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

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 i.v. 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 (<5%). In part 1, rilzabrutinib was absorbed rapidly after single oral dose of rilzabrutinib 400 mg tablet with a median (range) time to maximum concentration (T ) value of 2.03 h (1.83-2.50 h). The geometric mean (coefficient of variation) terminal half-life following the oral dose and i.v. microtracer dose of ~100 μg [14C]-rilzabrutinib, were 3.20 (51.0%) and 1.78 (37.6%) h, respectively. In part 2, rilzabrutinib was also absorbed rapidly following single oral dose of 300 mg [14C]-rilzabrutinib solution with a median (range) T value of 1.00 h (1.00-2.00 h). The majority of total radioactivity was in the feces for both non-bile collection subjects (92.9%) and bile collection subjects (87.6%), and ~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.