PHARMACOGENETICS


BCHE BUTYRYLCHOLINESTERASE

A variation in the BCHE gene can cause life-threatening prolonged apnea when these individuals are dosed with succinylcholine muscle relaxants

WARFARIN

Anticoagulant used for the prevention of thrombosis.

Major side effect is life threatening bleeding.

Vitamin K epoxide reductase subunit 1 VKORC1 polymorphism explain 30% of the dose variation.

CYP2C9 poor metabolises explain 10% of the dose variation.

  • Genotype-guided dosing of warfarin did not improve anticoagulation control during the first four weeks of therapy.

  • Pharmacogenetic-based dosing was associated with a higher percentage of time in the therapeutic INR range than was standard dosing during the initiation of warfarin therapy

ALLOPURINOL

Used for the treatment of gout.

Considered a safe drug and is highly prescribed, active metabolite is oxypurinol, a potent xanthine oxidase inhibitor preventing the formation of uric acid.

Associated with toxic epidermal necrolysis in Han Chinese populations HLA-B*5801

If testing is not done, but unexpected consequences are observed, the strategy is to avoid using allopurinol and prescribe febuxostat instead.

WHAT MAKES A GOOD PHARMACOGENETIC TEST

Replication

The marker must have a large effect/penetrance, but doesn’t need to explain all toxicity

Predictive not prognostic, alternate therapies or therapeutic strategies must be available

Clear patient benefit by reducing toxicity or improving efficacy.

Testing should not delay therapy

Testing must be cost effective

AZATHIOPRINE

Used for IBD

There is a variable response 40-65% improvement, and significant individual variation in therapeutic benefit

Patients are tested for TPMT and not excluded from therapy, but their target does is adjusted on the basis of the results of their test.

5-FLUOROURACIL

FLUROPYRIMIDE DRUGS: first line treatment for solid tumours, but 10-20% of patients develop severe toxicity.

DPD Dehyrdopyrimide dehydrogenase deficiency is the cause of 5FU toxicity.

Because 5FU has a narrow therapeutic window, and most of it is metabolised through DPD, it is dangerous if there is a deficiency in DPD and can even be fatal in the rare cases where DPD is absent.

DPD cannot be assayed in red cells. Not appropriate in white cells. And genotype-phenotype correlation in carriers is poor.

About 6% of the population have variants in DPYD and are at high risk for early Grade 3-4 toxicity.

They explain 35% of cases of grade 3-4 toxicity.

Some hospitals do this testing beforehand, some do not.

The main barrier to the uptake of a service is the need to change clinical practice.

#genomics

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