Absorption, Metabolism, and Excretion of [14C]-Tolebrutinib After Oral Administration in Humans, Contribution of the Metabolites to Pharmacological Activity

• DOI: 10.1007/s40261-023-01296-1
• Publication Date: 2023-08-29T06:02:28Z
• Authors: Olivier Nicolas; Patricia Moliner; Patrick Soubayrol; Olivier Vitse; Sebastien Roy; Marie-José Cabanis; Tim Turner; Sylvie Klieber; Stephane Muccio; Catherine Arabeyre; Priscilla Brun
• Keywords: Male; Feces; Agammaglobulinaemia Tyrosine Kinase; Humans; Administration, Oral; Original Research Article; Protein Kinase Inhibitors; Chromatography, Liquid

Tolebrutinib is a covalent inhibitor of Bruton’s tyrosine kinase, an enzyme expressed in B lymphocytes and myeloid cells including microglia, which are thought to be major drivers inflammation multiple sclerosis. This excretion balance metabolism study evaluated the metabolite profile tolebrutinib healthy male volunteers. Six volunteers received 60-mg oral dose [14C]-tolebrutinib, profiling 14C-labeled metabolites was performed using combination liquid chromatography, mass spectrometry, radioactivity assay methods. rapidly completely absorbed from gastrointestinal tract, followed by rapid extensive metabolism. Excretion via feces elimination pathway administered (78%). highly metabolized, with 19 identified human plasma. Phase 1 biotransformations were primarily responsible for circulating Seven that achieved exposure plasma similar or higher than parent compound characterized biochemically inhibition kinase activity. Metabolite M8 exceeded threshold 10% (18%) total but had little if any pharmacological M2 (4% radioactivity) retained ability irreversibly potently inhibit vitro, compound. short (3.5-h) half-lives durable pharmacodynamic effects as expected irreversible antagonist. extensively metabolized metabolites. The hydroxylated demonstrated inhibitory potency toward Both likely contributed activity vivo.