Abstract
Vanoxerine has been in clinical trials for Parkinsonism, depression and cocaine addiction but lacked efficacy. Although a potent blocker of hERG, it produced no serious adverse events. We attributed the unexpected result to offsetting Multiple Ion Channel Effects (MICE). Vanoxerine’s effects were strongly frequency-dependent and we repositioned it for treatment of atrial fibrillation and flutter. Vanoxerine terminated AF/AFL in an animal model and a dose-ranging clinical trial. Reversion to normal rhythm was associated with QT prolongation yet absent proarrhythmia markers for Torsade de Pointes (TdP). To understand the QT/TdP discordance, we used quantitative profiling and compared vanoxerine with dofetilide, a selective hERG-blocking torsadogen used for intractable AF, verapamil, a non-torsadogenic MICE comparator and bepridil, a torsadogenic MICE comparator. At clinically relevant concentrations, verapamil blocked hCav1.2 and hERG, as did vanoxerine and bepridil both of which also blocked hNav1.5. In acute experiments and simulations, dofetilide produced early after depolarizations (EADs) and arrhythmias, whereas verapamil, vanoxerine and bepridil produced no proarrhythmia markers. Of the MICE drugs only bepridil inhibited hERG trafficking following overnight exposure. The results are consistent with the emphasis on MICE of the CiPA assay. Additionally we propose that trafficking inhibition of hERG be added to CiPA.
Highlights
Vanoxerine, 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-[3-phenylpropyl] piperazine dihydrochloride, is a potent, highly selective dopamine transporter antagonist developed initially for treatment of Parkinson’s disease and depression
A potent hERG blocker, may be a safe, effective antiarrhythmic drug because it produces Multiple Ion Channel Effects (MICE) that offset the hERG block
Action potentials measured experimentally in iPSC-derived cardiomyocytes reflected the drug-induced changes in MICE currents that were observed in cell lines heterologously expressing hERG, hCav 1.2 and hNav 1.5
Summary
Vanoxerine, 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-[3-phenylpropyl] piperazine dihydrochloride (synonym GBR-12909), is a potent, highly selective dopamine transporter antagonist developed initially for treatment of Parkinson’s disease and depression. We used a uniform approach to provide a quantitative description of vanoxerine’s MICE profile in order to understand the drug’s actions on experimental and simulated human ventricular action potentials We achieved this by: 1) using similar step-ramp, cardiac-like, voltage protocols for hERG, hNav 1.5 and hCav 1.2 channels each of which was expressed heterologously in HEK 293 or CHO cell lines and measuring concentration-responses (CRs) of vanoxerine block in the steady state using manual patch clamp; 2) measuring the drug’s effects on human induced pluripotent stem cell (iPSC)-derived cardiomyocyte action potentials (SC-CMAPs); and 3) comparing the experimental action potentials with simulated action potentials using the O’Hara-Rudy model[12] of the human left ventricular action potential (hVAP). The conclusion supports the new regulatory approach embodied by the Comprehensive in vitro Proarrhythmia Assay (CiPA) in which cardiac safety is assessed using MICE and proarrhythmic liability rather than hERG block or APD/QT prolongation[14]
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