QTc modification after risperidone administration--insight into the mechanism of action with use of the modeling and simulation at the population level approach.

Context: Ensuring the safety of therapy is both expensive and time-consuming process, which may be supported by modeling and simulation.

Objective: The objective of this study was to gain insight into the effect of risperidone administration on QT interval by in silico evaluation of the effect in the individuals with different metabolic status of CYP2D6.

Materials And Methods: Evaluation was performed through the combination of empirical and mechanistic modeling with the use of the Cardiac Safety Simulator platform allowing for simulation of electrophysiological consequences of drug administration at the population level.

Serum potassium, sodium and calcium levels in healthy individuals - literature review and data analysis.

Purpose: The human body is known to be composed of 24 elements, among which potassium, sodium and calcium are considered to be essential. These necessary components play a significant physiological role which includes regulation of the electrical and mechanical action of the heart. Abnormal concentration of the above-mentioned ions, i.

The effects of six antipsychotic agents on QTc--an attempt to mimic clinical trial through simulation including variability in the population.

Background: Many drugs (belonging to different chemical groups) have the potential for QT interval prolongation associated with ionic channel blockade in the cardiomyocyte membrane. Due to the fact that this phenomenon is linked to a higher risk of TdP, the ability to predict its scale is one of the most important outcomes of cardiotoxicity assessment of new agents.

Methods: With use of the Cardiac Safety Simulator (CSS), the effect of six antipsychotic drugs was predicted in silico.

In vitro-in vivo extrapolation of drug-induced proarrhythmia predictions at the population level.

Drug cardiotoxicity is a serious issue for patients, regulators, pharmaceutical companies and health service payers because they are all affected by its consequences. Despite the wide range of data they generate, existing approaches for cardiac safety testing might not be adequate and sufficiently cost-effective, probably as a result of the complexity of the problem. For this reason, translational tools (based on biophysically detailed, mathematical models) allowing for in vitro-in vivo extrapolation are gaining increasing interest.

Wild type and K897T polymorphisms of the hERG gene: modeling the APD in Caucasians.

The presented study aims to assess the possibility of simulating changes in cardiac cell electrophysiology due to K897T polymorphism in the Caucasian population. In the first part of the experiment, the parameters of the equations describing channel gating were fitted to the experimental data. Then, the action potentials of midmyocardial cells of 100 individuals were simulated in the in vitro - in vivo extrapolation system - ToxComp.

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.

Predictive model for L-type channel inhibition: multichannel block in QT prolongation risk assessment.

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-à-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.

Slow delayed rectifying potassium current (IKs ) - analysis of the in vitro inhibition data and predictive model development.

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.

Virtual population generator for human cardiomyocytes parameters: in silico drug cardiotoxicity assessment.

Background: The anatomical and histological parameters of the human ventricle depend on many factors including age and sex. Myocyte volume and electric capacitance are significant physiological parameters of left ventricle cardiomyocyte mathematical models. They allow the assessment of inter-individual variability during in vitro-in vivo extrapolation of the drug cardiotoxic effect.

The open-access dataset for insilico cardiotoxicity prediction system.

Drug cardiotoxicity is one of the main reasons of fatal drug related problem events and the subsequent withdrawals. Therefore, its early assessment is a crucial element of the drug development process. For the drug driven hERG inhibition assessment, which is assumed to be the main reason for toxicity, in vitro techniques are used.