ORIGINAL RESEARCH article
Front. Drug Discov.
Sec. Cardiovascular and Hematologic Drugs
Volume 5 - 2025 | doi: 10.3389/fddsv.2025.1679626
This article is part of the Research TopicHuman iPSC Modeling of Heart Disease for Drug ScreeningView all articles
Leveraging Human Cardiac New Approach Methodologies (NAMs) to Evaluate the Combination of Repolarization Prolonging and Shortening Drugs
Provisionally accepted
- United States Food and Drug Administration, Silver Spring, United States
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Background and Purpose: Nonclinical human cardiac new approach methodologies (NAMs), including human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) combined with multielectrode array (MEA) represent a highly predictive in vitro model for identifying drug-induced cardiac liabilities of individual drugs. Here, we extend the use of an in vitro cardiac NAM to evaluate the safety of a drug combination including moxifloxacin, an antibiotic, and QT prolonging drug, and cobicistat a pharmacokinetic booster shown to shorten repolarization in vitro. Methods: To generate the in vitro cardiac NAM, MEA coupled with hiPSC-CMs were cultured for 7 to 8 days. Cells were treated with moxifloxacin and cobicistat individually or in combination and changes in electrophysiology and contractility were evaluated. Results: The combination of cobicistat and moxifloxacin resulted in a concentration-dependent shortening of the corrected field potential duration (FPDcF) relative to both vehicle control and moxifloxacin alone. This effect was observed at near clinical Cmax concentrations of cobicistat and moxifloxacin. Evaluation of local extracellular action potentials (LEAP) revealed early afterdepolarizations (EADs) with supratherapeutic concentrations of moxifloxacin which were subsequently eliminated by the addition of cobicistat at therapeutic concentrations. Finally, the Comprehensive in vitro Proarrhythmia Assay (CiPA) Torsades de Pointes (TdP) risk tool categorized moxifloxacin treated cells as having a high or intermediate risk probability for TdP while concomitant treatment with cobicistat resulted in a low-risk categorization. Conclusions: We conclude that cobicistat can attenuate moxifloxacin induced FPDcF prolongation at clinically relevant concentrations in vitro. Taken together, this work provides a foundation to evaluate drug combinations in vitro to aid regulatory decision-making and reduce the dependence on animal studies.
Keywords: New approach methodologies (NAMs), hiPSC-CM, Electrophysiology, NonclinicalStudy, complex in vitro model, microphysiological systems (MPS), Multielectrode Array(MEA), drug combination
Received: 06 Aug 2025; Accepted: 20 Oct 2025.
Copyright: © 2025 Geiger, Serna III, Bhardwaj, Feaster and Blinova. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Tromondae K Feaster, tromondae.feaster@fda.hhs.gov
Ksenia Blinova, ksenia.blinova@fda.hhs.gov
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