this data
- Seeking approval – NDA (new drug application) or MAA (marketing authorization application)
What factors may be involved in GMP?
Good manufacturing process- consistent and effective manufacturing, appropriate marketing, evaluation of the drug in Phase IV trial.
What must be done during the manufacturing and marketing phase of drug development?
Up-scale production – ensuring large quantities of this molecule can be made effectively and packaging considerations – light/temperature sensitivity, clear and understandable information.
What are the two types of bone metastases and what cells are involved in each and how these processes occur?
- Osteolytic – degradation of bone (breast) ->osteoclasts
Tumour cells secrete bone re-modelling factors like Cox-2 or IL-8(pre-metastatic niche) – which can acts directly on these osteoblasts or stimulate them to produce RANKL which interacts with RANK on osteoclast surface which leads to break down of the bone (and release of TFGβ which can stimulate breast cancers to produce more growth factors). - Osteoblastic – deposition of bone (prostate) – osteoblast
What molecular changes are associated with bone metastases (not viscous cycle)?
Osteoclasts have ruffled membrane and secrete cathepsin K’s to degrade bone which require an acidic pH – which is what this ruffles membrane does – in producing an enclosed environment for bone breakdown.
Discuss the various options for targeting bone metastasis in cancer?
Targeting the cytoskeleton to prevent these ruffles/attach tightly to bone (creating microenvironment)
Bisphosphonates can be used which inhibit farnesyl-diphosphate-synthase (in membrane localisation of rho/rac). Two side groups R1- helps bind calcium component and R2 can dictate potency
Inhibiting cathepsins
Odanacatib is a molecule that inhibits these enzymes, but was associated with arterial fibrillation
Inhibiting the interaction between RANKL and RANK by the anti-RANKL antibody denosumab
Describe the ways in which you would carry out target identification/validation?
- Look at its levels in tumour cells compared to normal cells; proteomics/gene microarray
- Gene overexpression/inhibition studies to look at changes in cell phenotype
What is a pharmacophore?
The minimum region of a drug that is essential for activity
