Utility of Normalized TdP Score System in Drug Proarrhythmic Potential Assessment: A Blinded in vitro Study of CiPA Drugs.

Drugs that prolong QT may cause torsade de pointes (TdP). However, translation of nonclinical assessment of QT prolongation or hERG channel, targeted by QT-prolonging drugs, into clinical TdP risk has been insufficient to date. In this blinded study, we confirmed the utility of a Normalized TdP Score System in predicting drug-induced TdP risks among 34 drugs, including 28 with low, intermediate and high TdP risks under the Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative plus 6 compounds with names blinded to the investigators, using the rabbit ventricular wedge assay. Concentration-dependent TdP scores were determined by drug-induced changes in QT, Tp-e and proarrhythmias. Disclosure of the names and testing concentrations was made after completion of the experiments and report to the sponsors. Drugs' normalized TdP scores were calculated thereafter based on their respective free clinical Cmax . Drugs' normalized TdP scores were calculated and ranked for 33 drugs, excluding one investigational drug, and the TdP risks of the 28 CiPA drugs were correctly distinguished according to their respective categories of low, intermediate and high TdP risks under the CiPA initiative. Accordingly, we are able to propose the cut-off values of the normalized TdP scores at 1xCmax : ≤0, >0 to <0.65 and ≥0.65 respectively for low, intermediate and high risk. This blinded study supports utility of our Normalized TdP Score System in predicting drug-induced TdP risks in 33 drugs including 28 used for characterization of other assays under the CiPA initiative. However, these results need to be replicated in other laboratories.