| Autor: |
Tariq B; Clinical Pharmacology, BeiGene USA, Inc, Fulton, MD, USA., Ou YC; Clinical Pharmacology, BeiGene USA, Inc, San Mateo, CA, USA., Stern JC; Clinical Pharmacology, BeiGene USA, Inc, San Mateo, CA, USA., Mundra V; Clinical Pharmacology, BeiGene USA, Inc, San Mateo, CA, USA., Wong Doo N; Department of Hematology, Concord Repatriation General Hospital, Concord, Australia.; Concord Clinical School, University of Sydney, Sydney, Australia., Walker P; Department of Hematology, Peninsula Health and Peninsula Private Hospitals, Frankston, Australia., Lewis KL; Department of Haematology, Sir Charles Gairdner Hospital and Linear Clinical Research, Nedlands, Australia., Lin C; Biostatistics, BeiGene, Ltd, Emeryville, CA, USA., Novotny W; Clinical Development, Hematology, BeiGene USA, Inc, San Mateo, CA, USA., Sahasranaman S; Clinical Pharmacology, BeiGene USA, Inc, San Mateo, CA, USA., Opat S; Clinical Hematology, Monash Health and Monash University, Clayton, Australia. |
| Abstrakt: |
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. |
