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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.

cpt: pharmacometrics and systems pharmacology

Evaluation of the Drug–Drug Interaction Potential of Acalabrutinib and Its Active Metabolite,  ACP ‐5862, Using a  Physiologically‐Based Pharmacokinetic  Modeling Approach