Moom R. Roosan, PharmD, PhD, Jerika Lam, PharmD, Mary A. Gutierrez, PharmD, Veronique Michaud, PhD, BPharm, Jacques Turgeon, BPharm, PhD
Published May 12, 2022
Abstract
More than 90% of patients harbor DNA variants that could affect their response to a medication.1
Each individual has a unique genetic makeup that affects drug absorption, efficacy, metabolism, and response. Pharmacogenomics (PGx) addresses how an individual’s DNA influences the response to a medication. With recent advances in health sciences, we can predict a patient’s phenotype, such as metabolic activity, from the genotype, such as genetic variants, to prevent serious adverse effects (AEs) and therapeutic failure or to optimize treatment efficacy.
Determining the presence of a certain genotype, such as thiopurine methyltransferase for patients treated with thiopurine drugs2 or HLA-B*57:01 for patients receiving abacavir,3 can help prevent potentially fatal adverse reactions. Furthermore, because enzymes are critical in the metabolism of many drugs, understanding the enzyme phenotypes is crucial to predicting adverse drug events (ADEs) or therapeutic outcomes. Many drug-metabolizing enzymes and drug transporters are subject to genetic polymorphisms.
Specifically, Cytochrome P450 (CYP) enzymes, such as CYP2C9, CYP2C19, and CYP2D6, are highly polymorphic and are associated with distinct phenotypes ranging from highly increased activity to no activity. This translates to individuals having intermediate, normal, rapid, poor, or ultrarapid metabolism of drugs.
A poor metabolizer of an enzyme that inactivates a drug may be at higher risk of AEs with standard dosing, because of supratherapeutic active drug concentration in the serum. By contrast, a poor metabolizer of an enzyme responsible for activating a drug may not get the therapeutic benefit of the drug, because of the subtherapeutic concentration of the active metabolites, whereas an ultrarapid metabolizer of the same enzyme may be at increased risk of AEs of the active compound (see the clinical example below).
Thus, pharmacists need to consider many factors and use clear guidance on predicting a phenotype from a genotype to intervene optimally based on the specific drug-gene interaction.
Predicting a phenotype from a genotype is becoming increasingly challenging, considering the ever-growing knowledge in PGx. There are PGx guidelines available from various consortia and regulatory agencies, including the FDA, to help translate the phenotype from genotype to guide intervention. The most well-accepted guidelines in the United States are provided by the Clinical Pharmacogenetic Implementation Consortium (CPIC).4
The CPIC evaluates evidence and provides specific recommendations regarding whether to alter dosing or avoid a drug. Pharmacists also need guidance on which PGx test to use based on the genes and allele coverage provided in each test.5 The Association of Molecular Pathology provides such guidance on allele selection for individual gene testing.6,7
As medication experts with adequate PGx training, pharmacists are best suited to identify patients at risk and use appropriate PGx tests to evaluate patients’ medications across multiple specialties, including cardiology, mental health, pain management, and oncology, to ensure patient safety and optimize care.
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