Effect of rifampin and itraconazole on the pharmacokinetics of zanubrutinib (a Bruton's tyrosine kinase inhibitor) in Asian and non-Asian healthy subjects

Song Mu, Zhiyu Tang, William Novotny, Manal Tawashi, Ta-Kai Li, Ying Ou, Srikumar Sahasranaman, Song Mu, Zhiyu Tang, William Novotny, Manal Tawashi, Ta-Kai Li, Ying Ou, Srikumar Sahasranaman

Abstract

Purpose: Zanubrutinib (BGB-3111) is a potent Bruton's tyrosine kinase inhibitor with promising clinical activity in B-cell malignancies. Zanubrutinib was shown to be mainly metabolized through cytochrome P450 3A (CYP3A) in vitro. We evaluated the effect of steady-state rifampin (a strong CYP3A inducer) and steady-state itraconazole (a strong CYP3A inhibitor) on the pharmacokinetics (PK), safety, and tolerability of zanubrutinib in healthy Asian and non-Asian subjects.

Methods: In this open-label, two-part clinical study, 20 participants received a single oral dose of zanubrutinib (320 mg) and oral rifampin (600 mg) in Part A, and 18 participants received a single oral dose of zanubrutinib (20 mg) and oral itraconazole (200 mg) in Part B. Serial blood samples were collected after administration of zanubrutinib alone and zanubrutinib in combination with rifampin or itraconazole for the measurement of PK parameters.

Results: Coadministration with rifampin decreased AUC0-∞ of zanubrutinib by 13.5-fold and Cmax by 12.6-fold. Coadministration with itraconazole increased the AUC0-∞ of zanubrutinib by 3.8-fold and Cmax by 2.6-fold. The PK of zanubrutinib was consistent between Asian and non-Asian subjects, and zanubrutinib was well tolerated in this study.

Conclusions: These results confirm that zanubrutinib is primarily metabolized by CYP3A in humans. The PK of zanubrutinib was comparable between Asian and non-Asian subjects and, therefore, no dose modifications are necessary for zanubrutinib in these ethnic populations.

Keywords: Clinical pharmacology; Clinical trials; Drug–drug interactions; Oncology; Pharmacokinetics and drug metabolism.

Conflict of interest statement

Song Mu, Zhiyu Tang, William Novotny, Manal Tawashi, Ta-Kai Li, Ying Ou, and Srikumar Sahasranaman are employees of BeiGene. The study was sponsored and funded by BeiGene, USA.

Figures

Fig. 1
Fig. 1
Arithmetic mean (+ SD) zanubrutinib plasma concentration profiles following a administration of 320 mg alone and coadministration with 600 mg rifampin or b administration of 20 mg alone and coadministration with 200 mg itraconazole. Zanubrutinib plasma concentrations on Y-axis are shown on log scale
Fig. 2
Fig. 2
Comparative box plots of area under the plasma concentration–time curve from 0 h to infinity (AUC0–∞, ng·h/mL) and maximal plasma concentration (Cmax; ng/mL) in Asian and non-Asian) subjects in a, b the absence and presence of rifampin and c, d in the absence and presence of itraconazole. The box plot represents 25th and 75th percentiles; whiskers extend to 5th and 95th percentiles. Median is indicated by a line within the box, and circles represent values for individual subject

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