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.

Steps in the Development & Utilization of Genomic Biomarkers for ADRs

Necessary steps in the pathway for development and utilization of pharmacogenomic biomarkers for ADRs begin with observation of ADRs in subsets of patients exposed to a certain drug, and continue with the performance of exploratory and replication studies that seek to identify and qualify biomarkers associated with these adverse events. In the study phase it is important to measure the sensitivity, specificity and predictive values of these markers. These steps are followed by the review and critique of all pertinent data by academics and regulators to establish the groundwork for their implementation as risk-management tools. An essential function in this phased process is effective communication with all appropriate stakeholders, including healthcare providers in order to gain feedback and enhance acceptance of newly developed biomarkers by the clinical community. A combined US National Cancer Institute-National Human Genome Research Institute (NCI-NHGRI) Working Group has recently developed a list of criteria that should be used to evaluate results that demonstrate a genotype-phenotype association, both in discovery and replication studies.^[10] In addition, the working group has emphasized the importance of publication of both positive and negative association study results. Finally, it is important to perform studies to evaluate the effectiveness of pharmacogenomic biomarker testing in a real-world setting.

When results of a pharmacogenomic test(s) provide significant value in forming a treatment decision, either to contraindicate usage or make an adjustment in dosaging of a drug or biologic agent, product labeling should be modified to reflect these findings and appropriately instruct healthcare providers regarding the utility of testing. There are a growing number of examples of pharmacogenomic tests that have been developed that add important value to the clinician's armamentarium of tools for managing drug treatment-related risk. Not surprisingly, since 1985 there has been a dramatic rise in the number of newly approved drugs by the US FDA that contain pharmacogenomic information.^[11,102] So far, of the product labels that refer to genomic biomarkers, a majority pertain to polymorphisms in cytochrome P450 isoenzymes. Testing for these typically is performed to inform optimal dosing.

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Cite this: Pharmacogenomic Biomarkers of Susceptibility to Adverse Drug Reactions: Just Around the Corner or Pie in the Sky? - Medscape - Jan 01, 2009.

Abstract and Personalized Medicine: A Framework for the Development of Pharmacogenomic Predictors of Drug Treatment Responses
Genomic Biomarkers of Risk for Idiosyncratic Adverse Drug Reactions
Steps in the Development & Utilization of Genomic Biomarkers for ADRs
Biomarkers of ADR Susceptibility in US FDA-approved Product Labels
Inheritance Characteristics of Genetically Determined ADR Susceptibility
Challenges for Future Discovery of Genomic ADR Biomarkers
Conclusion & Future Perspective
References
Sidebar: Executive Summary

Table 1. Altered Enzyme Activity and Genomic Biomarkers Associated with Adverse Drug Reaction Susceptibility: Examples Incorporated into US FDA-approved Product Labels
Drug(s)	Biomarker DNA locus or enzyme	Test(s)	Prevalence	Adverse event	Product label
Thioridazine	CYP2D6 PMs	PCR/DNA hybridization; enzyme activity	Multiple alleles; Caucasians ~7%; other ethnic groups 1-3%	Ventricular arrhythmia	Use contraindicated
Atomoxetine	CYP2D6 PMs	PCR/DNA hybridization; enzyme activity	Multiple alleles; Caucasians ~7%; other ethnic groups 1-3%	Ventricular arrhythmia	Information
Voriconazole	CYP2C19 PMs	PCR/DNA hybridization	Multiple alleles; Caucasians & Blacks ~3-4%; Asians 14-21%	Ventricular arrhythmia	Information
Irinotecan	UGT1A1 low activity	UGT1A128*	~10%	Diarrhea & neutropenia	Homozygotes: low initial dose
Azathioprine	TPMT low activity	TPMT2, 3, 3C*	Demographic variability; 0-4%	Myelosuppression	Homozygotes: use other treatment; Heterozygotes: use with caution
5-fluorouracil	DPD deficiency	Enzyme activity	0-1%	Neutropenia, diarrhea, stomatitis, neurotoxicity	Information
Primaquine	G6PD deficiency	Fluorescent spot test; enzyme activity	High: certain Black and Mediterranean populations	Hemolysis	Observe patient closely
Rasburicase	G6PD deficiency	Fluorescent spot test; enzyme activity	High: certain Black and Mediterranean populations	Hemolysis	Contraindicated
Carbamazepine	HLA-B1502*	High-resolution HLA typing/PCR	Demographic variability; Han Chinese ~8%	SJS/TEN	Screen prior to treatment; avoid use if positive unless benefit > risk
Abacavir	HLA-B5701*	High-resolution HLA typing/PCR	Demographic variability; Caucasians ~5%	Moderate/severe hypersensitivity reactions	Screen in high prevalence population prior to treatment; avoid use if positive unless benefit > risk
Isoniazid	NAT2 deficiency	Enzyme activity	Demographic variability	Hepatotoxicity	Information
Warfarin	VKORC1	-1639 G>A	AA genotype: Chinese ~80% Caucasians ~14%	Bleeding	Consider low initial dose
Warfarin	CYP2C9 PMs	Cyp2C9 2, 3	Caucasians 8-12% Blacks 1-3% Asians <1%	Bleeding	Consider low initial dose

CYP = Cytochrome P450; DPD = Dihydropyrimide dehydrogenase; G6PD = Glucose-6-phosphate dehydrogenase; HLA = Human leukocyte antigen; NAT2 = N-acetyltransferase-2; PM = Poor metabolizer; SJS = Stevens-Johnson syndrome; TEN = Toxic epidermal necrolysis; TMPT = Thiopurine S-methyltransferase; UGTA1 = Uridine diphosphate-glucuronosyl transferase A1; VKORC1 = Vitamin K 2,3-epoxide reductase complex subunit 1.