Bps Lecture 14 - Drug Development

Front 1

What is the typical development time of a drug from identification of a lead to approval for sales?

Back 1

8-15 years.

Front 2

What are the 4 major time phases of drug development? How many years (on avg.) per?

Back 2

1. Pre-clinical R&D (3-7 yr)

2. Clinical trials (4-8 yr)

3. New drug application review (1-2 yr)

4. Post-marketing surveillance

Front 3

What happens during pre-clinical R&D? (5 stages)

Back 3

1. Disease is studied (how it works, mechanisms, etc)

2. Development of a bio-assay

3. Identification of a lead compound

4. Chemical synthesis to improve the lead and identify a viable drug candidate

5. Toxicity testing in animal models

Front 4

What happens during post-marketing surveillance? (2 main things)

Back 4

- Adverse reaction reporting (agencies look @ these reports to determine risk factor, validity, etc)

- Market surveys

Front 5

Define IND.

Back 5

Investigational New Drug

Front 6

What 3 factors does Health Canada look at when considering an IND for the market?

Back 6

- Manufactered under GMP

- Knowledge of the pharmacokinetics of the drug (ADME)

- Safety and efficacy (as shown in clinical trials)

Front 7

What is involved in phase 1 clinical trials? What is the time frame?

Back 7

Involves healthy patients (~20) and determines safety.

- 1-2 months

Front 8

What is involved in phase 2 clinical trials? What is the time frame?

Back 8

Involves small (<50), highly controlled group of patients; determines efficacy.

- 3 months - 1 year

Front 9

What is involved in phase 3 clinical trials? What is the time frame?

Back 9

Involves large, diverse group of patients; determines efficacy AND safety.

- 3-8 years

Front 10

What is the approximate success rate of compounds in phase 1 clinical trials?

Back 10

2/3 pass safety test (or ~600 out of 1000)

Front 11

What is the approximate success rate of compounds in phase 2 clinical trials?

Back 11

2/3 pass efficacy test (or ~400 out of 1000)

Front 12

What is the approximate success rate of compounds in phase 3 clinical trials?

Back 12

1/10 pass safety/efficacy test (or ~50 out of 1000)

Front 13

What is the overall success rate of compounds undergoing the clinical trials?

Back 13

50/1000 or 5% success rate

Front 14

What is the most expensive step in drug development?

Back 14

Clinical trials (increases with each phase; phase 3 is highest)

Front 15

What are the 4 important guidelines for 'weeding out' unsuccessful compounds (prior to clinical trials)?

Back 15

- Apply ADME test

- Apply Lipinski rules for ''drug-like molecules''

- Remove compounds with suspected toxicity

- Use computer-based screens

Front 16

Why aren't all adverse side effects discovered in clinical trials?

Back 16

- Genetic diversity in a large population makes it impossible to test against all these adverse effects!

Front 17

What type of warning can be found on drugs with severe side effects?

Back 17

Black box warning

Front 18

What are the 6 steps of the drug discovery process?

Back 18

1. Target identification

2. HTS (High Throughput Screening)

3. Active-to-Hit (AtH)

4. Hit-to-Lead (HtL)

5. Lead Optimisation (LO)

6. Candidate Drug (CD)

Front 19

What 5 biological mechanisms are used in the top 50 drugs (by worldwide sales)? List IN ORDER.

Back 19

1. Enzyme inhibitors (38%)

2. Receptor Antagonists (24%)

3. Receptor Agonists (12%)

4. Biologicals (10%)

5. Ion Channel Modulators (8%)

Front 20

What is the mechanism of Lipitor? What does it treat? Who manufactures it?

Back 20

- HMG CoA inhibitor (enzyme inhibitor)

- Cholesterol

- Pfizer

Front 21

What is the mechanism of Nexium? What does it treat?

Back 21

- Proton-pump inhibitor (enzyme inhibitor)

- Anti-ulcer

- AstraZeneca

Front 22

What is the mechanism of Plavix? What does it treat?

Back 22

- Anti-platelet (receptor antagonist)

- Thrombosis (blood clotting)

- BMS/Sanofi

Front 23

What is the mechanism of Norvasc? What does it treat?

Back 23

- Calcium channel blocker (ion channel modulator

- Hypertension

- Pfizer

Front 24

What does a receptor agonist do?

Back 24

Binds to a receptor to increase a desired function.

Front 25

What does a receptor antagonist do?

Back 25

Binds to a receptor to decrease an undesired function.

Front 26

What is HTS?

Back 26

High Throughput Screening

- Industrial process using robotics, data processing, etc, to conduct millions of tests to rapidly identify a lead compound

Front 27

Describe radioligand binding assays.

Back 27

- Beads with receptors/antibodies that will bind to compatible molecule

- If a molecule is able to bind to receptor, the bead activates and light is produced

Front 28

What is SPA?

Back 28

Scintillation Proximity Assay

- First homogenous HTS tech

Front 29

What are the advantages of SPA?

Back 29

- ~30k compounds/day in 384 microtitres

- Easy to automate and no significant v of aq. waste

Front 30

What are the disadvantages of SPA?

Back 30

- Radioactive (safety headaches)

- Long read times (>30min/plate)

- Susceptible to quench artifacts

- Not applicable to all targets

Front 31

What is FLIPR?

Back 31

Fluorescent Imaging Plate Reader

- Real time imaging of 96 & 384 well plates

Front 32

What is FLIPR used for?

Back 32

- HTS calcium flux assays

- Ion channel screening

Front 33

How does FLIPR work?

Back 33

- Cells are loaded w/ fluorescent dye sensitive to Ca2+ (fluorine-3)

- Addition of receptor agonist stimulates Ca2+ release and results in increases fluorescence

- Whole plate read simultaneously using cameras at base of microtitre plates

-

Hint 33

Front 34

What is a colorimetric HTS?

Back 34

Uses single compounds bound to beads.

These compounds would only bind a dye if they are also able to bind a receptor of interest.

So, in the end have a bunch of beads with only some stained.

Front 35

Where are compounds isolated from? Name 4 sources.

Back 35

- Plants

- Microorganisms (i.e. bacteria)

- Marine organisms (i.e. sponges, molluscs)

- Synthetic efforts by academic + industrial organic chemists

Front 36

What are combinatorial libraries? What is one pro and one con?

Back 36

- Using combinatorial chemistry, combine a bunch of different compounds in class A (i.e. a bunch of amines) with a bunch of different compounds in class B (i.e. carboxylic acids).
These undergo same reaction to prouduce a compound (i.e. a bunch of different amides).

Pro: Large libraries can be generated

Con: Little diversity;

Difficult separation of active compounds found

Front 37

List 3 advantages of NP based libraries.

Back 37

- High diversity of chemical structures in each extract

- Active compound has a unique structure

- Compounds are likely bioavailable

Front 38

List 3 disadvantages of NP based libraries.

Back 38

- Extremely complex mixtures

- Small amounts of active ingredient

- Difficult to identify active component

Front 39

How is a "diversity oriented" library created?

Back 39

- Take a biological NP structure and modify it (i.e. via alkylation, oxidation, etc)

- This creates hundreds of other compounds

Front 40

What is ethnopharmacology?

Back 40

Study of the use of plant-derived materials in traditional societies for maintaining/improving health.

Front 41

___% of the world uses ethnopharmacology, and ___% of new cancer drugs + antibiotics are NPs inspired by ethnopharamacology.

Back 41

80% of the world uses ethnopharmacology, and ~50% of new cancer drugs + antibiotics are NPs inspired by ethnopharamacology.