{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T18:07:42Z","timestamp":1789150062820,"version":"build-2803163510"},"reference-count":14,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","license":[{"start":{"date-parts":[[2016,8,23]],"date-time":"2016-08-23T00:00:00Z","timestamp":1471910400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1"},{"start":{"date-parts":[[2016,8,23]],"date-time":"2016-08-23T00:00:00Z","timestamp":1471910400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2016,10,21]]},"abstract":"<jats:p>In 2015, European and U.S. health agencies issued warning letters in response to 9 reported clinical cases of severe bradycardia\/bradyarrhythmia in hepatitis C virus (HCV)\u2010infected patients treated with sofosbuvir (SOF) in combination with other direct acting antivirals (DAAs) and the antiarrhythmic drug, amiodarone (AMIO). We utilized preclinical <jats:italic toggle=\"yes\">in vivo<\/jats:italic> models to better understand this cardiac effect, the potential pharmacological mechanism(s), and to identify a clinically translatable model to assess the drug\u2010drug interaction (DDI) cardiac risk of current and future HCV inhibitors. An anesthetized guinea pig model was used to elicit a SOF+AMIO\u2010dependent bradycardia. Detailed cardiac electrophysiological studies in this species revealed SOF+AMIO\u2010dependent selective nodal dysfunction, with initial, larger effects on the sinoatrial node. Further studies in conscious, rhesus monkeys revealed an emergent bradycardia and bradyarrhythmia in 3 of 4 monkeys administered SOF+AMIO, effects not observed with either agent alone. Morever, bradycardia and bradyarrhythmia were not observed in rhesus monkeys when intravenous infusion of MK\u20103682 was completed after AMIO pretreatment. <jats:italic toggle=\"yes\">Conclusions<\/jats:italic>: These are the first preclinical <jats:italic toggle=\"yes\">in vivo<\/jats:italic> experiments reported to replicate the severe clinical SOF+AMIO cardiac DDI and provide potential <jats:italic toggle=\"yes\">in vivo<\/jats:italic> mechanism of action. As such, these data provide a preclinical risk assessment paradigm, including a clinically relevant nonhuman primate model, with which to better understand cardiovascular DDI risk for this therapeutic class. Furthermore, these studies suggest that not all HCV DAAs and, in particular, not all HCV nonstructural protein 5B inhibitors may exhibit this cardiac DDI with amiodarone. Given the selective <jats:italic toggle=\"yes\">in vivo<\/jats:italic> cardiac electrophysiological effect, these data enable targeted cellular\/molecular mechanistic studies to more precisely identify cell types, receptors, and\/or ion channels responsible for the clinical DDI. (H<jats:sc>epatology<\/jats:sc> 2016;64:1430\u20101441)<\/jats:p>","DOI":"10.1002\/hep.28752","type":"journal-article","created":{"date-parts":[[2016,8,23]],"date-time":"2016-08-23T10:56:40Z","timestamp":1471949800000},"page":"1430-1441","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":23,"title":["Assessment of the clinical cardiac drug\u2010drug interaction associated with the combination of hepatitis C virus nucleotide inhibitors and amiodarone in guinea pigs and rhesus monkeys"],"prefix":"10.1097","volume":"64","author":[{"given":"Christopher P.","family":"Regan","sequence":"first","affiliation":[{"name":"Department of Safety & Exploratory Pharmacology,Merck Research Laboratories,West Point,PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre","family":"Morissette","sequence":"additional","affiliation":[{"name":"Department of Safety & Exploratory Pharmacology,Merck Research Laboratories,West Point,PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hillary K.","family":"Regan","sequence":"additional","affiliation":[{"name":"Department of Safety & Exploratory Pharmacology,Merck Research Laboratories,West Point,PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffery J.","family":"Travis","sequence":"additional","affiliation":[{"name":"Department of Safety & Exploratory Pharmacology,Merck Research Laboratories,West Point,PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pamela","family":"Gerenser","sequence":"additional","affiliation":[{"name":"Department of Safety & Exploratory Pharmacology,Merck Research Laboratories,West Point,PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianzhong","family":"Wen","sequence":"additional","affiliation":[{"name":"Pharmacokinetics, Pharmacodynamics & Drug Metabolism,Merck Research Laboratories,West Point,PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Fitzgerald","sequence":"additional","affiliation":[{"name":"Department of Safety & Exploratory Pharmacology,Merck Research Laboratories,West Point,PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaun","family":"Gruver","sequence":"additional","affiliation":[{"name":"Department of Safety & Exploratory Pharmacology,Merck Research Laboratories,West Point,PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph J.","family":"DeGeorge","sequence":"additional","affiliation":[{"name":"Safety Assessment and Laboratory Animal Resources,Merck Research Laboratories,West Point,PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederick J.","family":"Sannajust","sequence":"additional","affiliation":[{"name":"Department of Safety & Exploratory Pharmacology,Merck Research Laboratories,West 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