{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T15:14:05Z","timestamp":1772118845484,"version":"3.50.1"},"reference-count":34,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2021,2,11]],"date-time":"2021-02-11T00:00:00Z","timestamp":1613001600000},"content-version":"am","delay-in-days":10,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2021,2,11]],"date-time":"2021-02-11T00:00:00Z","timestamp":1613001600000},"content-version":"vor","delay-in-days":10,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["U01 HL136297"],"award-info":[{"award-number":["U01 HL136297"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["U54 HG008098"],"award-info":[{"award-number":["U54 HG008098"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["MCB 1615677"],"award-info":[{"award-number":["MCB 1615677"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["75F40119C10021"],"award-info":[{"award-number":["75F40119C10021"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009210","name":"Food and Drug Administration","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009210","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["T32 GM062754"],"award-info":[{"award-number":["T32 GM062754"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CPT Pharmacom &amp; Syst Pharma"],"published-print":{"date-parts":[[2021,2]]},"abstract":"<jats:p>Many drugs that have been proposed for treatment of coronavirus disease 2019 (COVID\u201019) are reported to cause cardiac adverse events, including ventricular arrhythmias. In order to properly weigh risks against potential benefits, particularly when decisions must be made quickly, mathematical modeling of both drug disposition and drug action can be useful for predicting patient response and making informed decisions. Here, we explored the potential effects on cardiac electrophysiology of four drugs proposed to treat COVID\u201019: lopinavir, ritonavir, chloroquine, and azithromycin, as well as combination therapy involving these drugs. Our study combined simulations of pharmacokinetics (PKs) with quantitative systems pharmacology (QSP) modeling of ventricular myocytes to predict potential cardiac adverse events caused by these treatments. Simulation results predicted that drug combinations can lead to greater cellular action potential prolongation, analogous to QT prolongation, compared with drugs given in isolation. The combination effect can result from both PK and pharmacodynamic drug interactions. Importantly, simulations of different patient groups predicted that women with pre\u2010existing heart disease are especially susceptible to drug\u2010induced arrhythmias, compared with diseased men or healthy individuals of either sex. Statistical analysis of population simulations revealed the molecular factors that make certain women with heart failure especially susceptible to arrhythmias. Overall, the results illustrate how PK and QSP modeling may be combined to more precisely predict cardiac risks of COVID\u201019 therapies.<\/jats:p>","DOI":"10.1002\/psp4.12573","type":"journal-article","created":{"date-parts":[[2020,11,18]],"date-time":"2020-11-18T02:25:01Z","timestamp":1605666301000},"page":"100-107","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Investigational Treatments for COVID\u201019 may Increase Ventricular Arrhythmia Risk Through Drug Interactions"],"prefix":"10.1002","volume":"10","author":[{"given":"Meera","family":"Varshneya","sequence":"first","affiliation":[{"name":"Department of Pharmacological Sciences and Graduate School of Biomedical Sciences Icahn School of Medicine at Mount Sinai  New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Itziar","family":"Irurzun-Arana","sequence":"additional","affiliation":[{"name":"Department of Pharmacological Sciences and Graduate School of Biomedical Sciences Icahn School of Medicine at Mount Sinai  New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chiara","family":"Campana","sequence":"additional","affiliation":[{"name":"Department of Pharmacological Sciences and Graduate School of Biomedical Sciences Icahn School of Medicine at Mount Sinai  New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rafael","family":"Dariolli","sequence":"additional","affiliation":[{"name":"Department of Pharmacological Sciences and Graduate School of Biomedical Sciences Icahn School of Medicine at Mount Sinai  New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amy","family":"Gutierrez","sequence":"additional","affiliation":[{"name":"Department of Pharmacological Sciences and Graduate School of Biomedical Sciences Icahn School of Medicine at Mount Sinai  New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Taylor K.","family":"Pullinger","sequence":"additional","affiliation":[{"name":"Department of Pharmacological Sciences and Graduate School of Biomedical Sciences Icahn School of Medicine at Mount Sinai  New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric A.","family":"Sobie","sequence":"additional","affiliation":[{"name":"Department of Pharmacological Sciences and Graduate School of Biomedical Sciences Icahn School of Medicine at Mount Sinai  New York New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2021,2,11]]},"reference":[{"key":"e_1_2_10_1_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2001282"},{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.2174\/0929867327666200416131117"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2020.8857"},{"key":"e_1_2_10_4_1","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1186\/s13063-020-04407-x","article-title":"The COVIRL\u2010001 trial: a multicentre, prospective, randomised trial comparing standard of care (SOC) alone, SOC plus hydroxychloroquine monotherapy or SOC plus a combination of hydroxychloroquine and azithromycin in the treatment of non\u2010critical, SARS\u2010CoV\u20102 PCR\u2010positive population not requiring immediate resuscitation or ventilation but who have evidence of clinical decline: a structured summary of a study protocol for a randomised controlled trial","volume":"21","author":"Feeney E.","year":"2020","journal-title":"Trials"},{"key":"e_1_2_10_5_1","article-title":"An evaluation of co\u2010use of chloroquine or hydroxychloroquine plus azithromycin on cardiac outcomes: a pharmacoepidemiological study to inform use during the COVID19 pandemic","author":"Vouri S.M.","journal-title":"Res. Social Adm. Pharm."},{"key":"e_1_2_10_6_1","unstructured":"Smith T.B.J. LeClaire A.&Prosser T.Elsevier clinical solutions: COVID\u201019 drug therapy. Elsevier website Updated April 30 2020 <https:\/\/www.elsevier.com\/__data\/assets\/pdf_file\/0007\/988648\/COVID\u2010988619\u2010Drug\u2010Therapy_March\u2010982020.pdf> (2020)."},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCEP.120.008662"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2020.104854"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.apsb.2020.04.007"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-013-0122-1"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02904-14"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.1893"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.367"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.1184"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2017.00668"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.vascn.2016.03.009"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1002061"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1097\/QAI.0b013e31827fd47e"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.1983.tb01513.x"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00021.2015"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1124\/pr.110.003723"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP273142"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0106602"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2015.07.016"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCEP.118.006558"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41540-018-0047-2"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2012.12.055"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mex.2016.12.002"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.2165\/00003088-199631040-00003"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijantimicag.2020.105949"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mayocp.2020.03.024"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.3390\/jcm9082591"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2020.587709"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.3390\/jcm9041225"}],"container-title":["CPT: Pharmacometrics &amp; Systems Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/psp4.12573","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/psp4.12573","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/psp4.12573","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/psp4.12573","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,2]],"date-time":"2023-09-02T21:11:03Z","timestamp":1693689063000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1002\/psp4.12573"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2]]},"references-count":34,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2021,2]]}},"alternative-id":["10.1002\/psp4.12573"],"URL":"https:\/\/doi.org\/10.1002\/psp4.12573","archive":["Portico"],"relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2020.05.21.20109397","asserted-by":"object"}]},"ISSN":["2163-8306","2163-8306"],"issn-type":[{"value":"2163-8306","type":"print"},{"value":"2163-8306","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2]]},"assertion":[{"value":"2020-09-30","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-10-30","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-02-11","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}