In silico assessment of nifedipine effects on human heart cells : pharmacokinetic-pharmacodynamic analyses at the population level

This study aimed to utilise the value of integrating in vitro data and physiologically based pharmacokinetic (PBPK) models to quantitatively estimate the impact on pharmacokinetics (PK) and pharmacodynamics (PD). The objective was to predict pharmacodynamics (electrocardiogram (ECG) parameters) of nifedipine (NIF) after an oral administration by simulation. The computational models were performed for human transmural ECGs to model drug-induced changes in QT interval as well as changes in T-wave morphology. The differences in QTc interval due to NIF in healthy volunteers both males and females were predicted by the Cardiac Safety Simulator, providing a mechanistic understanding of clinical observation. The simulation results showed that NIF significantly shortened the QTcF in a concentration-dependent manner compared with baseline (placebo) control. Comparison of the simulated QT interval of non-QT-prolonging drug (NIF) against the clinical observations proved the accuracy of the model based prediction

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

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

Tox-Database.net : a curated resource for data describing chemical triggered in vitro cardiac ion channels inhibition

BACKGROUND: Drugs safety issues are now recognized as being factors generating the most reasons for drug withdrawals at various levels of development and at the post-approval stage. Among them cardiotoxicity remains the main reason, despite the substantial effort put into in vitro and in vivo testing, with the main focus put on hERG channel inhibition as the hypothesized surrogate of drug proarrhythmic potency. The large interest in the IKr current has resulted in the development of predictive tools and informative databases describing a drug's susceptibility to interactions with the hERG channel, although there are no similar, publicly available sets of data describing other ionic currents driven by the human cardiomyocyte ionic channels, which are recognized as an overlooked drug safety target. DISCUSSION: The aim of this database development and publication was to provide a scientifically useful, easily usable and clearly verifiable set of information describing not only IKr (hERG), but also other human cardiomyocyte specific ionic channels inhibition data (IKs, INa, ICa). SUMMARY: The broad range of data (chemical space and in vitro settings) and the easy to use user interface makes tox-database.net a useful tool for interested scientists. DATABASE URL: http://tox-database.net

The role of interaction model in simulation of drug interactions and QT prolongation

Computational modelling is a cornerstone of Comprehensive In Vitro Proarrhythmia Assay and is re-increasingly being used in drug development. Electrophysiological effects of drug-drug interactions can be predicted in silico, e.g. with the use of in vitro cardiac ion channel data, PK profiles and human ventricular cardiomyocyte models. There are, however, several approaches with different assumptions used to assess the combined effect of multiple drugs, and there is no agreed standard interaction model. The aim of this study was to assess whether the choice of the drug-drug interaction (DDI) model (Bliss independence, Loewe additivity, or simple sum) influences the results of QT interval simulation trial. The Simcyp Simulator version 12.1 (Simcyp Ltd. [part of Certara], Sheffield, UK) and Cardiac Safety Simulator 2.0 (Simcyp Ltd. [part of Certara], Sheffield, UK) were used to simulate results of 8 virtual trials mimicking clinical studies and generate individual QTc data. The combined effect of inhibitory actions of drugs which were given simultaneously was calculated with use of three different interaction models. The PD effect of DDI was assessed and the differences between mean observed and mean predicted ΔQTcB values for terfenadine interactions were not statistically significant in all but one cases. Differences between the three DDI models are not statistically significant, implying that the choice of the DDI model, in the case of lack of synergy or antagonism, is irrelevant to the average predicted effect at the clinical level. However, in some cases, it can influence the verdict on combinatorial therapy safety for individual patients

In silico assessment of antiarrhythmic effects of drug ranolazine on electrical activity in human ventricular myocardium

The aim of this study was to simulate the electrophysiological modifications by the ranolazine at the left ventricular wall level by using in vitro electrophysiological measurements from canine ventricular myocytes to generate early information on cardiac safety in the human heart. The antiarrhythmic effect of ranolazine on two proarrhythmic drugs was examined. The sensitivity of ionic currents to ranolazine was described as Action Potential Duration (APD) variations in response to different therapeutic concentrations. The observed results can be explained by the interplay between inhibition of the INaL and IKr currents. Simulation results are in agreement with in vitro and in vivo studies of arrhythmia and confirmed the antiarrhythmic properties of ranolazine which may be utilized for suppressing ventricular arrhythmias

A four-compartment PBPK heart model accounting for cardiac metabolism - model development and application

In the field of cardiac drug efficacy and safety assessment, information on drug concentration in heart tissue is desirable. Because measuring drug concentrations in human cardiac tissue is challenging in healthy volunteers, mathematical models are used to cope with such limitations. With a goal of predicting drug concentration in cardiac tissue, we have developed a whole-body PBPK model consisting of seventeen perfusion-limited compartments. The proposed PBPK heart model consisted of four compartments: the epicardium, midmyocardium, endocardium, and pericardial fluid, and accounted for cardiac metabolism using CYP450. The model was written in R. The plasma:tissues partition coefficients (Kp) were calculated in Simcyp Simulator. The model was fitted to the concentrations of amitriptyline in plasma and the heart. The estimated parameters were as follows: 0.80 for the absorption rate [h(−1)], 52.6 for Kp(rest), 0.01 for the blood flow through the pericardial fluid [L/h], and 0.78 for the P-parameter describing the diffusion between the pericardial fluid and epicardium [L/h]. The total cardiac clearance of amitriptyline was calculated as 0.316 L/h. Although the model needs further improvement, the results support its feasibility, and it is a first attempt to provide an active drug concentration in various locations within heart tissue using a PBPK approach

Physiologically based pharmacokinetic-quantitative systems toxicology and safety (PBPK-QSTS) modeling approach applied to predict the variability of amitriptyline pharmacokinetics and cardiac safety in populations and in individuals

The physiologically based pharmacokinetic (PBPK) models allow for predictive assessment of variability in population of interest. One of the future application of PBPK modeling is in the field of precision dosing and personalized medicine. The aim of the study was to develop PBPK model for amitriptyline given orally, predict the variability of cardiac concentrations of amitriptyline and its main metabolite-nortriptyline in populations as well as individuals, and simulate the influence of those xenobiotics in therapeutic and supratherapeutic concentrations on human electrophysiology. The cardiac effect with regard to QT and RR interval lengths was assessed. The Emax model to describe the relationship between amitriptyline concentration and heart rate (RR) length was proposed. The developed PBPK model was used to mimic 29 clinical trials and 19 cases of amitriptyline intoxication. Three clinical trials and 18 cases were simulated with the use of PBPK-QSTS approach, confirming lack of cardiotoxic effect of amitriptyline in therapeutic doses and the increase in heart rate along with potential for arrhythmia development in case of amitriptyline overdose. The results of our study support the validity and feasibility of the PBPK-QSTS modeling development for personalized medicine

Circadian models of serum potassium, sodium, and calcium concentrations in healthy individuals and their application to cardiac electrophysiology simulations at individual level

In the article a brief description of the biological basis of the regulation of human biological clocks was presented in order to introduce the role of circadian rhythms in physiology and specifically in the pharmacological translational tools based on the computational physiology models to motivate the need to provide models of circadian fluctuation in plasma cations. The main aim of the study was to develop statistical models of the circadian rhythm of potassium, sodium, and calcium concentrations in plasma. The developed ion models were further tested by assessing their influence on QT duration (cardiac endpoint) as simulated by the biophysically detailed models of human left ventricular cardiomyocyte. The main results are model equations along with an electronic supplement to the article that contains a fully functional implementation of all models