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

Background objective: Tolebrutinib is really a covalent inhibitor of Bruton’s tyrosine kinase, an enzyme expressed in B lymphocytes and myeloid cells including microglia, which can be major motorists of inflammation in ms. This excretion balance and metabolic process study evaluated the metabolite profile of tolebrutinib in healthy male volunteers.

Methods: Six healthy volunteers received a 60-mg dental dose of [14C]-tolebrutinib, and metabolite profiling of 14C-labeled metabolites was performed using a mix of liquid chromatography, mass spectrometry, and radioactivity assay methods.

Results: Tolebrutinib was quickly and completely absorbed in the gastrointestinal tract, adopted by rapid and extensive metabolic process. Excretion via feces was the main elimination path from the administered radioactivity (78%). Tolebrutinib was highly metabolized, with 19 metabolites identified in human plasma. Phase 1 biotransformations were mainly accountable for the circulating metabolites in plasma. Seven metabolites that achieved exposure in plasma much like or greater compared to parent compound were characterised biochemically for inhibition of Bruton’s tyrosine kinase activity. Metabolite M8 exceeded the exposure threshold of 10% (18%) from the total radioactivity but had minimum medicinal activity. Metabolite M2 (4% of circulating radioactivity) retained the opportunity to irreversibly and potently hinder Bruton’s tyrosine kinase in vitro, like the parent compound. Tolebrutinib and metabolite M2 had short (3.5-h) half-lives but durable pharmacodynamic effects not surprisingly to have an irreversible antagonist.

Conclusions: Tolebrutinib was extensively metabolized to multiple metabolites. The hydroxylated metabolite M2 shown similar inhibitory potency toward Bruton’s tyrosine kinase because the parent compound. Both tolebrutinib and metabolite M2 likely led to medicinal activity in vivo.