Pharmacogenomic Biomarkers of Susceptibility to Adverse Drug Reactions: Just Around the Corner or Pie in the Sky?

Mark I. Avigan


Personalized Medicine. 2009;6(1):67-78. 

In This Article

Genomic Biomarkers of Risk for Idiosyncratic Adverse Drug Reactions

It has been estimated that more than 2 million cases of adverse drug reactions (ADRs) associated with approximately 100,000 deaths occur annually in the USA.[6] In addition, between 1976 and 2007, 28 drugs were removed from the US market for safety reasons.[6,7] Idiosyncratic ADRs that occur in clinical trials can be causally associated with risk factors that are genetic and/or nongenetic (e.g., gender, age, background disease and concomitant medications). Identification of these will permit the prediction of risk and the development of rational risk management strategies that will enhance appropriate patient selection for treatment or safety monitoring practices.

In circumstances in which a genomic variant(s) reliably predicts increased risk for a serious idiosyncratic or dose-related ADR(s), there may be an excellent opportunity to utilize it as a biomarker to critically inform a clinical treatment decision. Most currently identified pharmacogenomic markers of ADR susceptibility have been linked to:

  • A vulnerability to chemical stress due to a biochemical deficiency state;

  • A tendency for immunoallergic drug-induced hypersensitivity reactions;

  • A perturbation of a pharmacological pathway(s) leading to change(s) in a drug's pharmacokinetic (PK) and/or pharmacodynamic (PD) profile.[8,9]

In the first category, a hereditary or acquired deficiency is unmasked by exposure to agents that have a common chemical characteristic (e.g., drugs with oxidant activity that precipitate hemolysis in patients with glucose-6-phosphate dehydrogenase [G6PD] deficiency). In the second category, the drug or a derivative elicits an immunoallergic reaction because of a heightened antigenic effect associated with the genetic variant. Finally, in the third category, a genomic variant(s) is the underlying cause of an alteration in a transporter- or enzyme-linked step(s) of drug absorption, distribution, metabolism, excretion and/or the modulation of a molecule(s) targeted by the pharmacological agent. Such changes are typically associated with an increase in dose-related susceptibility to drug-related toxicity. The risk for drug-induced toxicity may also be heightened by certain epigenetic modifications as well as nongenetic cofactors, such as underlying disease or drug-drug interactions. In some instances, these may further promote the development of toxic levels of the drug-derived toxic moiety.