Study investigates pharmacogenomics of COVID-19 therapies

By Leah Sherwood, Science Advisory Board contributing writer

August 31, 2020 -- Human genetic variation may alter the interactions of drugs being used to treat patients with COVID-19 symptoms, resulting in a range of clinical responses -- from no effect to high toxicity in some patients, according to a study published in Nature Genomic Medicine on August 18.

In response to the COVID-19 pandemic, a number of drugs, including antivirals and immune-based therapies, have been repurposed to treat COVID-19 symptoms despite a lack of safety and efficacy data.

The authors of the current paper set out to better understand the pharmacogenomics (the role of the genome in drug response) of these unproven treatments to discover if genetic variation among COVID-19 patients could provide insight into how the different drugs react in each individual patient.

"We asked the question if selecting a COVID-19 medication or the dose using an individual's genetic information could improve effectiveness or safety," said co-author Pamala Jacobson, PharmD, distinguished professor and associate department head in the department of experimental and clinical pharmacology in the University of Minnesota College of Pharmacy.

The drugs reviewed in the study included the antiviral drugs hydroxychloroquine and chloroquine; the macrolide antibacterial agent azithromycin; the RNA polymerase inhibitors emdesivir, ribavirin, and favipiravir; a family of interferons (IFNs), specifically IFN-β1b; interleukin-6 (IL-6) and IL-1 antagonists tocilizumab, sarilumab, siltuximab, and anakinra; Janus kinase inhibitors uxolitinib and baricitinib; and corticosteroids used in the treatment of acute respiratory distress syndrome (ARDS), a sudden and serious lung failure associated with COVID-19.

From the review of relevant literature and databases housing pharmacogenetic information, the authors found evidence that several genetic variants may alter the pharmacokinetics of hydroxychloroquine, azithromycin, ribavirin, lopinavir/ritonavir, and possibly tocilizumab.

One of the strongest pharmacogenetic associations identified in the review was an association between IFN-β1b and a variant of the IRF6 gene for the adverse outcome of liver damage in previous studies of patients with multiple sclerosis. This link should also be explored in COVID-19 patients, who are prone to liver injury, the authors noted.

In the case of hydroxychloroquine, they noted that patients with the CYP2D6*4 allele (present in nearly 20% of patients with European ancestry) may be at higher risk of QT prolongation, a heart rhythm condition that can lead to sudden cardiac death. The risk is compounded if hydroxychloroquine is used in combination with chloroquine and azithromycin to treat COVID-19 symptoms.

"The application of pharmacogenomic tests can help eliminate fatal hypersensitivity for patients prescribed certain drugs," Jacobson said. However, "clinical studies in patients with COVID-19 are needed before routine testing can be recommended."

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