Fecha de publicación: -- Fuente: PubMed "hive" Drug Metab Dispos. 2026 Oct 8;54(11):100417. doi: 10.1016/j.dmd.2026.100417. Online ahead of print.ABSTRACTRemibrutinib (LOU064), an oral, highly selective Bruton tyrosine kinase inhibitor, is approved in the United States, China, European Union, and Japan for treating adults with chronic spontaneous urticaria who remain symptomatic despite treatment with H1-antihistamines. This study characterized the absorption, distribution, metabolism, and excretion of remibrutinib in healthy participants to evaluate its pharmacokinetics, mass balance, and metabolite profile following oral and intravenous administration. Five participants received oral [14C]remibrutinib (100 mg) and 2 received an intravenous microdose of [14C]remibrutinib (100 μg) as a 2-mL bolus at steady state, alongside unlabeled remibrutinib. Remibrutinib showed fast absorption (time to reach maximum concentration: 0.5 hours, oral; 1.13-1.33 hours, intravenous), with fraction absorbed estimated at 75%-88%. Elimination half-life was 3.29 hours (oral), 1.85 hours (intravenous arm A), and 2.06 hours (intravenous arm B). Total radioactivity exposure area under the curve extrapolated to infinity in whole blood was 85% (oral arm) and >90% (intravenous arms) of that in plasma, indicating no preferential distribution to red blood cells, and total radioactivity remained detectable up to 600 hours, indicating extensive distribution (apparent volume of distribution: 576-2120 L). Remibrutinib was mainly metabolized at the acrylamide moiety (glutathione conjugation and dihydrodiol formation via an epoxide intermediate) and by amide hydrolysis. Predominant circulating metabolites were M68a/b diastereomers, with none exceeding 10% of the total drug-related material. Excretion was predominantly through feces, accounting for 31.8% of the dose after oral and ∼69.5% after intravenous administration. Mass balance was incomplete following oral dosing (56.2%) but nearly complete after intravenous dosing (96.8%-97.2%). Remibrutinib was well tolerated. In conclusion, this study comprehensively characterized the absorption, distribution, metabolism, and excretion profile of remibrutinib in humans. SIGNIFICANCE STATEMENT: At steady state, oral [14C]remibrutinib showed fast absorption and good systemic availability, with extensive metabolism after oral and intravenous dosing. Mass balance was incomplete after oral but complete after intravenous dosing. Radioactivity was predominantly excreted in feces (31.8% and ∼69.5% after oral and intravenous dosing, respectively). No circulating metabolite exceeded 10% of total radioactivity. The main fecal metabolite was M24, representing 7.22% and 16.9% of the dose following oral and intravenous dosing, respectively. Remibrutinib was well tolerated in healthy participants.PMID:42971100 | DOI:10.1016/j.dmd.2026.100417