Abstract
Background and PurposeWe evaluated the concordance of results from two sets of nonclinical cardiovascular safety studies on pitolisant.Experimental ApproachNonclinical 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 (KV11.1) channels, in vivo dog studies with follow‐up investigations in rabbit Purkinje fibres and the in vivo Carlsson rabbit pro‐arrhythmia model.Key ResultsBoth 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 INa 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 ImplicationsOur 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.
Highlights
In 2005, the International Conference on Harmonization (ICH) adopted two guidelines, requiring all new drugs to be evaluated for their effects on the QT interval of the surface ECG
We summarize the results of more recent Comprehensive in vitro Pro-arrhythmia Assay (CiPA)-style nonclinical studies with pitolisant and compare these with the findings from earlier ICH S7B nonclinical studies
After long-term exposure to pitolisant (1 μM) over a 24 h period and following a washout of the incubation medium, there was no significant effect on human ether-a-go-go potassium channel (hERG) current measured without pitolisant in the test medium, and a ratio of peak tail current amplitude over cell capacitance of 62 ± 4 versus 55 ± 5 pA pFÀ1 in control
Summary
In 2005, the International Conference on Harmonization (ICH) adopted two guidelines, requiring all new drugs to be evaluated for their effects on the QT interval of the surface ECG. The nonclinical guideline ICH S7B (ICH, 2005a) recommends an in vitro study on the Kv11.1 channel (hERG), responsible for the major outward repolarizing current (IKr), and an in vivo study to be followed, if necessary, by other investigations such as a repolarization assay measuring action potential parameters in a suitable in vitro preparation and the use of pro-arrhythmia models. The other guideline, ICH E14 (ICH, 2005b), recommends a clinical thorough QT (TQT) study Both guidelines focus on a drug’s effect on QT interval, rather than its pro-arrhythmic risk. 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. ICH S7B-recommended assays included in vitro hERG (KV11.1) channels, in vivo dog studies with follow-up investigations in rabbit Purkinje fibres and the in vivo Carlsson rabbit pro-arrhythmia model
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