Evaluation of drug interaction potential of zanubrutinib with cocktail probes representative of CYP3A4, CYP2C9, CYP2C19, P‐gp and BCRP

Aim This study aims to assess the potential effects of zanubrutinib on the activity of cytochrome P450 (CYP) enzymes and drug transporter proteins using a cocktail probe approach. Methods Patients received single oral doses of probe drugs alone and after at least 8 days of treatment with zanubrutinib 160 mg twice daily in a single‐sequence study in 18 healthy male volunteers. Simultaneous doses of 10 mg warfarin (CYP2C9) and 2 mg midazolam (CYP3A) were administered on Day 1 and Day 14, 0.25 mg digoxin (P‐glycoprotein [P‐gp]) and 10 mg rosuvastatin (breast cancer resistance protein [BCRP]) on Day 3 and Day 16, and 20 mg omeprazole (CYP2C19) on Day 5 and Day 18. Pharmacokinetic (PK) parameters were estimated from samples obtained up to 12 h post dose for zanubrutinib; 24 h for digoxin, omeprazole and midazolam; 48 h for rosuvastatin; and 144 h for warfarin. Results The ratios (%) of geometric least squares means (90% confidence intervals) for the area under the concentration–time curve from time zero to the last quantifiable concentration in the presence/absence of zanubrutinib were 99.80% (97.41–102.2%) for S‐warfarin; 52.52% (48.49–56.88%) for midazolam; 111.3% (103.8–119.3%) for digoxin; 89.45% (78.73–101.6%) for rosuvastatin; and 63.52% (57.40–70.30%) for omeprazole. Similar effects were observed for maximum plasma concentrations. Conclusions Zanubrutinib 320 mg total daily dose had minimal or no effect on the activity of CYP2C9, BCRP and P‐gp, but decreased the systemic exposure of CYP3A and CYP2C19 substrates (mean reduction