Clinical pharmacology and PK/PD translation of the second-generation Bruton’s tyrosine kinase inhibitor, zanubrutinib

Introduction: Bruton's tyrosine kinase (BTK) inhibitors have revolutionized the treatment of B-cell lymphomas. Zanubrutinib was designed to achieve improved therapeutic concentrations and minimize off-target activities putatively accounting, in part, for the adverse effects seen with other BTK inhibitors.Areas covered: This drug profile covers zanubrutinib clinical pharmacology and the translation of pharmacokinetics (PK) and pharmacodynamics (PD) to clinical efficacy and safety profiles, by highlighting key differences between zanubrutinib and other BTK inhibitors. We discuss PK, sustained BTK occupancy, and potential factors affecting PK of zanubrutinib, including food effects, hepatic impairment, and drug-drug interactions. These data, along with exposure-response analyses, were used to support the recommended dose of 320 mg, either once daily or as 160 mg twice daily. Translation of PK/PD attributes into clinical effects was demonstrated in a randomized, phase 3 head-to-head study comparing it with ibrutinib in patients with Waldenström macroglobulinemia.Expert opinion: Among the approved BTK inhibitors, zanubrutinib is less prone to PK modulation by intrinsic and extrinsic factors, leading to more consistent, sustained therapeutic exposures and improved dosing convenience. Zanubrutinib PK/PD has translated into durable responses and improved safety, representing an important new treatment option for patients who benefit from BTK therapy.