20.06.12 Pharmacogenetics

Question 1

What is pharmacogenetics

Answer 1

a study of genetic causes of individual variations in drug response

Question 2

What is pharmacogenomics

Answer 2

a genome wide analysis of genetic determinants of drug efficacy and toxicity.

Question 3

What 2 types of factor can influence a patient’s response to a drug

Answer 3

• Pharmacokinetic factors

- Pharmacodynamic factors

Question 4

Examples of pharmacokinetic factors

Answer 4

Asorption, distribution, metabolism, elimination

Question 5

Examples of pharmacodynamic factors

Answer 5

Target proteins, downstream messengers

Question 6

What are ADRs

Answer 6

• adverse drug reactions
• Side effects
• Cause 2,000 deaths a year.
• Cost NGS £1 billion per year

Question 7

Factors influencing side effects

Answer 7

• Dose
• Condition being treated
• Age/ sex
• Fast/slow metabolisers (genetic determinants)
• Interactions with other medicines/food (e.g. St John’s wort and oral contraceptive, grapefruit juice and statins)

Question 8

What are the benefits of pharmacogenomics

Answer 8

• Safer dosing options
• Avoid drug toxicity and ADR (adverse drug reactions)
• Ensure maximal efficacy
• Improve drug development/choices
• Explain variable response to drugs
• Reduce healthcare costs.

Question 9

Example of pharmacogenomics in Neonatal diabetes

Answer 9

• Diabetes before 6 months age (1 in 200,000 births)
• Due to activating mutations in KCNJ11 or ABCC8, subunits of the ATP sensitive potassium channel, causing it to be permanently open.
• Patients treated with sulphonylurea
• Sulphonylurea metabolised by cytochrome P450 CYP2C9 enzyme.
• Polymorphisms in this enzyme can result in slow or rapid metabolism of the drug.

Question 10

Example of pharmacogenomics of Warfarin

Answer 10

• Warafarin is an oral anti-coagulant.
• Acts by inhibiting VKOR (vitamin K epoxide reductase), which catalyses vitamin K-epoxide to active vitamin K (required for activation of clotting factors)
• VKORC1 SNPs (1173C>T and -1639G>A) are associated with increased warfarin sensitivity and require a reduced maintenance dose.
• CYP2C9 is a hepatic drug metabolising enzyme in the CYP450 family
• CYP2C92 and CYP2C93 confer a reduced rate of warfarin metabolism and a higher risk of bleeding complications.

Question 11

Clinical use of genotyping CYP2C9 and VKORC1 for warfarin dose determination

Answer 11

• Expensive to genotype

- Utility is limited, dose variability also due to patient height and dietary vitamin K.

Question 12

What is abacavir

Answer 12

• A reverse transcriptase inhibitor
• Part of anti-retroviral therapy in HIV infected patients.
• Side effects= hypersensitivity reaction (skin rash, fatigue, GI symptoms, respiratory problems)

Question 13

Genetics behind abacavir side effects

Answer 13

• Abacavir modifies endogenous peptides which are presented at the cell surface by HLA-B. HSP70 thought to acts as a chaperone
• SNPs in HLA-B and HSP70 are associated with hypersensitivity
• Genotyping done by sequencing, quantitative real time PCR, sequence specific primers.

Question 14

What is TPMT (Thiopurine S-methyltransferase)

Answer 14

• Involved in the metabolism of thiopurine drugs (used to treat chronic inflammatory and autoimmune diseases or ALL- acute lymphoblastic leukemia)
• 1 in 300 people are TPMT deficient- so likely to get an ADR at standard dose level)
• TPMT genotyping as an indicator of endogenous TPMT activity

Question 15

Review of pharmacogenetics in cancer

Answer 15

• Screening mutations in tumours to customize drug treatment

- Biomarkers associated with cancer treatment toxicities

Question 16

Drugs developed for common BRAF mutation

Answer 16

• V600E in BRAF seen in many cancers.

- Dabrafenib is a V600E mutant B-Raf inhibitor

Question 17

Pharmacogenetics of 5-Fluorouracil (5-FU)

Answer 17

• 5-FU is a uracil analog, used to treat solid tumours (colorectal and breast cancer)
• 5-FU to be activated into 5-fluoro-2-deoxyuridine monophosphate (5-FdUMP)
• dihydropyrimidine dehydrogenase (DPD) inactivates 5-FU
• Variants in DPD lead to excess 5-FdUMP, which causes toxicity

Question 18

Pharmacogenetics of platinum agents

Answer 18

• E.g. cisplatin, carboplatin.
• Act by inhibiting cell replication as a result of formation of DNA adducts.
• Drug efficacy is compromised by decreased drug accumulation, increased activity of DNA repair system or reduced DNA adduct formation.
• Polymorphisms in glutathionine (GSH)-dependent enzymes influences response to platinum chemotherapy drugs.
• Glutathione-S-transferases (GSTs) catalyse the conjugation of GSH to platinum agents forming less toxic and more water soluble conjugates.

Question 19

Challenges of pharmacogenetics in cancer

Answer 19

• Difficult to conduct studies in humans as chemotherapies are too toxic to give to healthy individuals
• Need to screen large numbers of patients to identify rare mutations
• Cancer patients are often treated with different combinations and dosages of drugs, so it’s hard to find large samples of patients who have been treated in the same way.
• Drug efficacy and toxicity are likely multigenic traits making it difficult to distinguish between functional driver mutations versus random non-functional mutations.