Inter-individual Variability in the Pre-clinical Drug Cardiotoxic Safety Assessment—Analysis of the Age–Cardiomyocytes Electric Capacitance Dependence

Abstract

Electrical phenomena located within the plasma membrane of the mammalian cardiac cells are connected with the cells’ main physiological functions—signals processing and contractility. They were extensively studied and described mathematically in so-called Hodgkin–Huxley paradigm. One of the physiological parameters, namely cell electric capacitance, has not been analyzed in-depth. The aim of the study was to validate the mechanistic model describing the capacitive properties of cells, based on a collected experimental dataset which describes the electric capacitance of human ventricular myocytes. The gathered data was further utilized for developing an empirical correlation between a healthy individual’s age and cardiomyocyte electric capacitance.

Real Patient and its Virtual Twin: Application of Quantitative Systems Toxicology Modelling in the Cardiac Safety Assessment of Citalopram

“…The CSS platform facilitates the generation of a virtual realistic population variability in cardiac physiology during simulations (Fig. IA) (28,29). The CSS platform is the first of its kind accounting for circadian variability in heart rate and plasma concentration of electrolytes Na + , K + , and Ca 2+ using covariate models derived from actual clinical data (30,31).…”

“…Epidemiological models which take into account the effect of gender and age on ventricular heart wall thickness, cardiomyocyte volume/capacitance, and sarcoplasmic reticulum are also built into the CSS platform (Fig. IB) (28). A 1D string of cells (ventricular wall thickness) paced at the endocardial side used the 50:30:20 distribution of the endo-, mid-, and epicardium cells, respectively, with an average diffusion coefficient of 0.0016 cm 2 /ms.…”

“…Many parameters defining the subject physiology were measured; however, there were some (e.g. heart wall thickness and conductance) rep reported in the respective clinical trial, calc calculated as described in the main text, CT citalopram, DCT desmethylcitalopram, DDCT didesmethylcitalopram, ID identification a Each set of drug and metabolite exposure points were simulated and given an ID for clarity in the discussion in the main text b The time reported is post hospitalisation as the exact time of drug administration was not available in the study which were not available, so we calculated those unavailable parameters using the covariate models of a healthy Caucasian population physiology from age and gender of a patient (28). The values of the heart rate and plasma ion concentrations reported in the clinical studies were either the average values recorded over a period of a few seconds or minutes or were a specific value at the time of measurement, both of which are known to have inter-occasion variability.…”

Maturing human pluripotent stem cell-derived cardiomyocytes in human engineered cardiac tissues

“…the amount of charge required to change the membrane potential. The reported capacitance for hPSC-CMs [158] was 8- to 10-fold lower than for adult human ventricular CMs [155, 159, 160] (Table 1). …”

In vitro to human in vivo translation – pharmacokinetics and pharmacodynamics of quinidine

“…the toxComp system contains a module for the virtual population development that is used subsequently as a basis for the simulation. Randomly picked individuals carry unique demographic and physiological characteristics; the specific parameters include, inter alia: cardiomyocyte area, electric capacitance, and volume (all parameters are age dependent), plasma ion concentration, left ventricle heart wall thickness and heart rate, with the latter following the circadian rhythm (Polak and Fijorek, 2012;Polak et al 2012b). An additional parameter is the genetic status described by potential modification of the heRG potassium channel gating parameters .…”