W2 The long journey Flashcards
What is the drug name for aspirin?
2- acetoxybenzoic acid
What is the definition of a drug?
What is the definition of a medicine?
Drugs- Chemical substances used to diagnose, treat or prevent disease, or are intended to affect the structure or any function of the body.
Medicines- Delivery systems for administering drugs to the body in a safe, effective, accurate, reproducible and convenient manner.
Excipients definition?
Substances other than the drug that are added to help deliver the medication to your system
Give some examples of excipients (5)
Answers are any of the below:
* Fillers
* Binders
* Disintegrants
* Glidants
* Colouring Agents
* Antiadherant
* Lubricants
* Coatings
* Preservatives
* Antioxidants
* Flavouring Agents
* Sweetening Agents
* Sorbents
* Solvent and Co-solvent
* Buffering Agents
* Chelating Agents
* Viscosity Imparting Agents
* Surface Active Agents
* Humectants
What is an API?
Active Pharmaceutical Ingredient
What are the 6 steps of the drug development process?
Basic research
Early discovery
Pre clinical
Clinical development
Review
Post market monitoring
What occurs during Basic Research?
Target identification-
Target validation-
- Target identification- Gene/protein that plays a significant role in a disease
- Target validation- Disease association, cell based models, protein interactions
What is classed as a ‘Good target’?
Has a therapeutic benefit with an acceptable safety window
Early discovery:
What happens during the Hit discovery process?
(4 steps of screening)
- Screen a large no. of compounds (high throughput screening HITS)
- Screen natural extracts
- “Copy” the structure of any endogenous/ any known ligands: ligand-based methods
- Computer-aided structure-based design (virtual screening)
What happens during the Hit process and Assay development?
- Selection and design of structural analogues with improved activity
- Confirmation of the core structures of the molecules
What is a Hit compound?
Molecule that shows desired type of activity in a screening assay
What are Assays?
Test systems that evaluate the effects of the new drug candidate at the cellular (in vitro) and biochemical levels (ELISA)
Analogues of HITS can be synthesised and tested in order to determine an initial SAR (structure-activity-relationship) of the compounds
- Selection of design of structural analogues with improved activity
- Confirmation of the core structures of the molecules
What happens in the Hit to Lead process and Lead Optimisation?
What is improved?
The best Hits molecules are further optimised into a lead compound.
Improve potency, selectivity and physicochemical properties (e.g. solubility and stability).
The best compounds are selected (2-20)
What assays are tested during early discovery- hit to lead process? (3)
-In vitro assays- activity against target
-In vitro assays to study off-target effects (i.e. cytotoxicity and genotoxicity)
-In vitro physicochemical and in vitro Pharmacokinetics (PK) studies (ADME-
absorption, distribution, metabolism and excretion).
What is Lead?
A chemical compound that shows promise as a treatment for a disease
What is studied during In vitro physicochemical and In vitro Pharmacokinetics (PK) study?
ADME- absorption, distribution, metabolism and excretion
In vitro assays test the…
- Activity against target
- Off target effects e.g. cytoxicity and genotoxicity
What happens during pre-clinical stage?
Lead compounds are tested on non-human subjects (in vivo animal models)
- In vitro tests are performed on mice, hamsters, dogs, chimpanzees
- In vivo ADME (adsorption, distribution, metabolism, excretion)
- Best dosage is found
- Formulation and Administration is found
e.g. oral, topical, parenteral
What happens during clinical development?
Phase 1 2 and 3?
3 Phases:
Phase 1- 100 HEALTHY volunteers tested, ADME and side effects observed. 66.4% chance of entering P2
Phase 2- 100-500 PATIENTS with DISEASE. Assess drug safety and efficacy. Pt receives placebo or standard drug. 58.3% to enter Phase 3
Phase 3= 1000-5000 PATIENTS with DISEASE. Generate data about safety, efficacy and overall benefit-risk relationship of the medicine. 59% chance to be approved.
How long can clinical development last?
What % probability to be approved at this stage?
6-7 years
14%
What happens during the Review stage?
Data submitted to the FDA (USA) MHRA (UK) or CFDA (China)
They decide whether to approve drug
2/5 drugs that reach P2 still fail to win approval
This can be accelerated/fast track for a priority review (0.5-2 yrs) e.g. covid vaccine
Why can clinical trials fail
Due to problems with:
Funding
Toxicity
Efficacy
PK properties
Bioavailability
Patient recruitment, retention, enrolment
What happens during post-marketing monitoring?
Phase lV
Safety surveillance
- During phase lV, manufacturers and HCP report problems with approved drugs
(extra) Can lead to drug problems being recalled from market
e.g. alatrofloxacin= 2006 antibiotic caused serious hepatoxicity.
Flunitrazepam= 1991 France used as an abuse drug and as a rape drug
