Simulation of multiple ion channel block provides improved early prediction of compounds' clinical torsadogenic risk

Abstract

Aims: The level of inhibition of the human Ether-à-go-go-related gene (hERG) channel is one of the earliest preclinical markers used to predict the risk of a compound causing Torsade-de-Pointes (TdP) arrhythmias. While avoiding the use of drugs with maximum therapeutic concentrations within 30-fold of their hERG inhibitory concentration 50% (IC(50)) values has been suggested, there are drugs that are exceptions to this rule: hERG inhibitors that do not cause TdP, and drugs that can cause TdP but are not strong hERG inhibitors. In this study, we investigate whether a simulated evaluation of multi-channel effects could be used to improve this early prediction of TdP risk.

Methods and results: We collected multiple ion channel data (hERG, Na, L-type Ca) on 31 drugs associated with varied risks of TdP. To integrate the information on multi-channel block, we have performed simulations with a variety of mathematical models of cardiac cells (for rabbit, dog, and human ventricular myocyte models). Drug action is modelled using IC(50) values, and therapeutic drug concentrations to calculate the proportion of blocked channels and the channel conductances are modified accordingly. Various pacing protocols are simulated, and classification analysis is performed to evaluate the predictive power of the models for TdP risk. We find that simulation of action potential duration prolongation, at therapeutic concentrations, provides improved prediction of the TdP risk associated with a compound, above that provided by existing markers.

Conclusion: The suggested calculations improve the reliability of early cardiac safety assessments, beyond those based solely on a hERG block effect.

Figure 1

Scatter plot of IC₅₀ values for the drugs against the risk categories. For all three channels and the EFTPC, there is significant overlap between categories. It is evident that no single channel's IC₅₀ value will allow accurate classification of a drug into its risk category.

Figure 2

Simulation of steady-state 1 Hz pacing of the Grandi et al. model under verapamil application when considering (left) a solely hERG block, and (right) a hERG, Na, and CaL block. Arrows indicate the effect on the AP of increasing drug concentration, displayed are: control (0 nM, solid line), low EFTPC (25 nM, dashed line), medium EFTPC (53 nM, dash–dotted line), and high EFTPC (81 nM, dotted line).

Figure 3

(A) Current state-of-the-art measure: [hERG IC₅₀]/[EFTPC_max] against TdP risk categories for the different drugs in this study, as suggested and presented in Redfern et al.; the dotted line is their safety factor of 30. (B) Proposed in silico marker: simulated % change in 1 Hz steady-state APD90 relative to control for the Grandi et al. human ventricular cell model. The dotted line is the ‘control’ case—i.e. 100%. In both (A) and (B), the measure is evaluated for low, middle, and high [EFTPC_max]; producing three points of increasing size, which we display joined with a line. This is intended to show the sensitivity of the measure to variations in dose concentrations which may occur, for example, between individuals or between drug applications. Drugs are presented in alphabetical order within their risk categories. From left to right: 1: ajmaline, amiodarone, dofetilide, quinidine, tedisamil; 2: cisapride, prenylamine, terfenadine, thioridazine; 3: bepridil, chlorpromazine, haloperidol, pimozide, sertindole; 4: amitriptyline, desipramine, diphenhydramine, fluvoxamine, imipramine, mexiletine, mibefradil, nifedipine, propafenone, quetiapine; 5: cibenzoline, diltiazem, nitrendipine, phenytoin, propranolol, risperidone, verapamil.

Figure 4

Histograms of classification errors for (A) allocation of categories at random; (B) log₁₀([hERG IC₅₀]); (C) log₁₀([hERG IC₅₀]/[high EFTPC]); and (D) simulated marker: Grandi et al. 1 Hz steady-state maximum APD90 at low/medium/high EFTPC.

Figure 5

Scatter plot of classification error for all of the different markers. Simulated markers from a hERG-only block are denoted with stars while multi-channel block markers are denoted by circles. Bold circles highlight the 30 ‘most-predictive’ markers. Solid lines indicate the expected values if classification was performed at random, dashed lines are the values given by log₁₀([hERG IC₅₀]/[high EFTPC]), and dotted lines are the values given by the longest APD90 at low/med/high EFTPC as shown in Figure 3B.