The objective was to characterize the human absorption, distribution, metabolism, and excretion profile of BGB–16673 and to evaluate the effect of strong CYP3A modulators on its pharmacokinetics.

Two phase 1 studies were conducted. One was a human ADME study (n=8) in healthy male participants receiving a single oral dose of [¹⁴C]-BGB–16673 (200 mg). The second was a fixed–sequence drug–drug interaction study (n=37) evaluating coadministration of BGB–16673 with the strong CYP3A inducer phenytoin or the strong CYP3A inhibitor itraconazole. Primary endpoints were pharmacokinetic parameters, including area under the plasma concentration–time curve (AUC) and maximum observed plasma concentration (Cmax), which were analyzed using mixed-effects models to derive geometric mean ratios (GMRs) and 90% CIs.

Following a single oral dose of [¹⁴C]-BGB–16673, mean total radioactivity recovery was 88.5%, with the majority recovered in feces and minimal recovery in urine. Unchanged BGB–16673 was the predominant circulating drug–related component, and no significant plasma metabolites were detected. Oxadiazole ring–cleaved metabolites generated by gut microbiota predominated in feces, while oxidative and amide hydrolysis pathways were minimal. The median time to maximum observed concentration was 12 hours, and the geometric mean terminal half–life was ≈82 hours.

In the drug–drug interaction study, coadministration of BGB–16673 with the strong CYP3A inducer phenytoin resulted in no clinically meaningful change in systemic exposure (AUC GMR [coadministration vs alone], ≈0.9–1.0; Cmax GMR, ≈1.2). Coadministration with the strong CYP3A inhibitor itraconazole did not meaningfully increase exposure (AUC GMR, ≈1.1), and a modest reduction in Cmax (GMR, ≈0.77). Despite moderate variability, these changes were not considered clinically relevant.