Abstract In addition to 170 approved therapeutic drugs whose adverse effects include QT prolongation, a prevalence of 1:2500 subjects in the US are genetically susceptible, or have a diabetic syndrome with increased risk of QT prolongation, torsade de pointes, and sudden death. To address this risk we determined the mitigating effect of a liposome and its components administered intravenously and orally on clinically approved QT-prolonging anticancer drugs, crizotinib and nilotinib, and an antibiotic moxifloxacin (MF) in vitro and in vivo in rats and guinea pigs. Intravenous MF at 20 mg/kg caused a statistically significant QTc prolongation of 35ms in guinea pigs. This observation is in line with peer-reviewed literature in which an oral dose of 400 mg (or approximately 6.1 mg/kg) in humans caused the FDA to black-label MF for causing QT interval prolongation in patients. The mitigating effect of a liposome consisting of dimyristoyl phosphatidylcholine (DMPC) and dimyristoyl phosphatidylglycerol (DMPG) on curcumin, a compound that inhibits the IKr (hERG) current, was initially discovered during preclinical testing with Lipocurc™. Additional patch-clamp studies with DMPC, DMPG, their metabolites myristoyl lysophosphatidylcholine (14:0 LPC) and myristoyl lysophosphatidylglycerol (14:0 LPG), and a synthetic compound, myristoyl ethyleneglycolphosphatidylglycerol (EGPG), revealed mitigation of crizotinib- and nilotinib-induced inhibition of the IKr current. Formulation of 14:0 LPG in a eutectic mixture with a monoglyceride and myristic acid (EU8120) given orally to both normal and diabetic rats prior to challenge with intravenous nilotinib resulted in significantly reduced QT prolongation. We quantified and compared the conduction delays on QT intervals in guinea pigs induced by MF alone with those of MF preceded by oral administration of EU8120, 14:0 LPG, 16:0 LPG, EGPG and DMPG. Three ratios of phospholipids:MF were tested for mitigation of conduction delays: 3:1, 1:1 and 0.3:1. At the 3:1 ratio, all the compounds tested mitigated MF-induced prolongation of QT intervals. While EGPG induced the most protection it caused bradycardia which limited its beneficial effects at that dose level. DMPG was the least potent. At lower ratios of 1:1 and 0.3:1 the mitigating effects of EU8120, EGPG and DMPG were maintained with equal potency. Lipid:MF ratios of 0.1:1 and 0.03:1 are currently being tested and will identify a lead compound for drug development, and offer insight into its mechanism of action. Citation Format: Lawrence Helson, Walter A. Shaw, Stephen W. Burgess, George Shopp, Annie Bouchard, Dany Savail, Muhammed Majeed. Identifying a lead compound for mitigation of drug-induced PQTS. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2610. doi:10.1158/1538-7445.AM2015-2610