Pharmacogenomics

Question 1

Patient with colon adenoCA undertakes DPYD genetic screening reveals

• Reduced-function DPYD genetic variant.

Chemotherapy – Capecitabine (50% reduced dose) and then when tolerated well, increased to 75%

Answer 1

• Fluoropyrimidines – may cause serious AE (myelosuppression and diarrhoea)
• DPD enzyme inactivates ~80% of 5-FU and encoded by gene DPYD
• Reduced activity leads to increase risk of 5FU related serious reactions

Question 2

Carbamazepine

HLA-B*15:02 highly prevalent in SE Asia and associated with:

Answer 2

Carbamazepine-induced SJS-TEN

Question 3

Thiopurine (Azathioprine, thioguanine) are used as anti-cancer agents and immunosuppressants

TPMT and NUDT15 genetic variants strongly influence risk of toxicity

Intermediate Metabolizers
and Poor Metabolizers:

Answer 3

Intermediate:
- Reduce dose to 30-80% of normal
- Allow 2-4 weeks to reach steady state

Poor:
- Alternative therapy OR
- Drastically reduce dose (10 fold reduction)
- Allow 4-6 weeks to reach steady state
- Adjust based on myelosuppression and disease guidelines

Question 4

Tacrolimus and CYP3A5
- CYP3A5 genetic variations strongly influence tacrolimus metabolism

Genetic testing can optimize initial dosing to achieve target levels faster

Answer 4

*Pre-renal/heart/Hematopoietic Stem Cell transplant – Need to do
*Pre-liver transplant – NO NEED. Cos it is a new liver

Question 5

Aminoglycoside Antibiotics and RNR1 gene

Gentamicin for acute pyelonephritis, resulted in moderate sensorineural hearing loss and require hearing aids

Answer 5

Due to Variant in mitochondrial RNR1 gene

Question 6

A patient with colon cancer is found to carry a DPYD variant before starting capecitabine.
a) What is the significance of this result?
b) How would this influence your treatment plan?
(5 marks)

Answer 6

DPYD encodes dihydropyrimidine dehydrogenase (DPD), which inactivates ~80% of 5-fluorouracil (5-FU) and its prodrug capecitabine.

A DPYD variant indicates reduced DPD enzyme activity, leading to drug accumulation and increased risk of severe toxicity, such as myelosuppression and diarrhea.

Management includes starting at a reduced dose (e.g., 50%), followed by titration based on tolerance, or choosing alternative therapies if risk is high.