Canterbury DHB

Pharmacogenetics

Genetic variability in pharmacokinetics and pharmacodynamics may lead to unexpected effects from ‘standard’ doses of drugs.

• Heterogeneity of drug response is partially genetically determined (both pharmacokinetics and pharmacodynamics).
• Knowledge of genotype (or phenotype) may help individualise drug choice and dose.
• Only a few pharmacogenetic tests have reached clinical practice.
• Genetic tests may be undertaken in family members after an index case has been identified.

Pharmacodynamic Associations

Examples of pharmacodynamic associations that are well established include:

Human Leukocyte Antigens (HLA)

• HLA-B*5701 is strongly associated with abacavir hypersensitivity. Testing is required prior to treatment.
• Other HLA-B mutations are associated with hypersensitivity but are not routinely done:
  • HLA-B*1502 in Han Chinese is associated with carbamazepine hypersensitivity but routine testing is not done.
  • HLA-B*5801 is associated with allopurinol hypersensitivity but routine testing is not done.

Mutations in cancer treatment

• Chronic Myeloid Leukaemia – BCR-ABL (e.g. imatinib)
• Breast cancer – HER-2 (e.g. trastuzumab)
• Lung cancer – EGFR (e.g. cetuximab)

Mutations of infections

• HIV resistance (e.g. protease inhibitors)
• Tuberculosis resistance (e.g. isoniazid)

Pharmacokinetic Associations

Metabolism

• Most drugs are metabolised by more than one enzyme so any single genetic change usually only has modest effects. Understanding pharmacogenetics helps understand clinical observations. An example of this would be a patient with bradycardia on low dose metoprolol who may be a poor CYP2D6 metaboliser (see below).
• Pharmacogenetics is important for the following drug metabolising enzymes:

  Note: Routine testing is not available. Obtain information in other ways (e.g. INR for warfarin).

CYP2D6

• Poor metabolisers: 6% of Caucasians, 0.8% of East Asians, uncertain for Māori.
• Poor metabolisers are unlikely to achieve effects from prodrugs activated by CYP2D6 (e.g. codeine to morphine, tamoxifen to endoxifen).
• Poor metabolisers risk toxicity from drugs metabolised by CYP2D6 (e.g. perhexiline, metoprolol). Tailor dose using phenotype (drug response or drug concentration ratio).
• Ultra-rapid metabolisers: 5% of North Africans, 4% of Caucasians.
• Ultrarapid metabolism leads to increased effects of prodrugs (e.g. codeine). It also leads to decreased effects of drugs metabolised by CYP2D6, including many psychoactive drugs, some betablockers, and perhexiline.

Other enzymes

• CYP2C9 – poor metabolisers: 1–3% of Caucasians. Other populations (e.g. Asians, Māori, Polynesians) are minimally affected (e.g. affecting warfarin dosing).
• CYP2C19 – poor metabolisers: 13–20% of Asians, 7% of Māori, 13% of Polynesians, and 1–8% of Caucasians (e.g. affecting clopidogrel activation).
• CYP3A5 is present in 10% of Caucasians who have increased elimination of substrates.
• UGT1A1 (Gilbert's syndrome) is deficient in 5% of patients (e.g. affecting irinotecan).
• Thiopurine methyltransferase (TPMT) (azathioprine and 6-mercaptopurine)
  • See Thiopurine methyltransferase (TPMT)
• Butyrylcholinesterase (suxamethonium and mivacurium)
  • Deficiency is rare (0.03%) but results in prolonged apnoea with these drugs.
  • Testing is usually undertaken in family studies after an index case has been found.

Transportation

• P-glycoprotein – MDR1 polymorphisms affects absorption and transport across membranes.

must be prescribed or recommended by a consultant.

Topic Code: 93244