W2 The long journey

Question 1

What is the drug name for aspirin?

Answer 1

2- acetoxybenzoic acid

Question 2

What is the definition of a drug?
What is the definition of a medicine?

Answer 2

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.

Question 3

Excipients definition?

Answer 3

Substances other than the drug that are added to help deliver the medication to your system

Question 4

Give some examples of excipients (5)

Answer 4

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

Question 5

What is an API?

Answer 5

Active Pharmaceutical Ingredient

Question 6

What are the 6 steps of the drug development process?

Answer 6

Basic research
Early discovery
Pre clinical
Clinical development
Review
Post market monitoring

Question 7

What occurs during Basic Research?
Target identification-
Target validation-

Answer 7

1. Target identification- Gene/protein that plays a significant role in a disease
2. Target validation- Disease association, cell based models, protein interactions

Question 8

What is classed as a ‘Good target’?

Answer 8

Has a therapeutic benefit with an acceptable safety window

Question 9

Early discovery:
What happens during the Hit discovery process?
(4 steps of screening)

Answer 9

1. Screen a large no. of compounds (high throughput screening HITS)
2. Screen natural extracts
3. “Copy” the structure of any endogenous/ any known ligands: ligand-based methods
4. Computer-aided structure-based design (virtual screening)

Question 10

What happens during the Hit process and Assay development?

Answer 10

1. Selection and design of structural analogues with improved activity
2. Confirmation of the core structures of the molecules

Question 11

What is a Hit compound?

Answer 11

Molecule that shows desired type of activity in a screening assay

Question 12

What are Assays?

Answer 12

Test systems that evaluate the effects of the new drug candidate at the cellular (in vitro) and biochemical levels (ELISA)

Question 13

Analogues of HITS can be synthesised and tested in order to determine an initial SAR (structure-activity-relationship) of the compounds

Answer 13

1. Selection of design of structural analogues with improved activity
2. Confirmation of the core structures of the molecules

Question 14

What happens in the Hit to Lead process and Lead Optimisation?

What is improved?

Answer 14

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)

Question 15

What assays are tested during early discovery- hit to lead process? (3)

Answer 15

-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).

Question 16

What is Lead?

Answer 16

A chemical compound that shows promise as a treatment for a disease

Question 17

What is studied during In vitro physicochemical and In vitro Pharmacokinetics (PK) study?

Answer 17

ADME- absorption, distribution, metabolism and excretion

Question 18

In vitro assays test the…

Answer 18

• Activity against target
• Off target effects e.g. cytoxicity and genotoxicity

Question 19

What happens during pre-clinical stage?

Answer 19

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

Question 20

What happens during clinical development?

Phase 1 2 and 3?

Answer 20

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.

Question 21

How long can clinical development last?
What % probability to be approved at this stage?

Answer 21

6-7 years
14%

Question 22

What happens during the Review stage?

Answer 22

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

Question 23

Why can clinical trials fail

Answer 23

Due to problems with:
Funding
Toxicity
Efficacy
PK properties
Bioavailability
Patient recruitment, retention, enrolment

Question 24

What happens during post-marketing monitoring?
Phase lV

Answer 24

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