Efficacy of the histamine 3 receptor (H3R) antagonist pitolisant (formerly known as tiprolisant; BF2.649) in epilepsy: Dose-dependent effects in the human photosensitivity model

• Published in: Epilepsy & behavior Vol. 28; no. 1; pp. 66 - 70
• Main Authors: Kasteleijn- Nolst Trenité, Dorothée, Parain, Dominique, Genton, Pierre, Masnou, Pascal, Schwartz, Jean-Charles, Hirsch, Edouard
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2013
• Subjects: Administration, Oral; Adult; Animals; Anticonvulsants - pharmacokinetics; Anticonvulsants - therapeutic use; BF2.649; Brain; Disease Models, Animal; Dose-Response Relationship, Drug; Electroencephalography; Electroshock - adverse effects; Electroshock - classification; Epilepsy; Epilepsy, Reflex - drug therapy; Epilepsy, Reflex - etiology; Excitatory Amino Acid Agonists - toxicity; Female; H3R; Histamine 3 antagonist; Humans; Kainic Acid - toxicity; Male; Mice; Neurology; Nonimidazole; Photosensitivity model; Piperidines - pharmacokinetics; Piperidines - therapeutic use; Pitolisant; PPR; Proof of concept; Time Factors; Tiprolisant; Young Adult; PPR; Tiprolisant; Photosensitivity model; H3R; Epilepsy; Histamine 3 antagonist; Pitolisant; Nonimidazole; BF2.649; Proof of concept
• ISSN: 1525-5050; 1525-5069; 1525-5069
• DOI: 10.1016/j.yebeh.2013.03.018

A new class of drugs, the nonimidazole histamine 3 receptor (H3R) antagonists, has been developed in the past decade for treatment of various brain diseases. Pitolisant is such a drug. We studied the pharmacodynamic effect of pitolisant in patients with epilepsy in early Phase II, using the photosensitivity proof of concept model. A total of 14 adult patients (11 females and 3 males; 5 drug naïve) were studied for three days to evaluate the effect of a single oral dose of pitolisant on EEG photosensitivity ranges. All patients showed repeatedly a generalized photoparoxysmal response (PPR) prior to drug administration on placebo Day 1. A statistically significant suppressive effect (standardized photosensitive response [SPR] reduction as measured with paired t-tests) for 20-, 40-, or 60-mg doses of pitolisant was seen in 9/14 (64%) patients of whom 6/14 (43%) showed abolition of the response to intermittent photic stimulation (IPS). Patients on the highest dosage (60mg) showed the strongest effect with an effect lasting up to 28h. Thus, full-scale Phase II studies with this novel H3R antagonist, pitolisant, in patients with epilepsy are warranted. [Display omitted] •Pitolisant, a histamine 3 receptor antagonist, is effective in animal models of epilepsy.•Pitolisant reduced the photosensitivity range in 64% of photosensitive subjects.•Pitolisant abolished the photoparoxysmal response in 43% of subjects.•Pitolisant effect was significant from 2-6 hours after dose.