By Admera Health on Mar 24, 2021 6:08:59 PM

Today is National Adverse Drug Event Awareness Day.

An adverse drug event (ADR) can be defined as an unwanted and harmful side effect of a drug.1 Adverse drug events are responsible for more than 3.5 million physician office visits, 1 million emergency department visits, and 125,000 hospital admissions.1 Health care costs associated with ADRs are estimated to be 136 billion dollars annually.2

There are multiple reasons why patients may experience ADRs, including individual genetics.3

Genetic polymorphisms may result in changes to both the pharmacokinetics and pharmacodynamics properties of a drug. Pharmacokinetic changes may affect absorption, distribution, metabolism, and excretion of the drug impacting a patient’s exposure to medications, while pharmacodynamic changes may affect drug receptors, ion channels, and enzymes, impacting a patient’s clinical response to medications.4

In addition, certain genes and drug interactions may produce hypersensitivity reactions.4

Adverse drug reactions come in different forms and are associated with different genes. Each gene may have genotypes that are associated with an increased risk of adverse events, many of which can result in fatal outcomes.5

• Cardiovascular adverse drug reactions, such as QT segment prolongation can occur in patients with a genetic variation in the CYP2D6 gene resulting in poor metabolism of certain drugs such as Iloperidone, an antipsychotic6

• Hypersensitivity reactions, such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) can occur when patients have a heterozygous or homozygous genotype of the HLA-B*5701 gene when taking abacavir, an antiviral7

• Blood disorders, such as methemoglobinemia (MetHb) occur when there is a hymozygous or hemozygous genotype in the G6PD gene. A patient with this genotype taking a drug such as Pegloticase will be at an increased risk of toxicity and adverse drug events8

• Skeletal muscle reactions, such as myopathy, occur when there is a poor function genotype in the SLCO1B1 gene. Thus, a person with this genotype may experience adverse reactions when given simvastatin, a common drug for cholesterol9

• Coagulation effects, such as increased risk of bleeding can occur because of the *17/*17 genotype in the CYP2C19 gene. Patients with this genotype taking a drug such as clopidogrel, are at an increased risk of bleeding10

Providers with knowledge of their patient’s genetic profiles are aware of these genotypes and thus can alter their prescribing behaviors, reducing or even minimizing the chances for adverse drug reactions.

Similarly, TMPT is a gene responsible for drug metabolism, specifically with 6-mercaptopurine.4 Genetic variations of TMPT can lead to drug toxicity. The most common genetic variations of the TPMT gene include TMPT *2, TMPT *3A, and TMPT *3C.4

For example, John a 65-year-old male has been diagnosed with acute lymphocytic leukemia and is prescribed mercaptopurine. However, the provider in unaware that John has a genetic variant in the TPMT gene resulting in a TMPT *2 genotype

• This means John is a poor metabolizer of mercaptopurine and is at an increased risk of severe and life-threatening myelotoxicity if given conventional doses of mercaptopurine due to higher systemic active metabolite concentrations

• A clinical provider with knowledge of John’s genotype would have reduced the dosage of mercaptopurine by 90-94% which would have eliminated toxicity and improved efficacy4

A pharmacogenomic report would have given the provider all pertinent information needed to select the most appropriate and safest medication, properly dose John and lower chances of an adverse drug event.

Genetic variations play a significant role in drug metabolism and ultimately adverse drug reactions. Pharmacogenomic testing can be an extremely useful tool to provide clinically actionable information safe and efficacious prescribing, improved clinical outcomes and a lower chance for adverse drug events.

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References:

1) Health.gov. https://health.gov/our-work/health-care-quality/adverse-drug-events. Accessed March 17, 2021.
2) FDA. https://www.fda.gov/drugs/drug-interactions-labeling/preventable-adverse-drug-reactions-focus-drug-interactions. Accessed March 17, 2021.
3) Khan DA. Pharmacogenomics and adverse drug reactions: Primetime and not ready for primetime tests. J Allergy Clin Immunol. 2016 Oct;138(4):943-955. doi: 10.1016/j.jaci.2016.08.002.
4) Pirmohamed M, Park BK. Genetic susceptibility to adverse drug reactions. Trends Pharmacol Sci. 2001 Jun;22(6):298-305. doi: 10.1016/s0165-6147(00)01717-x. PMID: 11395158
5) AAFP. https://www.aafp.org/afp/2003/1101/p1781.html. Accessed March 22, 2021.
6) FDA. https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations. Accessed March 22, 2021.                                                                                7) Martin MA, Klein TE, et al. Clinical pharmacogenetics implementation consortium guidelines for HLA-B genotype and abacavir dosing. Clin Pharmacol Ther. 2012;91(4):734-738. doi:10.1038/clpt.2011.355
8) Relling MV, McDonagh EM, et al. Clinical Pharmacogenetics Implementation Consortium. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for rasburicase therapy in the context of G6PD deficiency genotype. Clin Pharmacol Ther. 2014 Aug;96(2):169-74. doi: 10.1038/clpt.2014.97.
9) Ramsey LB, Johnson SG, et al. The clinical pharmacogenetics implementation consortium guideline for SLCO1B1 and simvastatin-induced myopathy: 2014 update. Clin Pharmacol Ther. 2014 Oct;96(4):423-8. doi: 10.1038/clpt.2014.125.
10) Scott SA, Sangkuhl K, et al. Clinical Pharmacogenetics Implementation Consortium. Clinical Pharmacogenetics Implementation Consortium guidelines for CYP2C19 genotype and clopidogrel therapy: 2013 update. Clin Pharmacol Ther. 2013 Sep;94(3):317-23. doi: 10.1038/clpt.2013.105.