title: Identification of Drug-Drug Interactions In Vitro: A Case Study Evaluating the Effects of Sofosbuvir and Amiodarone on hiPSC-Derived Cardiomyocytes.
abstract: Drug-drug interactions pose a difficult drug safety problem, given the increasing number of individuals taking multiple medications and the relative complexity of assessing the potential for interactions. For example, sofosbuvir-based drug treatments have significantly advanced care for hepatitis C virus-infected patients, yet recent reports suggest interactions with amiodarone may cause severe symptomatic bradycardia and thus limit an otherwise extremely effective treatment. Here, we evaluated the ability of human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) to recapitulate the interaction between sofosbuvir and amiodarone in vitro, and more generally assessed the feasibility of hiPSC-CMs as a model system for drug-drug interactions. Sofosbuvir alone had negligible effects on cardiomyocyte electrophysiology, whereas the sofosbuvir-amiodarone combination produced dose-dependent effects beyond that of amiodarone alone. By comparison, GS-331007, the primary circulating metabolite of sofosbuvir, had no effect alone or in combination with amiodarone. Further mechanistic studies revealed that the sofosbuvir-amiodarone combination disrupted intracellular calcium (Ca2+) handling and cellular electrophysiology at pharmacologically relevant concentrations, and mechanical activity at supra-pharmacological (30x Cmax) concentrations. These effects were independent of the common mechanisms of direct ion channel block and P-glycoprotein activity. These results support hiPSC-CMs as a comprehensive, yet scalable model system for the identification and evaluation of cardioactive pharmacodynamic drug-drug interactions.
authors: *Axion BioSystems, Inc, Atlanta, Georgia dmillard@axion-biosystems.com.
authors: Daniel C
authors: DC
authors: Millard
authors: Cyprotex, Watertown, Massachusetts.
authors: Christopher J
authors: CJ
authors: Strock
authors: Cellular Dynamics International, a Fujifilm Company, Madison, Wisconsin.
authors: Coby B
authors: CB
authors: Carlson
authors: Cellular Dynamics International, a Fujifilm Company, Madison, Wisconsin.
authors: Natsuyo
authors: N
authors: Aoyama
authors: Nanion Technologies GmbH, Munich, Germany.|Technische Universitat Munchen, Munich, Germany.
authors: Krisztina
authors: K
authors: Juhasz
authors: Nanion Technologies GmbH, Munich, Germany.
authors: Tom A
authors: TA
authors: Goetze
authors: Nanion Technologies GmbH, Munich, Germany.
authors: Sonja
authors: S
authors: Stoelzle-Feix
authors: Nanion Technologies GmbH, Munich, Germany.
authors: Nadine
authors: N
authors: Becker
authors: Nanion Technologies GmbH, Munich, Germany.
authors: Niels
authors: N
authors: Fertig
authors: School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin.
authors: Craig T
authors: CT
authors: January
authors: Cellular Dynamics International, a Fujifilm Company, Madison, Wisconsin.
authors: Blake D
authors: BD
authors: Anson
authors: *Axion BioSystems, Inc, Atlanta, Georgia.
authors: James D
authors: JD
authors: Ross
mesh_terms: D000638:Amiodarone / Q000633:toxicity*; D004347:Drug Interactions; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000187:drug effects*; D000069474:Sofosbuvir / Q000633:toxicity*
chemical_list: D000638:Amiodarone; D000069474:Sofosbuvir
keywords: cardiac electrophysiology; cardiomyocyte; drug interactions; safety; stem cell