title: Interaction between amiodarone and hepatitis-C virus nucleotide inhibitors in human induced pluripotent stem cell-derived cardiomyocytes and HEK-293 Cav1.2 over-expressing cells.
abstract: Several clinical cases of severe bradyarrhythmias have been reported upon co-administration of the Hepatitis-C NS5B Nucleotide Polymerase Inhibitor (HCV-NI) direct-acting antiviral agent, sofosbuvir (SOF), and the Class-III anti-arrhythmic amiodarone (AMIO). We model the cardiac drug-drug interaction (DDI) between AMIO and SOF, and between AMIO and a closely-related SOF analog, MNI-1 (Merck Nucleotide Inhibitor #1), in functional assays of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), to provide mechanistic insights into recently reported clinical cases. AMIO co-applied with SOF or MNI-1 increased beating rate or field potential (FP) rate and decreased impedance (IMP) and Ca(2+) transient amplitudes in hiPSC-CM syncytia. This action resembled that of Ca(2+) channel blockers (CCBs) in the model, but CCBs did not substitute for AMIO in the DDI. AMIO analog dronedarone (DRON) did not substitute for, but competed with AMIO in the DDI. Ryanodine and thapsigargin, decreasing intracellular Ca(2+) stores, and SEA-0400, a Na(+)/Ca(2+) exchanger-1 (NCX1) inhibitor, partially antagonized or suppressed DDI effects. Other agents affecting FP rate only exerted additive or subtractive effects, commensurate with their individual effects. We also describe an interaction between AMIO and MNI-1 on Cav1.2 ion channels in an over-expressing HEK-293 cell line. MNI-1 enhanced Cav1.2 channel inhibition by AMIO, but did not affect inhibition of Cav1.2 by DRON, verapamil, nifedipine, or diltiazem. Our data in hiPSC-CMs indicate that HCV-NI agents such as SOF and MNI-1 interact with key intracellular Ca(2+)-handling mechanisms. Additional study in a Cav1.2 HEK-293 cell-line suggests that HCV-NIs potentiate the inhibitory action of AMIO on L-type Ca(2+) channels.
authors: Merck Research Laboratories, SALAR Division, Safety & Exploratory Pharmacology (SEP) Department, West Point, PA, USA. Electronic address: armando_lagrutta@merck.com.
authors: Armando
authors: A
authors: Lagrutta
authors: Merck Research Laboratories, SALAR Division, Safety & Exploratory Pharmacology (SEP) Department, West Point, PA, USA.
authors: Haoyu
authors: H
authors: Zeng
authors: Merck Research Laboratories, SALAR Division, Safety & Exploratory Pharmacology (SEP) Department, West Point, PA, USA.
authors: John
authors: J
authors: Imredy
authors: Merck Research Laboratories, SALAR Division, Safety & Exploratory Pharmacology (SEP) Department, West Point, PA, USA.
authors: Bharathi
authors: B
authors: Balasubramanian
authors: Merck Research Laboratories, SALAR Division, Safety & Exploratory Pharmacology (SEP) Department, West Point, PA, USA.
authors: Spencer
authors: S
authors: Dech
authors: Merck Research Laboratories, SALAR Division, Safety & Exploratory Pharmacology (SEP) Department, West Point, PA, USA.
authors: Edward
authors: E
authors: Lis
authors: Merck Research Laboratories, SALAR Division, Safety & Exploratory Pharmacology (SEP) Department, West Point, PA, USA.
authors: Jixin
authors: J
authors: Wang
authors: Merck Research Laboratories, SALAR Division, Safety & Exploratory Pharmacology (SEP) Department, West Point, PA, USA.
authors: Jin
authors: J
authors: Zhai
authors: Merck Research Laboratories, SALAR Division, Safety & Exploratory Pharmacology (SEP) Department, West Point, PA, USA.
authors: Joseph
authors: J
authors: DeGeorge
authors: Merck Research Laboratories, SALAR Division, Safety & Exploratory Pharmacology (SEP) Department, West Point, PA, USA.
authors: Frederick
authors: F
authors: Sannajust
mesh_terms: D000638:Amiodarone / Q000494:pharmacology*; D000998:Antiviral Agents / Q000494:pharmacology*; D020746:Calcium Channels, L-Type; D057809:HEK293 Cells; D016174:Hepacivirus / Q000187:drug effects*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D020746:Calcium Channels, L-Type; C419385:L-type calcium channel alpha(1C); D000638:Amiodarone
keywords: Amiodarone; Calcium handling mechanism;; Drug-drug interaction; Hepatitis-C virus nucleoside inhibitors; Sofosbuvir; hiPSC-derived cardiomyocytes