Week 3

Question 1

What are the main steps of drug development?

Answer 1

1. Candidate drug
2. Preclinical development e.g. animal studies
3. Clinical development (phase I-III trials)
4. Regulatory approval
5. Product
6. Post-marketing surveillance

Question 2

Why is pharmacokinetics explored in drug development?

Answer 2

• Yields insight into amounts and timings for drug doses
• Enables decisions about route of administration, starting dose, frequency of drug administration
• Determining metabolic effects on drugs

Question 3

What are the main two reasons drugs fail in the development stage?

Answer 3

1. Efficacy

2. Toxicology

Question 4

What is systemic toxicity?

Answer 4

• Reversible or irreversible injury to organs/tissues/cells

- Can be acute (seen after one dose) or chronic (seen after multiple doses)

Question 5

What is reproductive toxicity?

Answer 5

• Damages germ cells
• Damages developing foetus (tetarogenic)
• Impacts fertility

Question 6

How is acute toxicity tested?

Answer 6

• Tested in preclinical animal studies
• A single dose (3 different levels) given to 2 different species
• Test animals oberved for mortality, clinical signs and autopsied to determine target organs
• Can determine the no adverse effect level (NOAEL) and the maximal tolerable dose (MTD)
• Can also determine the therapeutic index and gender based differences in reactions

Question 7

How is chronic toxicity/carcinogenic potential tested?

Answer 7

• Tested in preclinical animal studies
• Chronic dosing at 3 levels (low, medium, high) is given to 2 animal species
• Generally carried out as lifetime dosing e.g. 2 years in rats/mice
• Cumulative effects observed including changes to histopathology and incidence of tumours

Question 8

How is teratogenic toxicity tested?

Answer 8

• Uses 2 mammalian species
• Animals exposed prior to mating to determine effect on reproductive capacity
• Animals exposed during pregnancy to determine effect on implantation and organogenesis of the foetus

Determines effects on:

• Gamete development
• Pre- and post- implantation viability
• Parturition (birth) effects
• Lactation effects
• Viability and morphology of foetus/neonate

Question 9

What are 2 non-animal toxicity screens?

Answer 9

1. Toxicogenomics:
   - Microarray analysis
   - Simultaneous measurement of changes in expression of a large number of genes (especially human cancer causing genes) after exposure to test drug
2. Ames test:
   - Uses a bacterial strain of Salmonella unable to synthesise histidine that requires a histidine supplemented with his to survive
   - A suspected mutagen (the drug) is introduced to the test culture in addition to liver extract (to test for metabolites)
   - This test culture is incubated on non-histidine media
   - If the test culture grows the bacteria have mutated back to his+ phenotype and the drug is a mutagen

Question 10

Give an overview of the 4 stages of clinical trials:

Answer 10

1. Phase I: small group of healthy subjects, determines initial human safety of drug, pharmacokinetics of drug (potential dosing regimes)
2. Phase II: small group of affected people, determines safety and efficacy of drug in people with target disorder- early studies can be open label, later studies comparative
3. Phase III: a large group of affected people, acquires definitive evidence that drug is safe and effective against illness, tends to be longer term than phase II, includes comparative studies and double blind/crossover studies
4. Phase IV: post-marketing phase, periodic analysis of safety data including adverse drug reactions

Question 11

When do most drugs fail in clinical trials?

Answer 11

• Phase II

Question 12

What is the risk benefit ratio?

Answer 12

• Defined with the NNT concept
• The NNT concept is the number of people that are needed to treat in order for an effect (beneficial or unwanted) to be observed i.e. if you need to treat 5 people in order to see a benefit, the NNT for benefit = 5
• For an ideal drug the NNT for benefit should be as low as possible and the NNT for unwanted effects should be as high as possible

Question 13

What are traditional antidepressants targeting?

Answer 13

• These antidepressants aim to increase the concentration of monoamine neurotransmitters e.g. dopamine, adrenaline and serotonin by:
• Inhibiting monoamine oxidase e.g. MAOs
• Inhibiting reuptake channels on presynaptic membranes e.g. SSRIs, TCAs

Question 14

What is the most commonly animal model for depression?

Answer 14

• A forced swim test
• The time spent immobile by the animal is measured compared to time spent swimming/climbing
• Not great but adequate predictive value

Question 15

What is a novel target for an antidepressant?

Answer 15

-MT1 receptor agonist

Question 16

What is the current average placebo effect?

Answer 16

30-40%

Question 17

What is rheumatoid arthritis caused by?

Answer 17

• RA occurs when the immune system attacks the synovial membrane causing synovitis, an inflammation of the joint lining that causes a destruction of bone and cartilage
• Someone with rheumatoid arthritis has a high density of cells within their joint lining tissue (that is normally devoid of cells in a healthy individual)
• The cells that cumulate within this tissue are white blood cells including macrophages, dendritic cells, lymphocytes and mast cells
• Macrophages present in the synovial space develop into osteoclasts due to cytokines present and erode bone

Question 18

How is rheumatoid arthritis treated?

Answer 18

• RA is treated with immunosuppressant drugs including methotrexate, prednisolone and plaquenil as well as some biological disease modifying drugs

Question 19

Why do drugs fail after approval?

Answer 19

• When drugs are used to treat the general population a much wider range of people will be treated with the drug which can lead to a number of different interactions and effects (different age groups, ethnicities, co-morbidities, other drugs, difference in disease severity, varying levels of compliance)
• unpredictable on-target effects e.g. Vioxx

Question 20

What is a nocebo effect?

Answer 20

• Nocebo effect: when symptoms are worsened/side effects occur when a placebo is administered- if a patient receives a drug that has a possible side effect they can fixate on it and report that they are experiencing it; even if they are not