Abstract
The Comprehensive in vitro Proarrhythmia Assay (CiPA) project suggested the torsade metric score (TMS) which requires substantial computing resources as a useful biomarker to predict proarrhythmic risk from human ether-à-go-go–related gene (hERG) and a few other ion channel block data. The TMS was useful to predict low TdP risks of drugs blocking Na+ (ranolazine) and Ca2+ (verapamil) channels as well as the hERG channel. However, Mistry asserted that the simple linear metric, Bnet reflecting net blockade of a few influential ion channels has similar predictive power. Here we compared the predictability of Bnet and TMS for the 12 training and 16 validation CiPA drugs which were pre-classified into three categories according to the known TdP risks (low, intermediate, and high risk) by CiPA. Bnet at 5×Cmax (Bnet5×Cmax) was calculated using the ion-channel IC50 and Hill coefficients of CiPA drugs collected from previous reports by the CiPA team and others. The receiver operating characteristic curve area under curve (ROC AUC) values for TMS and Bnet5×Cmax as performance metrics in discerning low versus intermediate/high risk categories for the 28 CiPA drugs were similar. However, Bnet5×Cmax was much inferior to TMS at discerning between intermediate- and high-risk drugs. Dynamic Bnet, which used in silico hERG dynamic parameters unlike conventional Bnet, improved the misspecification. Thus, we propose that Bnet5×Cmax is used for quick screening of TdP risks of drug candidates and if the “intermediate/high” risk is predicted by Bnet5×Cmax, in silico approaches, such as dynamic Bnet or TMS, may be further considered.
Highlights
The International Council on Harmonization (ICH) established the guidelines, S7B for non-clinical evaluation and E14 for clinical evaluation of the proarrhythmic risk of drugs
As recommended by the guidelines, the conventional practice to evaluate the Torsades de Pointes (TdP) risks has been focused on the QTc interval from blockade of human ether-à-go-go–related gene channel (Shah, 2005) that is associated with rapidly activating delayed rectifier potassium current IKr. (Sager et al, 2014) ICH S7B and E14 regulatory guidelines have been successful in screening TdP risks of new drugs, there are several low TdP risk drugs with the prolonged action potential duration
A few groups have raised questions on the superiority in accuracies of model-driven in silico approaches. (Mistry et al, 2015; Mistry, 2017; Parikh et al, 2017; Mistry, 2018; Parikh et al, 2019; Mistry, 2019a) Especially, Mistry asserted that Bnet, a simple linear metric using the net difference between inward and outward ion channel blocking, has predictive power similar to that of torsade metric score (TMS). (Mistry, 2019a) Mistry questioned the usefulness of the complicated in silico approaches proposed by Comprehensive in vitro Proarrhythmia Assay (CiPA) if the performance to assess the proarrhythmic risk is similar, the CiPA researchers asserted the superiority of in silico approaches that consider the trapping of the human ether-à-go-go–related gene (hERG) and other channels through rigorous validation of the model (Li et al, 2019b)
Summary
The International Council on Harmonization (ICH) established the guidelines, S7B for non-clinical evaluation and E14 for clinical evaluation of the proarrhythmic risk of drugs. One of the major objectives of the Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative was to improve the current ICH guidelines to avoid the misclassification of TdP risks by evaluating mechanistically based in vitro assays and in silico reconstruction of the cardiac action potential. The CiPA ion channel working group and in silico modeling group suggested qNet and the torsade metric score (TMS) as conclusive markers via the CiPAORdv1.0, the mechanistic in silico model (Li et al, 2019b) based on a series of modification of O’Hara-Rudy (ORd) human ventricular myocyte model (O’hara et al, 2011). (Mistry, 2019a) Mistry questioned the usefulness of the complicated in silico approaches proposed by CiPA if the performance to assess the proarrhythmic risk is similar, the CiPA researchers asserted the superiority of in silico approaches that consider the trapping of the hERG and other channels through rigorous validation of the model (Li et al, 2019b) A few groups have raised questions on the superiority in accuracies of model-driven in silico approaches. (Mistry et al, 2015; Mistry, 2017; Parikh et al, 2017; Mistry, 2018; Parikh et al, 2019; Mistry, 2019a) Especially, Mistry asserted that Bnet, a simple linear metric using the net difference between inward and outward ion channel blocking, has predictive power similar to that of TMS. (Mistry, 2019a) Mistry questioned the usefulness of the complicated in silico approaches proposed by CiPA if the performance to assess the proarrhythmic risk is similar, the CiPA researchers asserted the superiority of in silico approaches that consider the trapping of the hERG and other channels through rigorous validation of the model (Li et al, 2019b)
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