Pharmacogenomics

Introduction

Pharmacogenomics is the science which examines inherited variations in genes that determine a patient's response to a drug.

  • Beyond tailoring a drug to an individual based on size, weight or age, the science of pharmacogenomics strives to tailor drug therapy to individual patients based on their own unique molecular characteristics (e.g. individual differences in drug-metabolizing enzymes, drug transporter activity, receptor sensitivity).



Genetic Variation

Major genetic variation is found in the cytochrome CYP450 group of isoenzymes.

  • This can result in either inadequate responses to drugs or increased risk of ADRs.
  • Clinically relevant genetic variation has been seen in CYP2D6, CYP2C9, CYP2C19 and CYP3A5.



Examples

Abacavir hypersensitivity occurs in at least 5% of patients, usually in the first 6 weeks; it is more common in white people and is associated with HLA-B*5701 allele.

Azathioprine - 1 in 300 people have low or no detectable thiopurine methyltransferase (TPMT) activity and are at risk of severe myelosuppression; avoid use in these people if possible or reduce the dose to one-tenth of normal or less.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrosis (TEN) are more common in South East Asian populations (including those from China, Thailand, Malaysia, Indonesia, the Philippines and Taiwan, and to a lesser extent, India and Japan.

  • The presence of HLA-B*1502 indicates an increased risk of skin reactions for carbamazepine, phenytoin, oxcarbazepine and lamotrigine.
  • The presence of HLA-B*5801 indicates an increased risk of skin reactions for allopurinol.

Capecitabine, fluorouracil or tegafur - A significant proportion of the general population has a deficiency of dihydropyridine dehydrogenase (DPD), which is needed to break down fluorouracil and the related medicines capecitabine, tegafur and flucytosine. As a result, following treatment with these medicines, fluorouracil can build up in their blood, leading to severe and life-threatening side effects such as neutropenia (low levels of neutrophils, a type of white blood cells needed to fight infection), neurotoxicity (damage to the nervous system), severe diarrhoea and stomatitis (inflammation of the lining of the mouth).

Clopidogrel - Clopidogrel is a prodrug and must be converted to the active metabolite by CYP2C19. Efficacy of clopidogrel may be reduced in CYP2C19 poor metabolisers; consider using an alternative antiplatelet.

Studies of genetic polymorphisms influencing the toxicity of warfarin have focused on CYP2C9, which metabolises warfarin, and vitamin K epoxide reductase (VKOR), the target of warfarin anticoagulant activity. In 2007, FDA changed the labelling requirement for warfarin, advising that a lower initial dose should be considered in people with certain genetic variations.

Tramadol is metabolised by CYP2D6 to its active metabolite:

  • 6-10% of Caucasians and 1-2% of Asians lack CYP2D6 and may not obtain pain relief.
  • Some people are ultra-rapid metabolisers and may have a greater risk of toxicity (those affected include up to 10% of Caucasians, 1-2% of Asians, 21% of people from the Middle East, e.g. Saudi Arabians, and 29% of Ethiopians)



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