Pharmacogenetics of Potassium Channel Blockers

Roden, Dan M.

doi:10.1016/j.ccep.2016.02.003

Cited by 15 publications

(7 citation statements)

References 58 publications

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“…Although our study provides valuable insight into the mechanistic origin of ventricular tachycardia and torsades de pointes, it has several important limitations that we need to keep in mind when interpreting its results: First, the major unknowns in arrhythmogenic risk assessment are pharmacodynamic variability caused by variability in drug action at the cellular, tissue, whole-organ, and whole organism levels and pharmacokinetic variability caused by variability in concentration at the target site of action (Roden, 2016). Both are essentially inputs to our model (Crumb et al ., 2016), summarized in Figure 3, and can be easily generalized to include more variability once this information becomes available.…”

Section: Discussionmentioning

confidence: 99%

Predicting the cardiac toxicity of drugs using a novel multiscale exposure–response simulator

Costabal

Jiang

Kuhl

2018

Computer Methods in Biomechanics and Biomedical Engineering

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A common but serious side effect of many drugs is torsades de pointes, a rhythm disorder that can have fatal consequences. Torsadogenic risk has traditionally been associated with blockage of a specific potassium channel and an increased recovery period in the electrocardiogram. However, the mechanisms that trigger torsades de pointes remain incompletely understood. Here we establish a computational model to explore how drug-induced effects propagate from the single channel, via the single cell, to the whole heart level. Our mechanistic exposure-response simulator translates block-concentration characteristics for arbitrary drugs into three-dimensional excitation profiles and electrocardiogram recordings to rapidly assess torsadogenic risk. For the drug of dofetilide, we show that this risk is highly dose-dependent: at a concentration of 1x, QT prolongation is 55% but the heart maintains its regular sinus rhythm; at 5.7x, QT prolongation is 102% and the heart spontaneously transitions into torsades de points; at 30x, QT prolongation is 132% and the heart adapts a quasi-depolarized state with numerous rapidly flickering local excitations. Our simulations suggest that neither potassium channel blockage nor QT interval prolongation alone trigger torsades de pointes. The underlying mechanism predicted by our model is early afterdepolarization, which translates into pronounced U waves in the electrocardiogram, a signature that is correctly predicted by our model. Beyond the risk assessment of existing drugs, our exposure-response simulator can become a powerful tool to optimize the co-administration of drugs and, ultimately, guide the design of new drugs toward reducing life threatening drug-induced rhythm disorders in the heart.

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Section: Discussionmentioning

confidence: 99%

Predicting the cardiac toxicity of drugs using a novel multiscale exposure–response simulator

Costabal

Jiang

Kuhl

2018

Computer Methods in Biomechanics and Biomedical Engineering

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“…An important but computationally rather straightforward next step would be to use a more advanced dynamic channel block model that would account for trapping compounds with high torsadogenic risk and show a stronger reverse use dependency of action potential prolongation [75]. Second, the major unknowns in arrhythmogenic risk assessment are pharmacodynamic variability caused by variability in drug action at the cellular, tissue, whole-organ, and whole organism levels and pharmacokinetic variability caused by variability in concentration at the target site of action [76]. Both are essentially inputs to our model [4], summarized in Figure 3, and can be easily generalized to include more variability once this information becomes available.…”

Section: Limitationsmentioning

confidence: 99%

Predicting critical drug concentrations and torsadogenic risk using a multiscale exposure-response simulator

Costabal

Jiang

Sher

et al. 2019

Progress in Biophysics and Molecular Biology

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Torsades de pointes is a serious side effect of many drugs that can trigger sudden cardiac death, even in patients with structurally normal hearts. Torsadogenic risk has traditionally been correlated with the blockage of a specific potassium channel and a prolonged recovery period in the electrocardiogram. However, the precise mechanisms by which single channel block translates into heart rhythm disorders remain incompletely understood. Here we establish a multiscale exposureresponse simulator that converts block-concentration characteristics from single cell recordings into three-dimensional excitation profiles and electrocardiograms to rapidly assess torsadogenic risk. For the drug dofetilide, we characterize the QT interval and heart rate at different drug concentrations and identify the critical concentration at the onset of torsades de pointes: For dofetilide concentrations of 2x, 3x, and 4x, as multiples of the free plasma concentration C max = 2.1nM, the QT interval increased by +62.0%, +71.2%, and +82.3% compared to baseline, and the heart rate changed by −21.7%, −23.3%, and +88.3%. The last number indicates that, at the critical concentration of 4x, the heart spontaneously developed an episode of torsades de pointes. Strikingly, this critical drug concentration is higher than the concentration estimated from early afterdepolarizations in single cells and lower than in one-dimensional cable models. Our results highlight the importance of whole heart modeling and explain, at least in part, why current regulatory paradigms often fail to accurately quantify the pro-arrhythmic potential of a drug. Our exposure-response simulator could provide a more mechanistic assessment of pro-arrhythmic risk and help establish science-based guidelines to reduce rhythm disorders, design safer drugs, and accelerate drug development.

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“…Therefore, amiodarone and dronedarone affect CV and the tissue excitability (Gautier et al, 2003 ; Patel et al, 2009 ; Saengklub et al, 2016 ). On the other hand, sotalol is a relatively pure potassium channel blocker (Roden, 2016 ), and it did not alter CV as much as amiodarone or dronedarone ( Supplementary Figure 2B ). The virtual AAD test was a feasible approach for evaluating the efficacy of multiple AADs in patients with AF.…”

Section: Discussionmentioning

confidence: 99%

Computational Modeling for Antiarrhythmic Drugs for Atrial Fibrillation According to Genotype

et al. 2021

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Background: The efficacy of antiarrhythmic drugs (AAD) can vary in patients with atrial fibrillation (AF), and the PITX2 gene affects the responsiveness of AADs. We explored the virtual AAD (V-AAD) responses between wild-type and PITX2+/−-deficient AF conditions by realistic in silico AF modeling.Methods: We tested the V-AADs in AF modeling integrated with patients' 3D-computed tomography and 3D-electroanatomical mapping, acquired in 25 patients (68% male, 59.8 ± 9.8 years old, 32.0% paroxysmal type). The ion currents for the PITX2+/− deficiency and each AAD (amiodarone, sotalol, dronedarone, flecainide, and propafenone) were defined based on previous publications.Results: We compared the wild-type and PITX2+/− deficiency in terms of the action potential duration (APD90), conduction velocity (CV), maximal slope of restitution (Smax), and wave-dynamic parameters, such as the dominant frequency (DF), phase singularities (PS), and AF termination rates according to the V-AADs. The PITX2+/−-deficient model exhibited a shorter APD90 (p < 0.001), a lower Smax (p < 0.001), mean DF (p = 0.012), PS number (p < 0.001), and a longer AF cycle length (AFCL, p = 0.011). Five V-AADs changed the electrophysiology in a dose-dependent manner. AAD-induced AFCL lengthening (p < 0.001) and reductions in the CV (p = 0.033), peak DF (p < 0.001), and PS number (p < 0.001) were more significant in PITX2+/−-deficient than wild-type AF. PITX2+/−-deficient AF was easier to terminate with class IC AADs than the wild-type AF (p = 0.018).Conclusions: The computational modeling-guided AAD test was feasible for evaluating the efficacy of multiple AADs in patients with AF. AF wave-dynamic and electrophysiological characteristics are different among the PITX2-deficient and the wild-type genotype models.

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Pharmacogenetics of Potassium Channel Blockers

Cited by 15 publications

References 58 publications

Predicting the cardiac toxicity of drugs using a novel multiscale exposure–response simulator

Predicting the cardiac toxicity of drugs using a novel multiscale exposure–response simulator

Predicting critical drug concentrations and torsadogenic risk using a multiscale exposure-response simulator

Computational Modeling for Antiarrhythmic Drugs for Atrial Fibrillation According to Genotype

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