br Experimental Procedures br Author Contributions

Experimental Procedures
Author Contributions
Acknowledgments The targeted Ainv15 mESC line with was a kind gift from Paul Gadue (University of Pennsylvania). We would like to thank Brian R. Tilton and Patrick Autissier from the BU Flow Cytometry Core Facility as well as Michael T. Kirber from the BU Cellular Imaging Core for technical assistance. We thank Nicholas Skvir for help with visualization of RNA-seq data and Matthew Lawton for his help with immunostaining and technical assistance. K.D. was supported by a CTSI TL1 grant TL1TR001410, J.C. and A.N.H. by NIHDK105029, L.I. by NIH R01 HL111574, D.N.K. by NIH R01 HL095993, NIH R01 HL122442, and NIH DK105029, and P.M. by a Simons Investigator in MMLS (Simons Foundation).
Introduction Serious adverse events (SAE) are major causes of drug attrition during clinical development (Hay et al., 2014) or withdrawal of marketed drugs. Although models for nonclinical toxicology and safety pharmacological studies have improved in recent years, predicting SAE in preclinical studies remains challenging because SAE often occur in a small SEA-prone patient subgroup (Stevens and Baker, 2009). Moreover, conventional cellular or animal models are not suitable for the investigation of interindividual differences in drug susceptibility. Interestingly, cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs; Takahashi et al., 2007) can be used to assess disease-associated genetic susceptibility to drug-induced cardiac toxicity in vitro (Liang et al., 2013). hiPSC-CMs from individuals with different susceptibilities to SAE have been proposed to serve as a novel translational research model for in vitro preclinical trials (Inoue et al., 2014). However, whether or not individual SAE susceptibility in a ppar antagonist of volunteers with unknown genetic susceptibility such as healthy volunteers can be recapitulated in hiPSC-derived cells remains unclear. Generally, in phase I studies healthy volunteers are recruited to assess the toxicity and drug distribution in the body under low dosing and, in many clinical trials, genetic background-associated drug susceptibility to SAE is unknown before dosing. Therefore, it is important to assess the intrinsic drug susceptibility before dosing to prevent side effects. Here, we tested this concept using healthy volunteer-derived hiPSC-CMs, which have contractile ability with ion channel activity and have been recognized for their potential in human heart disease modeling, preclinical cardiotoxicity evaluation, and drug discovery (Zhang et al., 2009). Drug-induced torsades de pointes (TdP) is the most common reason for market restriction or withdrawal of drugs (Lasser et al., 2002). TdP is typically caused by inhibition of the inward rectifying potassium channel hERG (human ether-à-go-go related gene encoded by KCNH2), resulting in a prolongation of the time between depolarization and repolarization, known as the QT interval (Guo et al., 2011). hiPSC-CMs are a useful tool for the assessment of drug-induced QT prolongation (Sallam et al., 2015; Mehta et al., 2011; Reppel et al., 2005; Braam et al., 2010). Thus, we evaluated the correlation between susceptibility to moxifloxacin (Mox)-induced QT prolongation (Chen et al., 2005; Roden, 2004; Sherazi et al., 2008) and that to Mox-induced prolonged repolarization in hiPSC-CMs generated from blood samples of the same individuals from our previous clinical investigational study, in which we observed interindividual susceptibility to QT prolongation (Shiramoto et al., 2014). Mox, a fluoroquinolone antibiotic and a rapid delayed-rectifier potassium channel blocker that prolongs QT, is commonly used as a positive control in “thorough QT” (TQT) studies (Chen et al., 2005; Florian et al., 2011). These are designed to measure QT prolongation to better assess the potential arrhythmia liability of a drug in healthy volunteers based on the regulatory guidelines for new drug development (Food and Drug Administration, HHS, 2005).