20.06.12 Pharmacogenetics Flashcards
What is pharmacogenetics
a study of genetic causes of individual variations in drug response
What is pharmacogenomics
a genome wide analysis of genetic determinants of drug efficacy and toxicity.
What 2 types of factor can influence a patient’s response to a drug
- Pharmacokinetic factors
- Pharmacodynamic factors
Examples of pharmacokinetic factors
Asorption, distribution, metabolism, elimination
Examples of pharmacodynamic factors
Target proteins, downstream messengers
What are ADRs
- adverse drug reactions
- Side effects
- Cause 2,000 deaths a year.
- Cost NGS £1 billion per year
Factors influencing side effects
- 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)
What are the benefits of pharmacogenomics
- 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.
Example of pharmacogenomics in Neonatal diabetes
- 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.
Example of pharmacogenomics of Warfarin
- 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.
Clinical use of genotyping CYP2C9 and VKORC1 for warfarin dose determination
- Expensive to genotype
- Utility is limited, dose variability also due to patient height and dietary vitamin K.
What is abacavir
- A reverse transcriptase inhibitor
- Part of anti-retroviral therapy in HIV infected patients.
- Side effects= hypersensitivity reaction (skin rash, fatigue, GI symptoms, respiratory problems)
Genetics behind abacavir side effects
- 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.
What is TPMT (Thiopurine S-methyltransferase)
- 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
Review of pharmacogenetics in cancer
- Screening mutations in tumours to customize drug treatment
- Biomarkers associated with cancer treatment toxicities
Drugs developed for common BRAF mutation
- V600E in BRAF seen in many cancers.
- Dabrafenib is a V600E mutant B-Raf inhibitor
Pharmacogenetics of 5-Fluorouracil (5-FU)
- 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
Pharmacogenetics of platinum agents
- 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.
Challenges of pharmacogenetics in cancer
- 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.
