Pharmacogenomics

Question 1

What examples are you aware of where Pharmacogenomics is used to inform treatment decisions

Answer 1

Cystic Fibrosis - mutation in the F508 gene
Drugs have been developed to target this gene variant
ONLY IN CF PATIENTS WITH F508 mutation.

NSCLC
EGFR binds to TK - downstream signalling - uncontrollable cell proliferation
TKI is used to prevent EGFR-TKI complexes

Mutation can occur where EGFR is resistant to TKI
Need different treatment options compared to normal NSCLC.

Question 2

Dosing adjustment for Thiopurine pro-drugs

Answer 2

Gene NUDT15 catalyses the conversion between thioguanine triphosphate to monophosphate

Thioguanine triphosphate - VERY TOXIC

NUDT gene mutation = Accumulation of toxic metabolite in the blood

Low starting dose for patients with mutation

Question 3

Dosing adjustment for N-acetyltransferase

Answer 3

Some patients have a mutation in n-acetyltransferase.

N-acetyltransferase catalyses the acetylation of drugs for effective elimination.

Low doses of drug to be given to slow acetylators - accumulation of toxic levels of metabolites in the blood and increased chance of liver toxicity and neurological ADRs

Fast acetylators - acetylate drugs rapidly - no accumulation BUT rapid release of toxic levels of metabolite in the blood - liver toxicity

Question 4

Dosing adjustments for UDP-glucuronosyltransferase

Answer 4

SN-38 is the prodrug of Irinotecan

UGT1A1 mutation
Ineffective glucuronidation (elimination) of SN-38

SN-38 will be slowly cleared - accumulation = GI ADRs and Haematological ADRs

Question 5

Initiation of Irinotecan. Why must this be carefully prescribed?

Answer 5

Patients with reduced UGT1A1 activity are poor metabolisers.

Prescribing Irinotecan increases the risk of severe neutropenia and diarrhoea.

Reduced starting dose must be considered for these patients.

Question 6

Dosing adjustment for Carbamazepine

Answer 6

Mutations in HLA-B15:02
HLA-A31:01 alleles

Increased risk of Steven-Johnsons Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN)

Question 7

Dosing adjustments for Clopidogrel

Answer 7

Mutation in CYP2C19 enzyme
The enzyme catalyses the conversion (Metabolism) of Clopidogrel (prodrug)

Mutation - Loss in efficacy of the drug, it will not be activated - Pt is a poor metaboliser

Use alternative anti-platelet

Question 8

Dosing adjustment for Fluropyrimidine chemotherapy

Answer 8

Mutation in DPYD variant - partial or complete DPD deficiency
DPD - catalyses the reduction of uracil/thymine to dihydro-uracil/thymine

Increasing the toxicity of 5-FU chemotherapy

Question 9

What is the difference between pharmacogenomics and pharmacogenetics?

Answer 9

Pharmacogenetics:
study of genetic causes of individual variations in drug response

Pharmacogenomics deals with the simultaneous impact of multiple mutations in the genome that may determine the patient’s response to drug therapy