A phase 1, open-label, randomized drug–drug interaction study of zanubrutinib with moderate or strong CYP3A inhibitors in patients with B-cell malignancies

Abstract

BTK inhibitor exposure increases significantly when coadministered with CYP3A inhibitors, which may lead to dose-related toxicities. This study explored the pharmacokinetics, efficacy, and safety of zanubrutinib when coadministered with moderate or strong CYP3A inhibitors in 26 patients with relapsed or refractory B-cell malignancies. Coadministration of zanubrutinib (80 mg BID) with moderate CYP3A inhibitors fluconazole and diltiazem or zanubrutinib (80 mg QD) with strong CYP3A inhibitor voriconazole resulted in comparable exposures to zanubrutinib (320 mg QD) with AUC_0-24h geometric least squares mean ratios approaching 1 (0.94, 0.81, and 0.83, for fluconazole, diltiazem, and voriconazole, respectively). The most common treatment-emergent adverse events were contusion (26.9%), back pain (19.2%), constipation and neutropenia (15.4% each), and rash, diarrhea, and fall (11.5% each). This study supports current United States Prescribing Information dose recommendations for the coadministration of reduced-dose zanubrutinib with moderate or strong CYP3A inhibitors and confirms the favorable efficacy and safety profile of zanubrutinib.

Keywords:

• Zanubrutinib
• BTK
• DDI
• CYP3A
• pharmacokinetics

Acknowledgments

We thank study patients, their supporters, the investigators and clinical research staff at the various study centers, Mara Giovannetti, Arjun Bhat, Jonathan Schroer, and Chris Di Simone. Medical writing and editorial assistance were provided, under the direction of the authors, by Laura S. Moye, PhD, of Bio Connections, LLC, (Chicago, IL), supported by BeiGene.

Author contributions

Study design: BT, YCO, JCS, WN, SS; collection and assembly of data: BT, JCS, CL, WN; enrolled patients: NWD, PW, KLL, SO; data analysis and interpretation: BT, YCO, JCS, VM, CL, SS.

Disclosure statement

BT is employed by BeiGene and holds stock with BeiGene. YCO is employed by BeiGene, is in a leadership position at BeiGene, holds stock with BeiGene, and has received research funding from BeiGene. JCS is employed by BeiGene and holds stock with BeiGene. VM is employed by BeiGene and holds stock with BeiGene. NWD has nothing to disclose. PW has nothing to disclose. KLL has received honoraria from AstraZeneca, Janssen, Roche, served as a consultant for AstraZeneca, Roche, Loxo/Lilly, IQVIA, and received travel expenses and compensation from conference attendances from Novartis, Janssen, and Loxo/Lilly. CL is employed by BeiGene and holds stock with BeiGene. WN was employed by BeiGene at the time of the study and holds stock with BeiGene. SS is employed by BeiGene, is in a leadership position at BeiGene, holds stock with BeiGene, and has received research funding and travel expenses from BeiGene. SO has received honoraria from AbbVie, BeiGene, AstraZeneca, BMS, CSL Behring, Gilead, Janssen, Merck, Roche, Takeda, served as a consultant for AbbVie, BeiGene, AstraZeneca, BMS, CSL Behring, Gilead, Janssen, Merck, Roche, Takeda, and received research funding from AbbVie, AstraZeneca, BeiGene, CSL Behring, Gilead, Janssen, Merck, Pharmacyclics, Roche, and Takeda.

Data availability statement

All authors had access to the original data for the analyses described here. On request and subject to certain criteria, conditions, and exceptions, BeiGene will provide access to individual deidentified participant data from BeiGene-sponsored global interventional clinical studies conducted for medicines (1) for indications that have been approved or (2) in programs that have been terminated. Data requests may be submitted to [email protected].

Additional information

Funding

This work was supported by BeiGene.