title: How in vitro influences in silico utilized for the prediction of in vivo - pilot study of the drug-induced pro-arrhythmic potency prediction.
abstract: The current drug cardiac safety risk assessment paradigm is about to be changed. The discussed modifications cover clinical as well as pre-clinical sides. As for the latter, the pre-clinical assessment, it is planned to be based on the analysis of the drug-triggered multiple ion currents inhibition. Considering the variability in the in vitro patch clamp studies results, it would be of benefit to assess how these apparatus- and protocol-dependent differences influence the risk prediction and, eventually, the decision making. Four compounds, namely dextromethorphan, ketoconazole, terfenadine, and quinidine were screened for hERG inhibition with an automated patch clamp apparatus (CytoPatch(TM)2). The results were then compared against the literature published data, and after being complemented with information about other current inhibitions and effective therapeutic plasma concentration, utilized for the in silico based safety assessment. Two endpoints were used: (1) the concentration dependent potential to induce early afterdepolarizations in the simulated action potential and (2) the arrhythmia-like disruption in the simulated pseudo-ECG signals. Data analysis results prove that IC50 values, describing the inhibition potential, significantly differ among studies, and the choice of input data can greatly influence the in silico based safety assessment and thus the decision making process.
authors: Unit of Pharmacoepidemiology and Pharmacoeconomics, Faculty of Pharmacy, Jagiellonian University Medical College, Krakow, Poland.|Department of Transplantation, Polish-American Institute of Pediatrics, Jagiellonian University Medical College, Krakow, Poland.
authors: Bogna
authors: B
authors: Badyra
authors: Bartosz
authors: B
authors: Lisowski
authors: Sebastian
authors: S
authors: Polak
authors: John
authors: J
authors: Kudolo
authors: Unit of Pharmacoepidemiology and Pharmacoeconomics, Faculty of Pharmacy, Jagiellonian University Medical College, Krakow, Poland. b.wisniowska@uj.edu.pl.
authors: Barbara
authors: B
authors: Wiśniowska
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000009:adverse effects* / Q000494:pharmacology*; D003915:Dextromethorphan / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000187:drug effects*; D066298:In Vitro Techniques; D007654:Ketoconazole / Q000494:pharmacology; D008955:Models, Cardiovascular; D018408:Patch-Clamp Techniques / Q000379:methods; D010865:Pilot Projects; D011802:Quinidine / Q000494:pharmacology; D016593:Terfenadine / Q000494:pharmacology
chemical_list: D002121:Calcium Channel Blockers; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D003915:Dextromethorphan; D016593:Terfenadine; D011802:Quinidine; D007654:Ketoconazole
keywords: Patch Clamp; hERG; ionic channels; proarrhythmia