Humans Vary, So Cardiac Models Should Account for That Too!

Abstract

The utilization of mathematical modeling and simulation in drug development encompasses multiple mathematical techniques and the location of a drug candidate in the development pipeline. Historically speaking they have been used to analyze experimental data (i.e., Hill equation) and clarify the involved physical and chemical processes (i.e., Fick laws and drug molecule diffusion). In recent years the advanced utilization of mathematical modeling has been an important part of the regulatory review process. Physiologically based pharmacokinetic (PBPK) models identify the need to conduct specific clinical studies, suggest specific study designs and propose appropriate labeling language. Their application allows the evaluation of the influence of intrinsic (e.g., age, gender, genetics, disease) and extrinsic [e.g., dosing schedule, drug-drug interactions (DDIs)] factors, alone or in combinations, on drug exposure and therefore provides accurate population assessment. A similar pathway has been taken for the assessment of drug safety with cardiac safety being one the most advanced examples. Mechanistic mathematical model-informed safety evaluation, with a focus on drug potential for causing arrhythmias, is now discussed as an element of the Comprehensive in vitro Proarrhythmia Assay. One of the pillars of this paradigm is the use of an in silico model of the adult human ventricular cardiomyocyte to integrate in vitro measured data. Existing examples (in vitro—in vivo extrapolation with the use of PBPK models) suggest that deterministic, epidemiological and clinical data based variability models can be merged with the mechanistic models describing human physiology. There are other methods available, based on the stochastic approach and on population of models generated by randomly assigning specific parameter values (ionic current conductance and kinetic) and further pruning. Both approaches are briefly characterized in this manuscript, in parallel with the drug-specific variability.

Uncertainty assessment of proarrhythmia predictions derived from multi-level in silico models

“…As for experimental variability, the consideration of inter-individual variability in cardiac model inputs can be seen as a step in the direction of realistic cardiac safety assessment. As described by Wisniowska et al ( 2017 ), “Humans vary, so cardiac models should account for that too…”. The importance of considering inter-individual differences with regard to drug effects is particularly important if it comes to the protection of individuals who are more prone to develop cardiac arrhythmias or TdP.…”

“…When applying in silico approaches, the electrophysiological models that integrate ion channel-specific IC 50 into ventricular arrhythmia biomarkers make use of a large number of parameters that were adjusted to fit experimental results. However, humans are not physiologically identical, and no single electrophysiological model can produce results suitable for representing all patients, nor accurately explain the observed differences between patients (Wisniowska et al 2017 ). Population-based approaches have been described as a useful strategy to consider the inter-individual variability in the parameters of in silico models.…”

Thoroughly Calibrated Modular Agent-Based Model of the Human Cardiovascular and Renal Systems for Blood Pressure Regulation in Health and Disease

“…All of the mentioned models and simulation platforms were created to investigate mechanisms of different cardiovascular and renal diseases in several abstract conditions, where parameter values are fixed on the basis of some average normal or pathological evaluations. However, cardiac models should account for the fact that humans vary ( Wiśniowska et al, 2017 ). If we consider, in addition, the mathematical modeling to predict real-world effectiveness of drug interventions, we find that the most important limitation is the lack of external validation applying other data than those used for developing the models.…”