Improved characterization of the pharmacokinetics of acalabrutinib and its pharmacologically active metabolite, ACP-5862, in patients with B-cell malignancies and in healthy subjects using a population pharmacokinetic approach
| Autor: | Francesco Bellanti, Núria Buil-Bruna, Helena Edlund, Karthick Vishwanathan, Shringi Sharma, Huan Liu, Joseph Ware, Helen Tomkinson |
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| Rok vydání: | 2021 |
| Předmět: |
Pharmacology
education.field_of_study business.industry Population Absorption (skin) Models Biological Healthy Volunteers Bioavailability medicine.anatomical_structure Pharmacokinetics Neoplasms Pyrazines Benzamides Medicine Humans Pharmacology (medical) Dosing business education Compartment (pharmacokinetics) B cell Active metabolite |
| Zdroj: | British journal of clinical pharmacology. 88(2) |
| ISSN: | 1365-2125 |
| Popis: | This analysis aimed to describe the pharmacokinetics (PK) of acalabrutinib and its active metabolite, ACP-5862. A total of 8935 acalabrutinib samples from 712 subjects and 2394 ACP-5862 samples from 304 subjects from 12 clinical studies in patients with B-cell malignancies and healthy subjects were analyzed by non-linear mixed-effects modelling. Acalabrutinib PK was characterized by a two-compartment model with first-order elimination. The large variability in absorption was adequately described by transit compartment chain and first-order absorption, with between-occasion variability on the mean transit time and relative bioavailability. The PK of ACP-5862 was characterized by a two-compartment model with first-order elimination, and the formation rate was defined as the acalabrutinib clearance multiplied by the fraction metabolized. Health status, Eastern Cooperative Oncology Group performance status, and co-administration of proton pump inhibitors were significant covariates. However, none of the investigated covariates led to clinically meaningful changes in exposure, supporting a flat dosing of acalabrutinib. |
| Databáze: | OpenAIRE |
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