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

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...

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Published inBritish journal of clinical pharmacology Vol. 88; no. 2; pp. 846 - 852
Main Authors Edlund, Helena, Bellanti, Francesco, Liu, Huan, Vishwanathan, Karthick, Tomkinson, Helen, Ware, Joseph, Sharma, Shringi, Buil‐Bruna, Núria
Format Journal Article
LanguageEnglish
Published England John Wiley and Sons Inc 01.02.2022
Subjects
acalabrutinib
ACP‐5862
Benzamides - pharmacokinetics
between‐occasion variability
B‐cell malignancies
Healthy Volunteers
Humans
Models, Biological
Neoplasms
pharmacokinetics
pH‐dependent solubility
population pharmacokinetics
Pyrazines - pharmacokinetics
Short Communication
Short Communications
pH-dependent solubility
between-occasion variability
pharmacokinetics
ACP-5862
B-cell malignancies
acalabrutinib
population pharmacokinetics
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Summary: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 analysed by nonlinear mixed‐effects modelling. Acalabrutinib PK was characterized by a 2‐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 2‐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 coadministration 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.
Bibliography:Funding information
Acerta Pharma, South San Francisco, CA, a member of the AstraZeneca Group
A principal investigator was not included in the author byline because the reported data are from a population PK model developed using the data from 12 different studies. The principle investigators of the original studies were not involved in performing these analyses or interpreting the data; therefore, they did not qualify for authorship according to ICMJE criteria.
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Funding information Acerta Pharma, South San Francisco, CA, a member of the AstraZeneca Group
ISSN:0306-5251
1365-2125
1365-2125
DOI:10.1111/bcp.14988