Single-dose Brilaroxazine Pharmacokinetics, Metabolism, and Excretion Profile in Animals and Humans

Abstract

<b>Abstract ID 53587</b> <b>Poster Board 579</b> <b>Background:</b> Brilaroxazine, a serotonin/dopamine modulator developed for treating schizophrenia, possesses differentiated pharmacological and safety profiles over other antipsychotic treatments. This work describes the pharmacokinetics, metabolism, and excretion (PME) of a single-dose [¹⁴C]-brilaroxazine in mouse, dog, and human studies. <b>Methods:</b> Brilaroxazine PME profile involved three single-dose studies, two animal and one clinical. The animal studies consisted of administering a single oral dose of [¹⁴C]-brilaroxazine 10 mg/kg (400 mCi/kg) and 10 mg/kg (75 mCi/kg) to CD-1 mice and beagle dogs (both male), respectively. Each study collected serial blood and excreta samples up to 144-168 hours post-dose. The clinical study of six healthy male volunteers involved administering a single 15 mg (∼163 mCi) oral dose of [¹⁴C]-brilaroxazine. This study collected serial blood and excreta samples up to 336 hours post-dose. Radioactivity concentrations determination in blood, plasma and excreta samples utilized liquid scintillation counting (LSC) or a combination of combustion with LSC. Plasma concentrations determination of unlabeled brilaroxazine and its metabolite RP5081 used a validated LC-MS/MS method. Calculating plasma pharmacokinetic parameters of total radioactivity, brilaroxazine and metabolite RP5081 employed non-compartmental analysis (WinNonlin). Identifying brilaroxazine-related metabolite structures in biological samples involved mass spectral analysis or via direct comparison with authentic standards. <b>Results:</b> Feces represented the predominant recovery route for administered dose for mice (77.9%), dogs (55.3%), and humans (52.3%). Urine recovery was the secondary route for mice (10.3%), dogs (15.0%), and humans (32.8%). Brilaroxazine accounted for approximately 12%, 7%, and 12% of the total circulating radioactivity, respectively, in mice, dogs and humans. A fragment of brilaroxazine, N-(2,3-chlorophenyl)-glycine (M219), was the major circulating metabolite in all species accounting for approximately 40%, 51% and 72% of the total radioactivity in mice, dogs, and humans, respectively. Human plasma showed no unique human-specific metabolite. All metabolites in human plasma were found in either mice or dogs. The major excreted metabolite identified was mono-hydroxylated brilaroxazine (M465a) in all species. <b>Conclusions:</b> Following a single oral dose of [¹⁴C]-brilaroxazine, the administered dose was predominantly recovered in feces of all species. The major circulating metabolite was the same in all species, and there was no human-specific metabolite in plasma. Oxidation, <i>N</i>- or <i>O</i>-dealkylation with subsequent sulfation and/or conjugation with glucuronic acid were the metabolic pathways of brilaroxazine.