TdP Risk Assessment Categorization (TRAC) Calculator

Introduction

The TdP risk assessment categorization calculator is used to assess the TdP risk of small molecule compounds using three (3) hiPSC-CM electrophysiological response predictors as part of the evolving Comprehensive In Vitro Proarrhythmia Assay (CiPA) paradigm.

Predictor Inputs

Did drug-induced arrhythmia-like event occur at any concentration? 0=no arrhythmia, 1=type A arrhythmia, 2=any other arrhythmia type. (Example)

Maximum repolarization change observed at any concentration (ms).

Standard deviation of the Predictor 4 measurement. If provided, a Monte Carlo simulation (10 000 draws) is used to propagate measurement uncertainty into the confidence interval.

Drug-induced repolarization change at expected Cmax (ms).

Standard deviation of the Predictor 7 measurement. If provided, a Monte Carlo simulation (10 000 draws) is used to propagate measurement uncertainty into the confidence interval.

Instructions

  1. For details on how to use the hiPSC-CM CiPA TdP Risk Categorization Tool, read the Context of Use (COU), which includes limitations of use.
  2. Insert the model predictor input parameters in the "Predictor Inputs" section. Ranges for Predictor 4 and Predictor 7 are shown in the input fields upon startup, they will be replaced when user inputs are entered.
  3. Optionally, enter standard deviation (SD) values for Predictor 4 and Predictor 7 to enable Monte Carlo-based confidence interval estimation that accounts for measurement uncertainty. If left blank, the delta method is used.
  4. Read the outputs in the “Program Outputs” section to obtain the TdP risk categorization estimated by the selected parameters.
  5. Graphical depiction of the estimated TdP risk potential will be displayed in the “Program Outputs” section.

► Cmax Interpolation

Program Outputs

The background calculation uses a logistic regression model. The model outputs are:

► Hill Fit Curve (only available when input is filled in Cmax Interpolation)

References

  • Blinova K, Dang Q, Millard D, Smith G, Pierson J, Guo L, Brock M, Lu HR, Kraushaar U, Zeng H, Shi H, Zhang X, Sawada K, Osada T, Kanda Y, Sekino Y, Pang L, Feaster TK, Kettenhofen R, Stockbridge N, Strauss DG, Gintant G. International Multisite Study of Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes for Drug Proarrhythmic Potential Assessment. Cell Reports. 2018 Sep 25;24(13):3582-3592. doi: 10.1016/j.celrep.2018.08.079. PMID: 30257217; PMCID: PMC6226030