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

Biomarkers of ADR Susceptibility in US FDA-approved Product Labels

Examples of altered enzyme activity and genomic biomarkers associated with ADR susceptibility described in FDA-approved labeling are shown in Table 1 . Labeled instructions for actions to be taken based on biomarker test results are shown, with the names of the specific corresponding drugs. Most of these biomarkers are the gene products or DNA variants of genes that encode enzymes that regulate the inactivation or clearance of pharmacologically active parent drugs, or their metabolites. In each case, treatment instructions are influenced by the size of the therapeutic index and the implied severity of a safety outcome caused by altered enzyme levels. For example, thiopurine S-methyltransferase (TPMT) is an enzyme that regulates the metabolism of azathioprine and 6-mercaptopurine (6-MP). This enzyme regulates one of the two major pathways for disposal of these drugs; the other pathway leads to the formation of 6-thioguanine (6-TG); homozygotes with low TPMT activity variant alleles are prone to developing toxic 6-TG levels and, consequently, serious leukopenia. Since this risk is very high, the product labels contraindicate usage of these agents in homozygous patients.[12,102]

Warfarin labeling lists three allelic variants, one of the vitamin K 2,3-epoxide reductase complex, subunit 1 (VKORC1) gene and the other two of CYP2C9, which influence optimal warfarin dosing requirements.[13] Importantly, the prevalence of each of these alleles varies among different demographic groups within the human population. Although these variants are a very small subset of all the allelic variants that have the potential to influence warfarin activity, both in these two genes as well as others, they have been shown to contribute significantly to interindividual variability in optimal dosaging of the anticoagulant.[13] Recently, a treatment algorithm integrating patient demographic, clinical and genetic characteristics to determine optimal therapeutic dosaging of warfarin during the early phase of treatment has been developed.[14] Study results have suggested that dose refinements based on this approach are associated with more time spent in the therapeutic range and fewer laboratory or clinical adverse events. Nonetheless, the current level of evidence supporting the systematic pharmacogenomic testing of all patients prior to initiating warfarin to achieve a reduction of treatment-induced bleeding events has been called into question, since these events also reflect the impact of multiple nongenetic factors.[15] Further studies must be completed to address this issue.

Another group of drug-related adverse event susceptibility biomarkers are human leukocyte antigen (HLA) allelic biomarkers that predict an increase in risk for hypersensitivity reactions. HLA-B*1502 has proven to be a sensitive marker for susceptibility to carbamazepine-associated Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). In certain Asian populations in which the prevalence of this allele is relatively high, screening patients prior to initiation of treatment with carbamazepine has been recommended.[103] Likewise, since HLA-B*5701 has proven to be a sensitive marker for an increased risk to develop abacavir-associated hypersensitivity reactions across different demographic populations, screening prior to treatment with this agent has been recommended.[16,17,102]