Informing selection of drugs for COVID-19 treatment through adverse events analysis

Guo, Wenjing; Pan, Bohu; Sakkiah, Sugunadevi; Ji, Zuowei; Yavas, Gokhan; Lu, Yanhui; Komatsu, Takashi E.; Lal-Nag, Madhu; Tong, Weida; Patterson, Tucker A.; Hong, Huixiao

doi:10.1038/s41598-021-93500-5

Informing selection of drugs for COVID-19 treatment through adverse events analysis

Journal Article · Wed Jul 07 00:00:00 EDT 2021 · Scientific Reports

DOI:https://doi.org/10.1038/s41598-021-93500-5· OSTI ID:1816937

Guo, Wenjing ^[1]; Pan, Bohu ^[2]; Sakkiah, Sugunadevi ^[2]; Ji, Zuowei ^[2]; Yavas, Gokhan ^[2]; Lu, Yanhui ^[3]; Komatsu, Takashi E. ^[3]; Lal-Nag, Madhu ^[3]; Tong, Weida ^[2]; Patterson, Tucker A. ^[2]; Hong, Huixiao ^[2]

U.S. Food and Drug Administration (FDA), Jefferson, AR (United States). National Center for Toxicological Research; OSTI
U.S. Food and Drug Administration (FDA), Jefferson, AR (United States). National Center for Toxicological Research
U.S. Food and Drug Administration (FDA), Silver Spring, MD (United States). Center for Drug Evaluation and Research

Coronavirus disease 2019 (COVID-19) is an ongoing pandemic and there is an urgent need for safe and effective drugs for COVID-19 treatment. Since developing a new drug is time consuming, many approved or investigational drugs have been repurposed for COVID-19 treatment in clinical trials. Therefore, selection of safe drugs for COVID-19 patients is vital for combating this pandemic. Our goal was to evaluate the safety concerns of drugs by analyzing adverse events reported in post-market surveillance. We collected 296 drugs that have been evaluated in clinical trials for COVID-19 and identified 28,597,464 associated adverse events at the system organ classes (SOCs) level in the FDA adverse events report systems (FAERS). We calculated Z-scores of SOCs that statistically quantify the relative frequency of adverse events of drugs in FAERS to quantitatively measure safety concerns for the drugs. Analyzing the Z-scores revealed that these drugs are associated with different significantly frequent adverse events. Our results suggest that this safety concern metric may serve as a tool to inform selection of drugs with favorable safety profiles for COVID-19 patients in clinical practices. Caution is advised when administering drugs with high Z-scores to patients who are vulnerable to associated adverse events.

View Accepted Manuscript (DOE)

Research Organization:: Oak Ridge Inst. for Science and Education (ORISE), Oak Ridge, TN (United States)

Sponsoring Organization:: USDOE

Grant/Contract Number:: SC0014664

OSTI ID:: 1816937

Journal Information:: Scientific Reports, Journal Name: Scientific Reports Journal Issue: 1 Vol. 11; ISSN 2045-2322

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

References (24)

Association of Treatment With Hydroxychloroquine or Azithromycin With In-Hospital Mortality in Patients With COVID-19 in New York State Rosenberg, Eli S.; Dufort, Elizabeth M.; Udo, Tomoko JAMA, Vol. 323, Issue 24 https://doi.org/10.1001/jama.2020.8630	journal	June 2020
Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China Huang, Chaolin; Wang, Yeming; Li, Xingwang The Lancet, Vol. 395, Issue 10223 https://doi.org/10.1016/S0140-6736(20)30183-5	journal	February 2020
Antivirals for COVID-19: A critical review Frediansyah, Andri; Tiwari, Ruchi; Sharun, Khan Clinical Epidemiology and Global Health, Vol. 9 https://doi.org/10.1016/j.cegh.2020.07.006	journal	January 2021
Molecular docking, molecular dynamics, and in vitro studies reveal the potential of angiotensin II receptor blockers to inhibit the COVID-19 main protease Alnajjar, Radwan; Mostafa, Ahmed; Kandeil, Ahmed Heliyon, Vol. 6, Issue 12 https://doi.org/10.1016/j.heliyon.2020.e05641	journal	December 2020
The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak Rothan, Hussin A.; Byrareddy, Siddappa N. Journal of Autoimmunity, Vol. 109 https://doi.org/10.1016/j.jaut.2020.102433	journal	May 2020
A systematic review on the efficacy and safety of chloroquine for the treatment of COVID-19 Cortegiani, Andrea; Ingoglia, Giulia; Ippolito, Mariachiara Journal of Critical Care, Vol. 57 https://doi.org/10.1016/j.jcrc.2020.03.005	journal	June 2020
No evidence of rapid antiviral clearance or clinical benefit with the combination of hydroxychloroquine and azithromycin in patients with severe COVID-19 infection Molina, J. M.; Delaugerre, C.; Le Goff, J. Médecine et Maladies Infectieuses, Vol. 50, Issue 4 https://doi.org/10.1016/j.medmal.2020.03.006	journal	June 2020
COVID-19 and therapeutic drugs repurposing in hand: The need for collaborative efforts Khan, Z.; Karataş, Y.; Ceylan, A. F. Le Pharmacien Hospitalier et Clinicien, Vol. 56, Issue 1 https://doi.org/10.1016/j.phclin.2020.06.003	journal	March 2021
Research and Development on Therapeutic Agents and Vaccines for COVID-19 and Related Human Coronavirus Diseases Liu, Cynthia; Zhou, Qiongqiong; Li, Yingzhu ACS Central Science, Vol. 6, Issue 3 https://doi.org/10.1021/acscentsci.0c00272	journal	March 2020
Immune-mediated approaches against COVID-19 Florindo, Helena F.; Kleiner, Ron; Vaskovich-Koubi, Daniella Nature Nanotechnology, Vol. 15, Issue 8 https://doi.org/10.1038/s41565-020-0732-3	journal	July 2020
COVID-19: immunopathology and its implications for therapy Cao, Xuetao Nature Reviews Immunology, Vol. 20, Issue 5 https://doi.org/10.1038/s41577-020-0308-3	journal	April 2020
Hydroxychloroquine use against SARS-CoV-2 infection in non-human primates Maisonnasse, Pauline; Guedj, Jérémie; Contreras, Vanessa Nature, Vol. 585, Issue 7826 https://doi.org/10.1038/s41586-020-2558-4	journal	July 2020
Chloroquine does not inhibit infection of human lung cells with SARS-CoV-2 Hoffmann, Markus; Mösbauer, Kirstin; Hofmann-Winkler, Heike Nature, Vol. 585, Issue 7826 https://doi.org/10.1038/s41586-020-2575-3	journal	July 2020
Systematic Analysis of Adverse Event Reports for Sex Differences in Adverse Drug Events Yu, Yue; Chen, Jun; Li, Dingcheng Scientific Reports, Vol. 6, Issue 1 https://doi.org/10.1038/srep24955	journal	April 2016
A Trial of Lopinavir–Ritonavir in Adults Hospitalized with Severe Covid-19 Cao, Bin; Wang, Yeming; Wen, Danning New England Journal of Medicine, Vol. 382, Issue 19 https://doi.org/10.1056/NEJMoa2001282	journal	May 2020
Identify potent SARS-CoV-2 main protease inhibitors via accelerated free energy perturbation-based virtual screening of existing drugs Li, Zhe; Li, Xin; Huang, Yi-You Proceedings of the National Academy of Sciences, Vol. 117, Issue 44 https://doi.org/10.1073/pnas.2010470117	journal	October 2020
In silico analysis and identification of promising hits against 2019 novel coronavirus 3C-like main protease enzyme Chatterjee, Shilpa; Maity, Arindam; Chowdhury, Suchana Journal of Biomolecular Structure and Dynamics, Vol. 39, Issue 14 https://doi.org/10.1080/07391102.2020.1787228	journal	July 2020
COVID-19 and the Drug Repurposing Tsunami Mucke, Hermann A. M. ASSAY and Drug Development Technologies, Vol. 18, Issue 5 https://doi.org/10.1089/adt.2020.996	journal	July 2020
BioPortal: ontologies and integrated data resources at the click of a mouse Noy, N. F.; Shah, N. H.; Whetzel, P. L. Nucleic Acids Research, Vol. 37, Issue Web Server https://doi.org/10.1093/nar/gkp440	journal	May 2009
DrugBank 5.0: a major update to the DrugBank database for 2018 Wishart, David S.; Feunang, Yannick D.; Guo, An C. Nucleic Acids Research, Vol. 46, Issue D1 https://doi.org/10.1093/nar/gkx1037	journal	November 2017
Study of serious adverse drug reactions using FDA-approved drug labeling and MedDRA Wu, Leihong; Ingle, Taylor; Liu, Zhichao BMC Bioinformatics, Vol. 20, Issue S2 https://doi.org/10.1186/s12859-019-2628-5	journal	March 2019
The Medical Dictionary for Regulatory Activities (MedDRA) Brown, Elliot G.; Wood, Louise; Wood, Sue Drug Safety, Vol. 20, Issue 2 https://doi.org/10.2165/00002018-199920020-00002	journal	January 1999
Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies Gao, Jianjun; Tian, Zhenxue; Yang, Xu BioScience Trends, Vol. 14, Issue 1 https://doi.org/10.5582/bst.2020.01047	journal	January 2020
Neuropsychiatric adverse events of chloroquine: a real-world pharmacovigilance study using the FDA Adverse Event Reporting System (FAERS) database Sato, Kenichiro; Mano, Tatsuo; Iwata, Atsushi BioScience Trends, Vol. 14, Issue 2 https://doi.org/10.5582/bst.2020.03082	journal	January 2020

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Database of adverse events associated with drugs and drug combinations Poleksic, Aleksandar; Xie, Lei Scientific Reports, Vol. 9, Issue 1 https://doi.org/10.1038/s41598-019-56525-5	journal	December 2019
Assessment of adverse events related to anti-influenza neuraminidase inhibitors using the FDA adverse event reporting system and online patient reviews Han, Nayoung; Oh, Jung Mi; Kim, In-Wha Scientific Reports, Vol. 10, Issue 1 https://doi.org/10.1038/s41598-020-60068-5	journal	February 2020
Effects of 28-day Bifidobacterium animalis subsp. lactis HN019 supplementation on colonic transit time and gastrointestinal symptoms in adults with functional constipation: A double-blind, randomized, placebo-controlled, and dose-ranging trial Ibarra, Alvin; Latreille-Barbier, Mathilde; Donazzolo, Yves Gut Microbes, Vol. 9, Issue 3 https://doi.org/10.1080/19490976.2017.1412908	journal	February 2018
Vedolizumab safety in pregnancy and newborn outcomes Julsgaard, Mette; Kjeldsen, Jens; Baumgart, Daniel C. Gut, Vol. 66, Issue 10 https://doi.org/10.1136/gutjnl-2016-313444	journal	January 2017
The RICORDO approach to semantic interoperability for biomedical data and models: strategy, standards and solutions de Bono, Bernard; Hoehndorf, Robert; Wimalaratne, Sarala BMC Research Notes, Vol. 4, Issue 1 https://doi.org/10.1186/1756-0500-4-313	journal	August 2011
The Ontology of Vaccine Adverse Events (OVAE) and its usage in representing and analyzing adverse events associated with US-licensed human vaccines Marcos, Erica; Zhao, Bin; He, Yongqun Journal of Biomedical Semantics, Vol. 4, Issue 1 https://doi.org/10.1186/2041-1480-4-40	journal	November 2013
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In silico analysis of autoimmune diseases and genetic relationships to vaccination against infectious diseases McGarvey, Peter B.; Suzek, Baris E.; Baraniuk, James N. BMC Immunology, Vol. 15, Issue 1 https://doi.org/10.1186/s12865-014-0061-0	journal	December 2014
Towards early detection of adverse drug reactions: combining pre-clinical drug structures and post-market safety reports Liu, Ruoqi; Zhang, Ping BMC Medical Informatics and Decision Making, Vol. 19, Issue 1 https://doi.org/10.1186/s12911-019-0999-1	journal	December 2019
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