Rilzabrutinib, a reversible covalent Bruton's tyrosine kinase inhibitor: Absorption, metabolism, excretion and absolute bioavailability in healthy participants.

Abstract

This single-center, open-label, non-randomized, two-part, phase I study was conducted 1) to evaluate the absolute oral bioavailability of rilzabrutinib 400 mg tablet following an IV microtracer dose of ~100 μg [14C]-rilzabrutinib (~1 μCi) and single oral dose of 400 mg rilzabrutinib tablet (Part 1), and 2) to characterize the absorption, metabolism, and excretion (AME) of 14C-radiolabeled rilzabrutinib following single oral dose (300 mg) of [14C]-rilzabrutinib (~1000 μCi) (administered as a liquid) in healthy male participants (Part 2). A total of 18 subjects were enrolled (n=8 in Part 1; n=10 in Part 2). The absolute bioavailability of 400 mg rilzabrutinib oral tablet was low (less than 5%). In Part 1, rilzabrutinib was absorbed rapidly after single oral dose of rilzabrutinib 400 mg tablet with a median (range) tmax value of 2.03 h (1.83-2.50). The geometric mean (CV%) t1/2 following the oral dose and IV microtracer dose of ~100 μg [14C]-rilzabrutinib, were 3.20 (51.0%) and 1.78 (37.6%) hours, respectively. In Part 2, rilzabrutinib was also absorbed rapidly following single oral dose of 300 mg [14C]-rilzabrutinib solution with a median (range) tmax value of 1.00 h (1.00-2.00). The majority of total radioactivity was in the feces for both non-bile collection subjects (92.9%) and bile collection subjects (87.6%), and approximately 5% of radioactivity was recovered in urine after oral administration. Urinary excretion of unchanged rilzabrutinib was low (3.02%). The results of this study advance the understanding of the absolute bioavailability and AME of rilzabrutinib and can help inform its further investigation.