Personalised Medicine

Question 1

What is personalised medicine?

Answer 1

The tailoring of medical treatment to the individual characteristics of each patient… to classify individuals into subpopulations that differ in their susceptibility to a particular disease or their response to a specific treatment.

Question 2

What is stratified medicine?

Answer 2

The management of a group of patients with shared biological characteristics by using molecular, biochemical or diagnostic imaging and testing

Question 3

What is pharmacogenetics?

Answer 3

The study of how differences in single genes affect the body’s handling of drugs.

Whereas pharmacogenomics deals with the overall effects of the whole genome.

Question 4

How do variants in genes affect adverse drug reactions and therefore influence PM?

Answer 4

Alter the PK (ADME)/PD (receptor binding and downstream) processes

This knowledge has led to greater understanding of inherited genetic variation (eg Warfarin) and acquired genetic variation (eg vermurafenib for melanoma)

Question 5

How is Warfarin an example of the benefits of PM?

Answer 5

Genetic variation depends on both PK (CYP2C9 variants) and PD (variation in VKORC1)

PK:
the different alleles for CYP292 affect the rate at which Warfarin is metabolised, the wild type 1/1 homozygote allele is an extensive metaboliser, where as the 2/3 heterozygote, 2/2 and 3/3 homozygotes are poor metabolisers. These patients therefore need a lower dose to prevent toxic build up.

PD:
Carriers of the A variant have lower levels of VKORC1 protein and require a 28% lower dose for each A allele they have. The frequency of variation varies between populations.

Together these genetic defects account for 40% of the variation in Warfarin requirement.

Question 6

How is Vermurafenib an example of the benefits of PM for acquired conditions?

Answer 6

This for of melanoma is an acquired genetic variation in the BRAF gene, it is a missense mutation: valine to glutamic acid.

Vemurafenib inhibits the action of mBRAF thus preventing gene transcription, cell growth, proliferation and metastasis. Though resistance can occur due to the ability of the disease response to cause a secondary mutation/amplification/activation of target gene or bipeds the oncagenic pathway vemurafenib targets entirely and cause disease progression through an alternate pathways.