Pharmacogenomics

Question 1

Define pharmacogenomics:

Answer 1

The study of the relationship between variants in a large collection of genes (up to the whole genome) and drug effects.

Question 2

Define pharmacogenetics:

Answer 2

The study of the relationship between individual gene variants and drug effects.

Question 3

What physiological factors affect drug response?

Answer 3

Age
Sex 
Weight
Disease Status
Ethnicity

Question 4

What environmental factors affect drug response?

Answer 4

Polypharmacy
Diet
Smoking 
Alcohol
Substance Use

Question 5

What genetic factors affect drug response?

Answer 5

Variations in PK pharmacogenes.

Variations in pd pharmacogenes.

Question 6

What is PGX?

Answer 6

The molecular study of genetic factors that determine drug efficacy and toxicity.

Question 7

What are the potential benefits of PGX?

Answer 7

Personalised / stratified / precision medicine.

Focused treatments by identification of people likely to respond.

Minimising ADRs by predicting people at risk.

Identification of those with an unmet clinical need for future drug development.

Question 8

What is the potential benefit of adjusting dose to PK genotype?

Answer 8

Uniform drug exposure would reduce dose dependant ADRs and prevent therapeutic failure when efficacy cannot be immediately assessed.

Question 9

What is cytochrome P450s?

Answer 9

Important drug metabolising enzyme involved in phase 1 oxidative metabolism of xenobioitcs.

There are about 50 types of P450 enzymes and these are involved in the oxidative degradation of chemicals.

There are many allelic variations according to ethnic background and several variations are associated with drug effectiveness.

Question 10

What is CYP2D6?

Answer 10

~25% of drugs metabolised by CYP2D6

eg: codeine, tamoxifen, antipsychotics, antidepressants.

PMs may suffer from ADRs at the usual doses of drugs with narrow therapeutic window.

PM phenotype can also be a consequence of CYP2D6 inhibition by a drug interactions (phenocopy) .

Question 11

When is codeine & UM CYP2D6 contraindicated?

Answer 11

Women during breastfeeding - UM may have higher levels of the active metabolites in breast milk and on very rare occasions may result in symptoms of opioid toxicity in the infant, which may be fatal.

In patients known to be ultra-rapid metabolisers -increased risk of developing adverse effects of opioid toxicity even at commonly prescribed doses.

Question 12

How does coumarin anticoagulant therapy work?

Answer 12

Warfarin - effective anticoagulant - used as a thromboprophylatic but has a narrow therapeutic index and serious ADRS.

Question 13

Explain warfarin’s pharmacokinetics:

Answer 13

S-Warfarin is 3-5 times more potent than R-Warfarin.

CYP2C9 is the principle isoform responsible for metabolism of the S isomer and is polymorphic.

Question 14

Explain warfarin’s pharmacodynamics:

Answer 14

Warfarin achieves its anticoagulant effect by inhibiting the enzyme vitamin K epoxide reductase (VKORC1).

VKORC1*2 allele (-1639 G>A) has a SNP in the promotor region within the transcription factor binding site.

“A” allele associated with reduced expression of the enzyme and reduced dose phenotype.

Question 15

What can drug induced hypersensitivity cause?

Answer 15

Can just affect the skin or in combination with systemic effects (e.g. liver toxicity).

Can cause blistering of the skin.

Inappropriate immune reaction where the drug is acting as the antigen leading to activation of the adaptive immune response.

Question 16

What is carbamazepine?

Answer 16

Anticonvulsant used in the treatment of epilepsy and bipolar disorder.

Causes rashes in 10% of Patients, hypersensitivity syndrome and can rarely lead to SJS or TEN.

Question 17

What is TPMT?

Answer 17

Thiopurine S-methyltransferase (TPMT) is a phase II enzyme required for the inactivation of thiopurines.

Thiopurines e.g. 6-mercaptopurine are converted into active metabolites (thioguanine nucleotides) which are incorporated into DNA and inhibit DNA replication.

Question 18

Explain the low activity SNPs of TPMT:

Answer 18

Thiopurine associated myelotoxicity is associated with low enzyme activity.

Three missense variations account for 95% of individuals with reduced TPMT activity.

The variant alleles result in significant decreases in levels of TPMT protein or its activity.

Actionable PGX - Determining TPMT status is recommended before treatment.

Question 19

What is UGT1A1?

Answer 19

Uridine diphosphoglucyronyl transferase (UGT1A1) is a enzyme involved in phase II metabolism.

Responsible for the inactivation by glucuronidation of the active metabolite SN-38 of topoisomerase inhibitor Irinotecan.

Actionable PGX - A reduced initial dose is recommended for *28 (TA)7 homozygotes.

Question 20

What is gefitinib?

Answer 20

A small molecule inhibitor targeted against the tyrosine kinase domain of the epidermal growth factor receptor (EGFR / HER1).

Binds to the ATP binding site of the tyrosine kinase domain and down regulates receptor autophosphorylation and phosphorylation of downstream molecules.

Has anti-tumour activity in a subgroup of non small cell lung cancer patients.

Question 21

Explain what happens in gefitinib sensitising genotypes:

Answer 21

Greater efficacy is seen in those with mutations in the kinase domain of the receptor.

The SNP (L858R) or inframe deletions in exon 19 are predictive of a response to Gefitinib.

Question 22

What is K-Ras?

Answer 22

K-Ras is involved primarily in regulating cell division. As part of a signaling pathway known as the RAS/MAPK pathway, the protein relays signals from outside the cell to the cell’s nucleus.

The K-Ras protein is a small GTPase.

TheKRASgene belongs to a class of genes known as oncogenes. When mutated, oncogenes have the potential to cause normal cells to become cancerous.

TheKRASgene is in the Ras family of oncogenes, which also includes two other genes:HRASandNRAS. These proteins play important roles in cell division, cell differentiation, and the self-destruction of cells (apoptosis).

Question 23

What is the EGFR signalling pathway?

Answer 23

Gefitinib acts via down regulation of egfr autophosphorylation and its downstream molecules.

STAT = Signal Transducers and Activators of Transcription 
PI3k = phosphoinositide 3-kinase
PTEN = phosphatase and tensin homolog

Question 24

What is Akt?

Answer 24

Protein kinase B (PKB), also known asAkt, is a serine/threonine-specific protein kinase that plays a key role in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, transcription and cell migration.

Question 25

Explain what happens in gefitinib resistant genotypes:

Answer 25

Presence of K-ras mutation or p-Akt overexpression is associated with disease progression.