Open AccessEvaluation of the Drug–Drug Interaction Potential of Acalabrutinib and Its Active Metabolite, ACP ‐5862, Using a Physiologically‐Based Pharmacokinetic Modeling Approach
Author(s) -
Zhou Diansong,
Podoll Terry,
Xu Yan,
Moorthy Ganesh,
Vishwanathan Karthick,
Ware Joseph,
Slatter J. Greg,
AlHuniti Nidal
Publication year - 2019
Publication title -
cpt: pharmacometrics and systems pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.53
H-Index - 37
ISSN - 2163-8306
DOI - 10.1002/psp4.12408
Subject(s) - physiologically based pharmacokinetic modelling , active metabolite , pharmacology , metabolite , pharmacokinetics , chemistry , drug , drug drug interaction , pharmacodynamics , medicine , biochemistry
Acalabrutinib, a selective, covalent Bruton tyrosine kinase inhibitor, is a CYP 3A substrate and weak CYP 3A/ CYP 2C8 inhibitor. A physiologically‐based pharmacokinetic (PBPK) model was developed for acalabrutinib and its active metabolite ACP ‐5862 to predict potential drug–drug interactions ( DDIs ). The model indicated acalabrutinib would not perpetrate a CYP 2C8 or CYP 3A DDI with the sensitive CYP substrates rosiglitazone or midazolam, respectively. The model reasonably predicted clinically observed acalabrutinib DDI with the CYP 3A perpetrators itraconazole (4.80‐fold vs. 5.21‐fold observed) and rifampicin (0.21‐fold vs. 0.23‐fold observed). An increase of two to threefold acalabrutinib area under the curve was predicted for coadministration with moderate CYP 3A inhibitors. When both the parent drug and active metabolite (total active components) were considered, the magnitude of the CYP 3A DDI was much less significant. PBPK dosing recommendations for DDIs should consider the magnitude of the parent drug excursion, relative to safe parent drug exposures, along with the excursion of total active components to best enable safe and adequate pharmacodynamic coverage.