Nonclinical CardiovascularSafety of Pitolisant: Comparing ICH S7B and CiPA Initiative Studies.

BACKGROUND AND PURPOSE We evaluated the concordance of results from two sets of nonclinical cardiovascular safety studies on pitolisant. EXPERIMENTAL APPROACH 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(V)11.1) channels, in vivo dog studies with follow-up investigations in rabbit Purkinje fibres and the in vivo Carlsson rabbit pro-arrhythmia model. KEY RESULTS 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-Na reducing activities at high concentrations, which resulted in pitolisant reducing dofetilide-induced early after-depolarizations (EADs) in the ICH S7B studies. Studies in stem cell-derived human cardiomyocytes with dofetilide or E-4031 given alone and in combination with pitolisant confirmed these properties. In silico modelling confirmed that the ion channel effects measured are consistent with results from both the stem cell-derived cardiomyocytes and rabbit Purkinje fibres and categorized pitolisant as a drug with low torsadogenic potential. Results from the two sets of nonclinical studies correlated well with those from two clinical QT studies. CONCLUSIONS AND IMPLICATIONS 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.