Pharmacokinetic and pharmacodynamic assessment of histamine H₃ receptor occupancy by enerisant: a human PET study with a novel H₃ binding ligand, [¹¹C]TASP457

Purpose: Histamine H₃ receptor antagonists and inverse agonists have been extensively developed to treat sleep–wake, neurocognitive, and allied disorders. However, potential adverse effects, including insomnia, hampered the clinical use of these drugs, possibly due to their persistent interaction with the target molecules. The purpose of the present study was to estimate the pharmacokinetics and pharmacodynamics of enerisant, a novel antagonist and inverse agonist for histamine H₃ receptors. Methods: To measure the histamine H₃ receptor occupancy by enerisant, positron emission tomography studies using [¹¹C]TASP457, a specific radioligand for histamine H₃ receptors, were performed in 12 healthy men at baseline and at 2 h after oral administration of enerisant hydrochloride. For three of these subjects, two additional scans were performed at 6 and 26 h after the administration. Relationships between the receptor occupancy by enerisant and its dose and plasma concentrations were then analyzed. Results: Administration of enerisant hydrochloride decreased the radioligand binding in a dose-dependent manner. The estimated receptor occupancy values at 2 h varied as a function of its dose or plasma concentration. The time course of the occupancy showed persistently high levels (> 85%) in the two subjects with higher doses (25 and 12.5 mg). The occupancy was also initially high at 2 h and 6 h with the lower dose of 5 mg, but it decreased to 69.7% at 26 h. Conclusion: The target engagement of enerisant was demonstrated in the brains of living human subjects. The occupancy of histamine H₃ receptors by enerisant at 2 h can be predicted by applying the plasma concentration of enerisant to Hill’s plot. The preliminary time-course investigation showed persistently high brain occupancy with high doses of enerisant despite the decreasing plasma concentration of the drug. Five milligrams or less dose would be appropriate for the treatment for narcolepsy with initially high occupancy allowing for effective treatment of narcolepsy, and then the occupancy level would be expected to decrease to a level to avoid this drug’s unwanted side effect of insomnia at night, although further research is warranted to confirm the statement since the expected decrease is based on the finding in one subject. Trial registration: This study was retrospectively registered with ClinicalTrials.gov (NCT04631276) on November 17, 2020.