Pharmacogenomics of COVID-19 therapies

Abstract

A new global pandemic of coronavirus disease 2019 (COVID-19) has resulted in high mortality and morbidity. Currently numerous drugs are under expedited investigations without well-established safety or efficacy data. Pharmacogenomics may allow individualization of these drugs thereby improving efficacy and safety. In this review, we summarized the pharmacogenomic literature available for COVID-19 drug therapies including hydroxychloroquine, chloroquine, azithromycin, remdesivir, favipiravir, ribavirin, lopinavir/ritonavir, darunavir/cobicistat, interferon beta-1b, tocilizumab, ruxolitinib, baricitinib, and corticosteroids. We searched PubMed, reviewed the Pharmacogenomics Knowledgebase (PharmGKB ®) website, Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines, the U.S. Food and Drug Administration (FDA) pharmacogenomics information in the product labeling, and the FDA pharmacogenomics association table. We found several drug-gene variant pairs that may alter the pharmacokinetics of hydroxychloroquine/chloroquine (CYP2C8, CYP2D6, SLCO1A2, and SLCO1B1); azithromycin (ABCB1); ribavirin (SLC29A1, SLC28A2, and SLC28A3); and lopinavir/ritonavir (SLCO1B1, ABCC2, CYP3A). We also identified other variants, that are associated with adverse effects, most notable in hydroxychloroquine/chloroquine (G6PD; hemolysis), ribavirin (ITPA; hemolysis), and interferon β-1b (IRF6; liver toxicity). We also describe the complexity of the risk for QT prolongation in this setting because of additive effects of combining more than one QT-prolonging drug (i.e., hydroxychloroquine/chloroquine and azithromycin), increased concentrations of the drugs due to genetic variants, along with the risk of also combining therapy with potent inhibitors. In conclusion, although direct evidence in COVID-19 patients is lacking, we identified potential actionable genetic markers in COVID-19 therapies. Clinical studies in COVID-19 patients are deemed warranted to assess potential roles of these markers.

Dysregulated transcriptional responses to SARS-CoV-2 in the periphery

“…3E and s4 ). While the small number of severely ill subjects ( n = 12) limits significant conclusion, the heterogeneity seen in expression of target inflammatory pathways across these individuals combined with the suboptimal performance of potential immunomodulatory agents when broadly applied 29 , 30 , suggests pharmacogenomic approaches to selecting host-directed therapies should be further explored 31 .…”

In-silico network-based analysis of drugs used against COVID-19: Human well-being study

“…For Azithromycin, we identified the most significant pathways to induce its effect by identifying twenty-nine genes representing 94.07% of shared protein domains and 5.03% of genetic interactions. Takahashi et al (2020) reported that azithromycin effect on only one ABCB1 gene encoded for P-glycoprotein transporter could be found in the pathway identified in our study ( Takahashi et al, 2020 )…”

Pharmacogenomics and COVID-19: clinical implications of human genome interactions with repurposed drugs

“…Therefore, the purpose of this review is to look at some drugs commonly used in regimens for COVID-19 and provides specific examples of how genetics may affect drug efficacy and toxicity. It adds to the efforts of recently published relevant articles [18][19][20] and does not serve as an exhaustive review of all relationships between host genetics and these drugs.…”