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

Autor: Yuying Gao, Ashutosh Jindal, Ying C. Ou, Kun Wang, Srikumar Sahasranaman, Zhiyu Tang, Lucy Liu, Bilal Tariq
Rok vydání: 2021
Předmět:
Male
030213 general clinical medicine
030226 pharmacology & pharmacy
Gastroenterology
Tyrosine-kinase inhibitor
chemistry.chemical_compound
0302 clinical medicine
Piperidines
General Pharmacology
Toxicology and Pharmaceutics
Aged
80 and over
Clinical Trials as Topic
education.field_of_study
biology
lcsh:Public aspects of medicine
General Neuroscience
Articles
General Medicine
Middle Aged
Healthy Volunteers
medicine.anatomical_structure
Female
Waldenstrom Macroglobulinemia
Adult
medicine.medical_specialty
Lymphoma
B-Cell
medicine.drug_class
Bilirubin
Population
Renal function
Models
Biological
Article
General Biochemistry
Genetics and Molecular Biology
Young Adult
03 medical and health sciences
Text mining
Pharmacokinetics
Internal medicine
Leukemia
B-Cell
medicine
Humans
Bruton's tyrosine kinase
education
Protein Kinase Inhibitors
B cell
Aged
Dose-Response Relationship
Drug
business.industry
Research
lcsh:RM1-950
lcsh:RA1-1270
lcsh:Therapeutics. Pharmacology
Pyrimidines
Biological Variation
Population
chemistry
Case-Control Studies
biology.protein
Pyrazoles
business
Zdroj: Clinical and Translational Science
Clinical and Translational Science, Vol 14, Iss 2, Pp 764-772 (2021)
ISSN: 1752-8062
1752-8054
DOI: 10.1111/cts.12948
Popis: 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.
Databáze: OpenAIRE
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