Nonclinical cardiovascular safety of pitolisant: comparing International Conference on Harmonization S7B and Comprehensive in vitro Pro‐arrhythmia Assay initiative studies

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.

Clinical characteristics of a large cohort of patients with narcolepsy candidate for pitolisant: a cross-sectional study from the Italian PASS Wakix® Cohort

“…These findings are in line with current Fig. 2 Significant post hoc comparisons between subgroups ("add-on group," "switched group," and "naive group" [3], but may also reflect the preference, in clinical practice, to prescribe pitolisant in patients with high cardiovascular burden, given its known negligible impact on the cardiovascular system [34]. Therefore, the high prevalence of cardiovascular comorbidities may be over-estimated in our sample.…”

Comprehensive network medicine-based drug repositioning via integration of therapeutic efficacy and side effects

“…In particular, pitolisant is a potent histamine H3 receptor antagonist/inverse agonist that is approved for the treatment of narcolepsy in adults. It has also been reported to inhibit KCNH2, showing voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization 30 . From the inferred subnetworks, we also observed that KCNH2 indirectly interacts with BRAF via the AKT serine/threonine kinase 1.…”

Sleep Disturbances in Pediatric Craniopharyngioma: A Systematic Review

“…Some drugs used in the treatment of narcolepsy have shown promising results in patients with craniopharyngioma with EDS or secondary narcolepsy, such as modafinil ( 18 , 26 ), methylphenidate ( 18 ), dexamphetamine ( 29 ), and pitolisant ( 24 ). In particular, pitolisant, given its low cardiovascular risk profile, may be specifically indicated for CP patients, who have many metabolic comorbidities ( 69 ).…”