Traditionally, vanoxerine was developed as a dopamine transporter antagonist for use in the treatment of cocaine addiction, however, its development was halted due to potent hERG inhibition. Further research suggested that vanoxerine was a multichannel inhibitor, blocking Cav1.2 and Nav1.5, the effects of which were believed to counteract the hERG inhibition. Subsequently, vanoxerine was repurposed as a potential therapy for atrial fibrillation, and was advanced through clinical trials. Although Phase 3 trials suggested that vanoxerine was effective in 69% of patients for atrial fibrillation, the trial was halted due to torsades de pointes being observed in 11.5% of patients.
With the advent of the CiPA (Comprehensive In Vitro Proarrhythmia Assay) initiative coupled with advances in stem cell biology and electrophysiology, new in vitro models have been developed which can predict the overall effects of multiple ion channels in a single study. These technologies utilise human iPSC-derived cardiomyocytes in combination with sensitive MEA (microelectrode array). Recent research by Cyprotex has evaluated the effects of vanoxerine on human iPSC-derived cardiomyocytes using the MEA platform in order to understand the multichannel effects. The concentrations evaluated were representative of human plasma levels. The platform was able to identify a proarrythmic liability as well as effects on field potential duration. A dose dependent decrease in sodium amplitude and slope was also observed. The study also indicated that time dependency was important with the effects observed after approximately 3 hours.
So why did only a subset of the patients observed the effects? Well, a number of reasons could be explain the selective effects. Inter-individual differences in pharmacokinetics or potential drug-drug interactions are two of the most likely explanations. As well as being extensively plasma protein bound, vanoxerine is cleared rapidly by CYP3A4. Inter-patient differences in CYP3A4 levels or co-administered CYP3A4 inhibitors could potentially increase vanoxerine levels above the safety threshold. Further analysis of the patients in the trial may be warranted to fully understand the reasons behind the patient-specific cardiac liability.
In summary, the use of human iPSC-derived cardiomyocytes in combination with MEA is a valuable technique in understanding the overall effects of multiple ion channels in a single study, and predicting potential cardiotoxicity in the clinic. In the case of vanoxerine, if this platform had been available during the early drug development, it would have successfully detected the potential adverse effects, saving considerable money and protecting the patients from the cardiotoxic liability.
Our research into vanoxerine cardiotoxicity was presented at the SOT conference in Baltimore in March 2017.