Nonclinical cardiovascular safety of pitolisant: comparing International Conference on Harmonization S7B and Comprehensive in vitro Pro-arrhythmia Assay initiative studies.
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Ligneau X, Shah RR, Berrebi-Bertrand I, Mirams GR, Robert P, Landais L, Maison-Blanche P, Faivre JF, Lecomte JM, Schwartz JC
Nonclinical cardiovascular safety of pitolisant: comparing International Conference on Harmonization S7B and Comprehensive in vitro Pro-arrhythmia Assay initiative studies.
Br J Pharmacol. 2017 Dec;174(23):4449-4463. doi: 10.1111/bph.14047. Epub 2017 Oct 19.
- PubMed ID
- 28941245 [ View in PubMed]
- Abstract
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 (KV 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 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 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.
DrugBank Data that Cites this Article
- Drugs
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Pitolisant Potassium voltage-gated channel subfamily H member 2 Protein Humans NoBlockerDetails - Drug Interactions
Drugs Interaction Integrate drug-drug
interactions in your softwarePitolisantAnagrelide Anagrelide may increase the QTc-prolonging activities of Pitolisant. PitolisantIbutilide Ibutilide may increase the QTc-prolonging activities of Pitolisant. PitolisantTrovafloxacin Trovafloxacin may increase the QTc-prolonging activities of Pitolisant. PitolisantLithium cation Lithium cation may increase the QTc-prolonging activities of Pitolisant. PitolisantTemafloxacin Temafloxacin may increase the QTc-prolonging activities of Pitolisant.