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Drugs carry a proarrhythmic risk, which gets even greater when they are used in combination. In vitro assessment of the proarrhythmic potential of drugs is limited to one compound and thus neglects the potential of drug-drug interactions, including those involving active metabolites. Here we present the results of an in vitro study of potential drug-drug interactions at the level of the hERG channel for the combination of up to three compounds: loratadine, desloratadine and ketoconazole. Experiments were performed at room temperature on an automated patch-clamp device CytoPatch 2, with the use of heterogeneously, stably transfected HEK cells. Single drugs, pairs and triplets were used. The results provided as the inhibition of the IKr current for pairs were compared against the calculated theoretical interaction. Models applied to calculate the combined effect of inhibitory actions of simultaneously given drugs include: (1) simple additive model with a maximal inhibition limit of 1 (all channels blocked in 100%); (2) Bliss independence; and (3) Loewe additivity. The observed IC50 values for loratadine, desloratadine and ketoconazole were 5.15, 1.95 and 0.74 μm respectively. For the combination of drugs tested in pairs, the effect was concentration dependent. In lower concentrations, the synergistic effect was observed, while for the highest tested concentrations it was subadditive. To triple the effect, it was subadditive regardless of concentrations. The square root of sum of squares of differences between the observed and predicted total inhibition was calculated to assess the theoretical interaction models. For most of the drugs, the allotopic model offered the best fit.

Little is known about the uptake of drugs into the human heart, although it is of great importance nowadays, when science desires to predict tissue level behavior rather than to measure it. Although the drug concentration in cardiac tissue seems a better predictor for physiological and electrophysiological changes than its level in plasma, knowledge of this value is very limited. Tissue to plasma partition coefficients (Kp) come to rescue since they characterize the distribution of a drug among tissues as being one of the input parameters in physiologically based pharmacokinetic (PBPK) models. The article reviews cardiac surgery and forensic medical studies to provide a reference for drug concentrations in human cardiac tissue. Firstly, the focus is on whether a drug penetrates into heart tissue at a therapeutic level; the provided values refer to antibiotics, antifungals and anticancer drugs. Drugs that directly affect cardiomyocyte electrophysiology are another group of interest. Measured levels of amiodarone, digoxin, perhexiline and verapamil in different sites in human cardiac tissue where the compounds might meet ion channels, gives an insight into how these more lipophilic drugs penetrate the heart. Much data are derived from postmortem studies and they provide insight to the cardiac distribution of more than 200 drugs. The analysis depicts potential problems in defining the active concentration location, what may indirectly suggest multiple mechanisms involved in the drug distribution within the heart. Copyright © 2015 John Wiley & Sons, Ltd.

The currently changing cardiac safety testing paradigm suggests, among other things, a shift towards using in silico models of cellular electrophysiology and assessment of a concomitant block of multiple ion channels. In this study, a set of four enhanced QSAR models have been developed: for the rapid delayed rectifying potassium current (IKr), slow delayed rectifying potassium current (IKs), peak sodium current (INa) and late calcium current (ICaL), predicting ion currents changes for the specific in vitro experiment from the 2D structure of the compounds. The models are a combination of both in vitro study parameters and physico-chemical descriptors, which is a novel approach in drug–ion channels interactions modeling. Their predictive power assessed in the enhanced, more demanding than standard procedure, 10-fold cross validation was reasonably high. Rough comparison with published pure in silico hERG interaction models shows that the quality of the model predictions does not differ from other models available in the public domain, however, it takes its advantage in accounting for inter-experimental settings variability. Developed models are implemented in the Cardiac Safety Simulator, a commercially available platform enabling the in vitro–in vivo extrapolation of the drugs proarrhythmic effect and ECG simulation. A more comprehensive assessment of the effects of the compounds on ion channels allows for making more informed decisions regarding the risk – and thus avoidance – of exclusion of potentially safe and effective drugs. Copyright © 2015 John Wiley & Sons, Ltd.

Evaluation of the proarrhythmic potential of an investigated compound is now an integral element of the safety profile required for the approval of new drugs. The human ether-a-go-go-related gene (hERG) channel blocking potency is regarded as a surrogate marker of the proarrhythmic risk at the early stages of the research and development process. However, there is no straight correlation between QT prolongation and TdP occurrence probability, and hERG inhibition potential can be an inadequate predictor of QT prolongation. The L-type calcium channel plays a pivotal role in cardiomyocytes' physiology. Thus the main aim of this study was to develop a predictive model for drug-triggered CaL channel inhibition and also the assessment of drug–multichannel interaction effects on the heart rate-corrected QT interval. The data set, consisting of 123 records describing in vitro experimental settings, measured IC50 values and calculated physico-chemical properties for 72 various chemicals, was collected. The models were tested in a modified 10-fold cross-validation procedure. The generalization ability of the best model was as follows: root mean squared error (RMSE) = 1.10, normalized root mean squared error (NRMSE) = 16.09%. Out of the 10 most important variables, 5 described conditions of the in vitro experiments thus their description and experiment's conditions standardization might be the key to the models better performance. The simulations performed with the ToxComp system showed that the hERG block alone causes concentration-dependent QT prolongation, whereas when multichannel block is regarded, the effect could be reversed. For that reason, the multichannel interaction of tested compounds should be taken into consideration, in order to make the proarrhythmic risk assessment more reliable. Copyright © 2012 John Wiley & Sons, Ltd.

The excitable cell membranes contain ion channels that allow the ions passage through the specific pores via a passive process. Assessment of the inhibition of the IKr (hERG) current is considered to be the main target during the drug development process, although there are other ionic currents for which drug-triggered modification can either potentiate or mask hERG channel blockade. Information describing the results of in vitro studies investigating the chemical–IKs current interactions has been developed in the current study. Based on the publicly available data sources, 145 records were collected. The final list of publications consists of 64 positions and refers to 106 different molecules connected with IKs current inhibition, with at least one IC50 value measured. Ultimately, 98 of the IC50 values expressed as absolute values were gathered. For 36 records the IC50 was expressed as a relative value. For the 11 remaining records, the inhibition was not clearly expressed. Based on the collected data the predictive models for the IC50 estimation were developed with the use of various algorithms. The extended Quantitative Structure-Activity Relationships (QSAR) methodology was applied and the in vitro research settings were included as independent variables, apart from the physico-chemical descriptors calculated with the use of the Marvin Calculator Plugins. The root mean squared error and normalized root mean squared error values for the best model (an expert system based on two independent artificial neural networks) were 0.86 and 14.04%, respectively. The model was further built into the ToxComp system, the ToxIVIVE tool specialized for cardiotoxicity assessment of drugs. Copyright © 2012 John Wiley & Sons, Ltd.

The assessment of the torsadogenic potency of a new chemical entity is a crucial issue during lead optimization and the drug development process. It is required by the regulatory agencies during the registration process. In recent years, there has been a considerable interest in developing in silico models, which allow prediction of drug–hERG channel interaction at the early stage of a drug development process. The main mechanism underlying an acquired QT syndrome and a potentially fatal arrhythmia called torsades de pointes is the inhibition of potassium channel encoded by hERG (the human ether-a-go-go-related gene). The concentration producing half-maximal block of the hERG potassium current (IC50) is a surrogate marker for proarrhythmic properties of compounds and is considered a test for cardiac safety of drugs or drug candidates. The IC50 values, obtained from data collected during electrophysiological studies, are highly dependent on experimental conditions (i.e. model, temperature, voltage protocol). For the in silico models' quality and performance, the data quality and consistency is a crucial issue. Therefore the main objective of our work was to collect and assess the hERG IC50 data available in accessible scientific literature to provide a high-quality data set for further studies. Copyright © 2008 John Wiley & Sons, Ltd.