KJB - Pharmacogenetics

Question 1

Failure of drugs is usually at which stage?

Answer 1

Clinical stage

Question 2

What is the most expensive stage and why?

Answer 2

Clinical trials is most expensive stage due to hiring of health and non healthy volunteers

Question 3

What are the two past strategies to overcome this?

Answer 3

1. Sell low risk follow on drugs

2. Invest money in blockbuster drugs

Question 4

What is meant by low risk follow on drugs?

Answer 4

(parent molecule that is already known to be effective is modified slightly so that the new drug is still effective but may have different pharmacological profiles/ properties)

Question 5

How does genetic variation contribute to drug failure?

Answer 5

1. Efficacy issues - a significant number of people fail to respond to drug treatment e.g:
   - HTN drugs (15-25%)
   - Antidepressants (20-50%)
   - Cholesterol drugs (30-70%)
   - Asthma drugs (40-70%)
   - This may be due to underlying genetic differences.
   - However need to also consider: age, gender, pathology, other medications etc.
2. Safety issues - adverse reactions to licensed drugs account for quite a number of:
   - Hospitalisations
   - Readmissions
   - Withdrawing drugs that are already on the market from the market
   - They are as costly as the drug treatment itself
   - Not entirely down to genetics but may be in part due to genetics

Question 6

Define pharmacogenetics/genomics.

Answer 6

The study of genetic variation and how that contributes to drug response. Both are closely associated with the concept of personalised/ individualised medicine.

Question 7

Define pharmacogenetics.

Answer 7

When looking at the impact of just a few genes/ gene polymorphisms on drug response.

Question 8

Define pharmacogenomics.

Answer 8

When looking at the whole genome differences and how it is related to drug response.

Question 9

Difference between pharmacogenetics and pharmacogenomics.

Answer 9

Pharmacogenetics only looks at a few genes so it is a limited number.

Question 10

Where can genetic polymorphisms occur?

Answer 10

Pharmacokinetic: ADME
Pharmacodynamic: Ion channels, Receptors, Immune System, Enzymes

Question 11

What causes the variation in drug response?

Answer 11

Genetic variation (e.g. SNP - single nucleotide polymorphism) in genes on all of these pathways may lead to people to respond to drugs differently.

Question 12

What is the clinical potential of PGx?

Answer 12

For the same empirical diagnosis (e.g HTN), we can use the same treatment.
Pharmacogenetic testing allows stratification into groups of patients or subtypes of the disease e.g.
Type 1 - predicted good response to tested drug
Type 2 - predicted poor response = use different drug
Type 3 - predicted increased risk of toxicity = reduce dose OR use different drug

Question 13

Explain PGx in drug discovery

Answer 13

Aim is to search for drug candidates against all common alleles (a.k.a variants; Type 1, 2 and 3) of a drug target.

• Find a drug that works universally. If not, then:
• Find a drug that works for majority. If not, then:
• Find a drug that works for genetic sub populations

Question 14

How can you use SNP information in drug target identification?

Answer 14

• Variant drug receptors are a result of gene SNPS.
• If those SNPS ‘cause’ the disease, drug candidates may be designed specifically against THOSE variants.
• If the SNPS prevent treatment success (genetic non responders) that can
  a) be identified at an early stage
  b) alternative versions of the drug may be designed

Question 15

Briefly explain PGx clinical trials

Answer 15

• Aim is to redesign them so that they are smaller, cheaper and safer
• Need to use a study population that represents a full spectrum of variants
• Use a study population that represents the most common variant
• Identify non-responders and ADR risk variants early and exclude them

Question 16

What are the possible challenges of PGx clinical trials?

Answer 16

1. CLINICAL TRIAL DESIGN
   - No consensus on best design of pharmacogenomics trials
   - Variable degree of penetrance for drug response + adverse effects (just because you have a particular genotype you’e not necessarily going to get that adverse side effect –> lifestyle, age, co-morbidities etc. may play a role)
2. STRATIFICATION OF RESEARCH SUBJECTS
   - Possible loss of benefits from trial participation (some people mat no longer be able to take part if they have the wrong genotype)
   - some possible unfair representation of certain groups or populations in trials
   - possible sampling biases.

Question 17

-ves of PGx

Answer 17

• traditional monitoring and dose adjustment may be easier to use and CHEAPER
• ethical issues: poor responders may be regarded unfavourably by insurance companies OR drugs may be withheld from which patients may still benefit; ADRS could be managed.

Question 18

+ves of PGx

Answer 18

• can discover drugs that work for more patients
• reduce drug attrition at clinical trial stage by including genetic testing in the process
• improve prescription of a range of existing drugs