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

Background and objective: 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 of inflammation in multiple sclerosis. This excretion balance and metabolism study evaluated the metabolite profile of tolebrutinib in healthy male volunteers.

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

Results: Tolebrutinib was rapidly and completely absorbed from the gastrointestinal tract, followed by rapid and extensive metabolism. Excretion via feces was the major elimination pathway of the administered radioactivity (78%). Tolebrutinib was highly metabolized, with 19 metabolites identified in human plasma. Phase 1 biotransformations were primarily responsible for the circulating metabolites in plasma. Seven metabolites that achieved exposure in plasma similar to or higher than the parent compound were characterized biochemically for inhibition of Bruton's tyrosine kinase activity. Metabolite M8 exceeded the exposure threshold of 10% (18%) of the total radioactivity but had little if any pharmacological activity. Metabolite M2 (4% of circulating radioactivity) retained the ability to irreversibly and potently inhibit Bruton's tyrosine kinase in vitro, similar to the parent compound. Tolebrutinib and metabolite M2 had short (3.5-h) half-lives but durable pharmacodynamic effects as expected for an irreversible antagonist.

Conclusions: Tolebrutinib was extensively metabolized to multiple metabolites. The hydroxylated metabolite M2 demonstrated similar inhibitory potency toward Bruton's tyrosine kinase as the parent compound. Both tolebrutinib and metabolite M2 likely contributed to pharmacological activity in vivo.

 

Comments:

This study on tolebrutinib provides valuable insights into its metabolism and potential pharmacological activity. Tolebrutinib, as a covalent inhibitor of Bruton's tyrosine kinase (BTK), showed rapid absorption and extensive metabolism in healthy volunteers. Here's a breakdown of the key findings:

1. **Absorption and Metabolism:** Tolebrutinib was swiftly absorbed after oral administration and extensively metabolized. The gastrointestinal tract absorbed it completely.

2. **Elimination Pathway:** The primary pathway for eliminating the administered radioactivity was through feces (78%), indicating a major excretion route.

3. **Metabolite Profile:** A total of 19 metabolites were identified in human plasma, with Phase 1 biotransformations being the primary mechanism for generating these metabolites.

4. **Pharmacological Activity:** Seven metabolites showed exposure in plasma similar to or higher than the parent compound. Among these, metabolite M2 (constituting 4% of circulating radioactivity) retained potent inhibition of BTK, similar to tolebrutinib itself. This suggests that both the parent compound and metabolite M2 could contribute to the pharmacological activity of tolebrutinib in vivo.

5. **Pharmacokinetics:** Tolebrutinib and metabolite M2 had short half-lives (3.5 hours) but exhibited durable pharmacodynamic effects typical of irreversible antagonists.

6. **Significance:** The findings suggest that while tolebrutinib undergoes extensive metabolism, the presence of metabolite M2, which retains the potent BTK inhibition, indicates its potential contribution to the drug's therapeutic effects.

This study underscores the importance of understanding the metabolite profile and pharmacological activity of tolebrutinib, indicating that not only the parent compound but also certain metabolites may play a role in its therapeutic efficacy.

Related Products

Cat.No.	Product Name	Information
E0041	Tolebrutinib	Tolebrutinib is an oral, CNS-penetrant, irreversible inhibitor of Bruton's tyrosine kinase (BTK) with IC50s of 0.4 nM and 0.7 nM in Ramos B cells and in HMC microglia cells, respectively.

Related Targets

BTK