Pharmacogenomics

Question 1

List four main factors that can affect the genetic variability of the drug response

Answer 1

Drug metabolisms - can be polymorphic
Drug transporters
Drug therapeutic targets
Drug toxic targets

Question 2

How do the polymorphisms 2C92 and 2C93 contribute towards the variability in the response to warfarin?

Answer 2

2C9 - metabolism of 15-20% of drugs - warfarin is a substrate; Warfarin consists of equal amts R-warfarin and S-warfarin (most potent)

i. 2C92 and 2C93 - reduced function variants
1. Decreased metabolic inactivation of S-warfarin
2. Increased concentration of active warfarin w standard dose
3. Prone to experience bleeding events
4. Patients require lower warfarin dosing

PS - 2C915 and 2C925 are null variants

Question 3

How do polymorphisms in VKORC1 contribute towards the variability in the response to warfarin?

Answer 3

• VKORC1 is the direct target of warfarin
• Common polymorphism found in the VKORC1 promoter region: -1639G>A
  A is associated with lower VKORC1 expression and a lower warfarin dose needed
  37% whites, 14% Africans & 90% Asians carry the A-allele

Question 4

Discuss two pharmacokinetic mechanisms by which genetic polymorphisms can contribute towards drug-induced adverse effects

Answer 4

• Pharmacokinetic-based adverse reactions
  - polymorphisms in drug metabolizing enzymes causing elevated drug levels
  e. g. 2C93 results in ↑ warfarin at standard dosing & ↑ risk of bleeding
  - polymorphisms in drug transporters causing elevated drug levels
  e. g. OATP1B115 results in ↑Statins and ↑ risk of myopathy

Question 5

List some of the current barriers to the full implementation of pharmacogenetics into
clinical practice

Answer 5

a. Physician education and understanding of pharmacogenetics
b. Absence of data demonstrating clinical utility
c. Lack of evidence for added value to existing prescribing method
d. Availability of alternative medications where genetic variability is not an issue
e. Cost effectiveness
f. Timeliness of turnaround for genetic testing
g. Lack of reimbursement for tests/insurance coverage
h. Lack of clear clinical guidelines

Question 6

Discuss the pharmacodynamic mechanisms by which genetic polymorphisms can contribute
towards drug-induced adverse effects

Answer 6

• Pharmacodynamic-based adverse reactions

e. g. polymorphisms in drug targets affect drug responsiveness (e.g. warfarin and VKORC1)

Question 7

Discuss two idiopathic mechanisms by which genetic polymorphisms can contribute
towards drug-induced adverse effects

Answer 7

• Drug-induced hepatotoxicity
  e. g. Flucloxacillin-induced liver damage occurs in 8.5 in every 100,000 new users
  - Linked to HLA-B*57:01

D. Drug-induced hypersensitivity reactions
(Allergic-like reactions, often life threatening)
e.g. Carbamazepine-induced Steven Johnson Syndrome
- linked to HLA-B*1502 in Han Chinese

Question 8

Define targeted therapy and explain how pharmacogenetic data is used in the therapeutic decision making process

Answer 8

Target therapy - targeted towards a molecular target based upon unique mutations or genetics, usu. in the treatment of specific cancers

• ID patients that will respond to drug treatment
• Optimize drug dosing based on pharmacogenetic information
• Minimize toxicity
• Only treat responders not susceptible to toxicity