An Introduction to Pharmacogenomics, Pharmacogenetics and Personalised Medicine REVIEW LECTURE NOTES

Question 1

What is pharmacogenomics?

Answer 1

Pharmacogenomics can be thought of as the whole genome application of pharmacogenetics, which examines the single gene interactions with drugs
Terms gene, genes or genome are often used interchangeably

Question 2

What is genomics?

Answer 2

The study of a person’s entire genome
Genome: an organisms hereditary information, encoded by DNA
Human genome project to map the entire genome
Potential to understand relationships between genes, peptides, proteins and disease

Question 3

What are polymorphisms?

Answer 3

Variations in DNA sequences that occur in at least 1% of the population
Single nucleotide polymorphisms (SNPs) are single base differences in DNA sequence
SNP profiles (haplotypes) can alter clinical phenotypes
Some of these may be responsible for changes in enzymes, transporters and receptors

Question 4

What is expression profiling?

Answer 4

Synthesise a range of drugs for a particular target
Expose cells in culture to the drug
Investigate response of groups of genes
To indicate toxicity, efficacy or specificity
Select the drug used for good responders

Question 5

What is disease stratification?

Answer 5

Understand molecular mechanisms of disease
Detect altered gene expression patterns by pharmacogenomics testing
Develop targeted therapies
e.g. Gilvec for chronic myeloid leukaemia, identify chromosomal abnormality- Philadelphia chromosome produces mutant, overactive protein (kinase) resulting in excessive proliferation

Question 6

Decisions for pre-clinical testing

Answer 6

Exclude/include patient groups?

OR ensure inclusive patient groups?

Question 7

Rescue in late stage trial

Answer 7

Later stages of trials
Retrospective rescue of drugs with serious ADRs if genetically identified
4% withdrawn due to ADRs
Drug developed for sub-populations

Question 8

The identification of good responders

Answer 8

Test prospective drugs in patient sub-groups or retrospective rescue in later trials
Marginal patient benefit within a population
Identify the group of patients who respond well to treatment
Licensed in a specific genomic group

Question 9

Pharmacogenetics and personalised medicine

Answer 9

Individual response (PKs and PDs) to treatment
Genetic factors account for ~15-30% of inter-individual differences
Can account for 95%
May be due to mutations of a single gene

Question 10

Which individual responses are relevant to practice?

Answer 10

Relevance is determined by:
Allele frequency
Clinical outcome
Therapeutic window of a drug

Question 11

Metabolic status (PK) affecting pharmacogenomics

Answer 11

Monogenic traits affecting metabolism
Best recognised and understood examples
Single gene defects that may enhance or reduce metabolism

Question 12

CYP 450 enzymes

Answer 12

Genetic polymorphisms in CYP450 can be associated with disease e.g. hypertension and cancer
Genetic polymorphisms associated with drug metabolism
Multiple families of the enzyme with different levels of activity for different drugs

Question 13

CYP 2D6 alleles

Answer 13

More than 51 recognised 2D6 alleles
~20-25% of drugs in use are metabolised at least in part by this enzyme
Western Europe ~7% are poor metabolisers
Varies geographically
Poor metabolisers- increased accumulation of drug and potential side effects
Rapid metabolisers- poor therapeutic response

Question 14

CYP 2D6 and pro drugs

Answer 14

Codeine is a pro drug of morphine
Therefore the reverse effect to antidepressants
Poor metabolisers get less morphine, fast metabolisers get more

Question 15

Warfarin algorithms

Answer 15

CYP2C9 *2 and 3 genotypes reduce metabolism by 30 and 80% respectively
Variant genotypes therefore need lower dose than wild type (1)
Consider homo/heterozygous
Carriers of certain polymorphism need higher warfarin maintenance dose

Question 16

Extending drugs restricted by ADRs

Answer 16

Restricted use of marketed drugs due to severe side effects
Limits clinical usefulness
Identify sub group at most risk of ADR to expand therapy

Question 17

Stratification through PG

Answer 17

PGx can determine interaction with receptor targets and ADME

Principle: right drug to the right individual at the optimal dose

Question 18

Is there a clinical need for testing?

Answer 18

Other biomarkers
Magnitude of effect
Avoid by selecting alternative drug
Disease severity- mild, chronic, severe
Side effects- severity
Therapeutic window- chemotherapy
Complex medical situations- clozapine

Question 19

Is the test reliable and valid?

Answer 19

PGx dependent on testing
Test development is complex and time consuming
Accuracy
Complexity
Difference between populations e.g. TPMT testing
Invasive conditions
Easy to perform, reliable, inexpensive, interpretable

Question 20

Genetic inequalities

Answer 20

Stratification
Disease susceptibility
Racial grouping
Stigmatisation
Patient consent
Health insurance
Employment 
Offspring

Question 21

Abacavir

Answer 21

HIV/AIDS drug severe hypersensitivity reaction (5%)
Close monitoring required
Identify sub-group at most risk of ADR to expand therapy

Question 22

Thiopurine S-methyl-transferase (TPMT)

Answer 22

Developed in 1950s
Genetic testing, identify TPMT deficient patients, reduce drug dose 5-10% of conventional dose
Enzyme detection, myelosuppression, higher cost, applicability across populations, ADRs