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

doi:10.1007/s00280-019-04015-w

Abstract

PurposeZanubrutinib (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.MethodsIn 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.ResultsCoadministration 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.ConclusionsThese 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.

Highlights

The B-cell receptor signaling pathway is essential for normal B-cell development but is implicated in the survival and proliferation of malignant B cells [1,2,3,4]
DDI with strong cytochrome P450 3A (CYP3A) inducers and inhibitors have been reported for other Bruton’s tyrosine kinase (BTK) inhibitors such as ibrutinib (24-fold increase in area under the plasma concentration–time curve (AUC) with ketoconazole and tenfold reduction in AUC with rifampin) and acalabrutinib (5.1-fold increase in AUC with itraconazole and 77% decrease in AUC with rifampin) [25, 28]
The absolute bioavailability of zanubrutinib is unknown and, based on the magnitude of interaction observed in Part A of this study and the known interactions between CYP3A inhibitors and other BTK inhibitors, a Pharmacokinetic parametera

Summary

Introduction

The B-cell receptor signaling pathway is essential for normal B-cell development but is implicated in the survival and proliferation of malignant B cells [1,2,3,4]. B-cell receptor signaling has recently been established as an effective approach for the management of B-cell malignancies [2]. Bruton’s tyrosine kinase (BTK) is a key component of the B-cell receptor signaling pathway [3], and the firstgeneration BTK inhibitor, ibrutinib, has become a standard of care in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), mantle cell lymphoma, and Waldenström macroglobulinemia [5,6,7,8,9,10,11,12,13]. Pharmacokinetic (PK) data showed that zanubrutinib was rapidly absorbed after oral administration, with Cmax observed at

Methods

Results

Conclusion