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Population Pharmacokinetic Analysis of the BTK Inhibitor Zanubrutinib in Healthy Volunteers and Patients With B‐Cell Malignancies

Zanubrutinib is a potent, second‐generation Bruton’s tyrosine kinase inhibitor that is currently being investigated in patients with B‐cell malignancies and recently received accelerated approval in the United States for treatment of relapsed/refractory mantle cell lymphoma. The objective of this an...

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Autores principales: Ou, Ying C., Liu, Lucy, Tariq, Bilal, Wang, Kun, Jindal, Ashutosh, Tang, Zhiyu, Gao, Yuying, Sahasranaman, Srikumar
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993273/
https://www.ncbi.nlm.nih.gov/pubmed/33306268
http://dx.doi.org/10.1111/cts.12948
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author Ou, Ying C.
Liu, Lucy
Tariq, Bilal
Wang, Kun
Jindal, Ashutosh
Tang, Zhiyu
Gao, Yuying
Sahasranaman, Srikumar
author_facet Ou, Ying C.
Liu, Lucy
Tariq, Bilal
Wang, Kun
Jindal, Ashutosh
Tang, Zhiyu
Gao, Yuying
Sahasranaman, Srikumar
author_sort Ou, Ying C.
collection PubMed
description Zanubrutinib is a potent, second‐generation Bruton’s tyrosine kinase inhibitor that is currently being investigated in patients with B‐cell malignancies and recently received accelerated approval in the United States for treatment of relapsed/refractory mantle cell lymphoma. The objective of this analysis was to develop a population pharmacokinetic (PK) model to characterize the PKs of zanubrutinib and identify the potential impact of intrinsic and extrinsic covariates on zanubrutinib PK. Data across nine clinical studies of patients with B‐cell malignancies and data of healthy volunteers (HVs) were included in this analysis, at total daily doses ranging from 20 to 320 mg. In total, 4,925 zanubrutinib plasma samples from 632 subjects were analyzed using nonlinear mixed‐effects modeling. Zanubrutinib PKs were adequately described by a two‐compartment model with sequential zero‐order then first‐order absorption, and first‐order elimination. A time‐dependent residual error model was implemented in order to better capture the observed maximum concentration variability in subjects. Baseline alanine aminotransferase and health status (HVs or patients with B‐cell malignancies) were identified as statistically significant covariates on the PKs of zanubrutinib. These factors are unlikely to be clinically meaningful based on a sensitivity analysis. No statistically significant differences in the PKs of zanubrutinib were observed based on age, sex, race (Asian, white, and other), body weight, mild or moderate renal impairment (creatinine clearance ≥ 30 mL/minute as estimated by Cockcroft‐Gault), baseline aspartate aminotransferase, bilirubin, tumor type, or use of acid‐reducing agents (including proton pump inhibitors). These results support that no dose adjustment is considered necessary based on the aforementioned factors.
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spelling pubmed-79932732021-03-29 Population Pharmacokinetic Analysis of the BTK Inhibitor Zanubrutinib in Healthy Volunteers and Patients With B‐Cell Malignancies Ou, Ying C. Liu, Lucy Tariq, Bilal Wang, Kun Jindal, Ashutosh Tang, Zhiyu Gao, Yuying Sahasranaman, Srikumar Clin Transl Sci Research Zanubrutinib is a potent, second‐generation Bruton’s tyrosine kinase inhibitor that is currently being investigated in patients with B‐cell malignancies and recently received accelerated approval in the United States for treatment of relapsed/refractory mantle cell lymphoma. The objective of this analysis was to develop a population pharmacokinetic (PK) model to characterize the PKs of zanubrutinib and identify the potential impact of intrinsic and extrinsic covariates on zanubrutinib PK. Data across nine clinical studies of patients with B‐cell malignancies and data of healthy volunteers (HVs) were included in this analysis, at total daily doses ranging from 20 to 320 mg. In total, 4,925 zanubrutinib plasma samples from 632 subjects were analyzed using nonlinear mixed‐effects modeling. Zanubrutinib PKs were adequately described by a two‐compartment model with sequential zero‐order then first‐order absorption, and first‐order elimination. A time‐dependent residual error model was implemented in order to better capture the observed maximum concentration variability in subjects. Baseline alanine aminotransferase and health status (HVs or patients with B‐cell malignancies) were identified as statistically significant covariates on the PKs of zanubrutinib. These factors are unlikely to be clinically meaningful based on a sensitivity analysis. No statistically significant differences in the PKs of zanubrutinib were observed based on age, sex, race (Asian, white, and other), body weight, mild or moderate renal impairment (creatinine clearance ≥ 30 mL/minute as estimated by Cockcroft‐Gault), baseline aspartate aminotransferase, bilirubin, tumor type, or use of acid‐reducing agents (including proton pump inhibitors). These results support that no dose adjustment is considered necessary based on the aforementioned factors. John Wiley and Sons Inc. 2021-01-25 2021-03 /pmc/articles/PMC7993273/ /pubmed/33306268 http://dx.doi.org/10.1111/cts.12948 Text en © 2020 BeiGene. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Research
Ou, Ying C.
Liu, Lucy
Tariq, Bilal
Wang, Kun
Jindal, Ashutosh
Tang, Zhiyu
Gao, Yuying
Sahasranaman, Srikumar
Population Pharmacokinetic Analysis of the BTK Inhibitor Zanubrutinib in Healthy Volunteers and Patients With B‐Cell Malignancies
title Population Pharmacokinetic Analysis of the BTK Inhibitor Zanubrutinib in Healthy Volunteers and Patients With B‐Cell Malignancies
title_full Population Pharmacokinetic Analysis of the BTK Inhibitor Zanubrutinib in Healthy Volunteers and Patients With B‐Cell Malignancies
title_fullStr Population Pharmacokinetic Analysis of the BTK Inhibitor Zanubrutinib in Healthy Volunteers and Patients With B‐Cell Malignancies
title_full_unstemmed Population Pharmacokinetic Analysis of the BTK Inhibitor Zanubrutinib in Healthy Volunteers and Patients With B‐Cell Malignancies
title_short Population Pharmacokinetic Analysis of the BTK Inhibitor Zanubrutinib in Healthy Volunteers and Patients With B‐Cell Malignancies
title_sort population pharmacokinetic analysis of the btk inhibitor zanubrutinib in healthy volunteers and patients with b‐cell malignancies
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993273/
https://www.ncbi.nlm.nih.gov/pubmed/33306268
http://dx.doi.org/10.1111/cts.12948
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