Understanding the Effect of Hydroxypropyl‐β‐Cyclodextrin on Fenebrutinib Absorption in an Itraconazole–Fenebrutinib Drug–Drug Interaction Study

作者：Matthew R. Durk, Nicholas S. Jones, Jia Liu, Karthik Nagapudi, Chen Mao, Emile G. Plise, Susan Wong, Jacob Z. Chen, Yuan Chen, Leslie W. Chinn, Po‐Chang Chiang · 发表于：Clinical Pharmacology & Therapeutics · 年份：2020 · DOI：10.1002/cpt.1943 · 被引用次数：24 · 研究领域：Drug Solubulity and Delivery Systems、Biochemical and Molecular Research、Chronic Lymphocytic Leukemia Research

Cyclodextrins are widely used pharmaceutical excipients, particularly for insoluble compounds dosed orally, such as the oral solution of itraconazole, which is frequently used in clinical drug–drug interaction studies to inhibit cytochrome P450 3A. Since cyclodextrins act by forming inclusion complexes with their coformulated drug, they could have an unintended consequence of affecting absorption if they form a strong complex with the potential victim drug in an itraconazole drug–drug interaction study. This observation was made in a drug–drug interaction study with the Bruton’s tyrosine kinase (BTK) inhibitor fenebrutinib and itraconazole, in which, relative to the control group, the expected increase in fenebrutinib maximum plasma concentration (C max ) was not observed in the itraconazole group, and a delay in time to reach maximum plasma concentration (T max ) was observed in the itraconazole group. The in vitro binding constant between fenebrutinib and hydroxypropyl‐ β ‐cyclodextrin was determined to be 2 × 10 5 M −1 , and the apparent permeability of fenebrutinib across a Madin‐Darby canine kidney cell monolayer decreased in a cyclodextrin concentration‐dependent manner. This observation was confirmed in vivo , in a pentagastrin‐pretreated dog model, in which fenebrutinib was administered with or without cyclodextrin; a reduction in C max , a prolonged T max , and increased fenebrutinib recovery in feces replicated the previous observation in healthy volunteers and supp...