Prediction of Thorough QT study results using action potential simulations based on ion channel screens

Abstract

IntroductionDetection of drug-induced pro-arrhythmic risk is a primary concern for pharmaceutical companies and regulators. Increased risk is linked to prolongation of the QT interval on the body surface ECG. Recent studies have shown that multiple ion channel interactions can be required to predict changes in ventricular repolarisation and therefore QT intervals. In this study we attempt to predict the result of the human clinical Thorough QT (TQT) study, using multiple ion channel screening which is available early in drug development.MethodsIon current reduction was measured, in the presence of marketed drugs which have had a TQT study, for channels encoded by hERG, CaV1.2, NaV1.5, KCNQ1/MinK, and Kv4.3/KChIP2.2. The screen was performed on two platforms — IonWorks Quattro (all 5 channels, 34 compounds), and IonWorks Barracuda (hERG & CaV1.2, 26 compounds). Concentration–effect curves were fitted to the resulting data, and used to calculate a percentage reduction in each current at a given concentration.Action potential simulations were then performed using the ten Tusscher and Panfilov (2006), Grandi et al. (2010) and O'Hara et al. (2011) human ventricular action potential models, pacing at 1 Hz and running to steady state, for a range of concentrations.ResultsWe compared simulated action potential duration predictions with the QT prolongation observed in the TQT studies. At the estimated concentrations, simulations tended to underestimate any observed QT prolongation. When considering a wider range of concentrations, and conventional patch clamp rather than screening data for hERG, prolongation of ≥ 5 ms was predicted with up to 79% sensitivity and 100% specificity.DiscussionThis study provides a proof-of-principle for the prediction of human TQT study results using data available early in drug development. We highlight a number of areas that need refinement to improve the method's predictive power, but the results suggest that such approaches will provide a useful tool in cardiac safety assessment.

Multi-parametric assessment of cardiomyocyte excitation-contraction coupling using impedance and field potential recording: A tool for cardiac safety assessment

“…One of the major drawbacks of the existing guidelines has been its narrow focus on the surrogates for TdP arrhythmias, rather than directly on the risk itself, namely arrhythmias (Fermini et al, 2016;Gintant, Sager, & Stockbridge, 2016;Mirams et al, 2014;Sager et al, 2014). For example, as part of the ICH S7B guidelines the emphasis of compound effect has been primarily focused on the repolarization current as manifested by the IK r through the hERG channel.…”

Computational modeling for cardiac safety pharmacology analysis: Contribution of fibroblasts

“…This brief communication also introduces a theoretical platform for the in silico prediction of the safety of cardiac sensitive drug compounds. While we did not extend our analysis to study all compounds listed in the study by Mirams et al (Mirams et al 2014), from this list we selected dofetilide, nebivolol and vardenafil that inhibit different combinations of the ion channel currents I Kr , I Na , I CaL , I Ks and I to . Any drug with experimental data of its effects on these five channel currents can be simulated in an analogous manner to the three compounds tested here.…”

“…The simplest relationship between the ion channel conductance and the compound concentration is the Hill equation which is written as: $$G=\frac{{[{IC}_{50}]}^n}{{false[{IC}_{50}false]}^n+{false[Cfalse]}^n}{G}^0$$ where G and G 0 are the electrical conductance of a given ion channel with and without compound, respectively, [ IC 50 ] is the half-maximal inhibitory concentration of the cardiac sensitive compound that was determined from the results of IonWorks Quattro screening performed at AstraZeneca (Elkins et al 2013; Mirams et al 2014), [ C ] is the compound concentration, and n is the Hill coefficient which was set to 1 (Mirams et al 2014). The inhibition of five membrane ion channel currents were modeled in this study: rapid delayed inward rectifying K + current ( I Kr ), slow delayed inward rectifying K + current ( I Ks ), fast Na + current ( I Na ), long-lasting type Ca 2+ current ( I CaL ), and transient outward K + current ( I to ).…”

“…Dofetilide and vardenafil were used to illustrate the results of the application of a cardiac sensitive drug to the model. Nebivolol was also tested (see supplement) however, the effects of fibroblasts on the drug-induced proarrhythmia potential of any compound can be analyzed using [ IC 50 ]s on each of the five defined ion channel current as described in Mirams et al study (Mirams et al 2014). …”

The Cardiac Electrophysiology Web Lab

“…We have already used the Web Lab to examine recent human ventricular models under drug-induced blockade of certain ion channels. These data formed part of a recent study (31), making this part of the study quick to produce, immediately replicable, and trivial to extend should a novel model be produced (or an existing model be updated).…”