pitolisant and Arrhythmias--Cardiac

We evaluated the concordance of results from two sets of nonclinical cardiovascular safety studies on pitolisant.. Nonclinical studies envisaged both in the International Conference on Harmonization (ICH) S7B guideline and Comprehensive in vitro Pro-arrhythmia Assay (CiPA) initiative were undertaken. The CiPA initiative included in vitro ion channels, stem cell-derived human ventricular myocytes, and in silico modelling to simulate human ventricular electrophysiology. ICH S7B-recommended assays included in vitro hERG (K. Both sets of nonclinical data consistently excluded pitolisant from having clinically relevant QT-liability or pro-arrhythmic potential. CiPA studies revealed pitolisant to have modest calcium channel blocking and late I. Our findings support the CiPA initiative but suggest that sponsors should consider investigating drug effects on EADs and the use of pro-arrhythmia models when the results from CiPA studies are ambiguous.

Topics: Animals; Arrhythmias, Cardiac; Computer Simulation; Disease Models, Animal; Dogs; Electrocardiography; Female; Humans; Ion Channels; Male; Myocytes, Cardiac; Piperidines; Purkinje Fibers; Rabbits; Research Design