Quantitative Systems Pharmacology Models for a New International Cardiac Safety Regulatory Paradigm: An Overview of the Comprehensive In Vitro Proarrhythmia Assay In Silico Modeling Approach

Figures

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  Figure 1. The Comprehensive In Vitro Proarrhythmia Assay (CiPA) in silico model validation strategy. The CiPA in silico model validation strategy is shown as a flowchart. The model training process includes model optimization and metric development using published human cardiomyocyte experimental data originally used for O'Hara Rudy model development and newly acquired in vitro drug block data against various cardiac currents for the 12 training compounds. A “freezing” step makes sure the model structure and parameters, the metric, the simulation procedure, classification thresholds, and acceptable performance measures were all prespecified prior to the model validation process, where the torsade de pointes risk profiles of the 16 validation drugs were predicted. After successful validation, the classification thresholds for risk prediction can be updated using all 28 drugs. This procedure was approved by the CiPA Steering Committee and time stamped in the validation strategy document (Supplementary Text 1 of ref. 36) before the actual validation took place. The figure was adapted from ref. 36 and is licensed under CC BY 4.0. ©2018 The authors.

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  Figure 2. The pharmacodynamic submodel of drug–human ether‐à‐go‐go related gene (hERG) dynamic interaction and its impact on risk prediction. (a) A diagram of the hERG submodel describing the channel‐gating (physiological component) and drug‐binding (pharmacodynamic component) processes of the hERG–drug interaction. Each node represents a distinct state (conformation) of the channel. States with an asterisk indicate drug‐bound states, whereas those without are drug‐free channel states. O, open state; C, closed state; IO, inactivated open state; IC, inactivated closed state; O*, open‐bound state; IO*, inactivated open‐bound state; C*, closed‐bound state. Note that there are two inactivated closed (IC) and closed (C) states, and they are distinguished by a numeric suffix (such as IC1, IC2 for the two IC states). (b) Using a dynamic voltage protocol to manifest the different binding kinetics of two selective hERG blockers, dofetilide (at 30 nM) and cisapride (at 300 nM). The voltage protocol is briefly shown in the top panel as voltage steps alternating between −80 and 0 mV. For the main panels, x‐axis is the time in milliseconds (ms) after the protocol was applied to the cell. y‐axis is…