CYP3A-Mediated Drug Interaction Profile of Bruton Tyrosine Kinase Inhibitor, Acalabrutinib

Background: Acalabrutinib (ACP-196) is a highly selective, potent, covalent inhibitor of Bruton tyrosine kinase (BTK), in development for the treatment of hematologic malignancies. Acalabrutinib has rapid absorption and a short pharmacokinetic (PK) half-life; twice daily dosing resulted in near complete and continuous BTK inhibition in patients with chronic lymphocytic leukemia (CLL) (Byrd JC, et al. 2016). CYP3A-mediated oxidation is the primary route of elimination for the marketed BTK inhibitor, ibrutinib (de Zwart et al., 2016). Coadministration of ibrutinib with ketoconazole (a strong CYP3A inhibitor) increased dose-normalized maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) by 29- and 24-fold, respectively, whereas coadministration of rifampin (a strong CYP3A inducer) decreased Cmax and AUC of ibrutinib by more than 13- and 10-fold, respectively (IMBRUVICA® (ibrutinib) package insert 2017). Grapefruit juice, which is known to contain CYP3A inhibitors, resulted in a 3.6- and 2.1-fold increase in Cmax and AUC of ibrutinib, respectively (de Jong J. et al., 2015). To evaluate the effects of CYP3A inhibitors and inducers on the PK profile, safety and tolerability of acalabrutinib, administered alone and coadministered with itraconazole, rifampin, or grapefruit juice, three CYP3A-related drug-drug interaction (DDI) studies were performed in healthy subjects. Methods: DDI study 1: Strong CYP3A inhibitor: Subjects (N=18) received 50 mg acalabrutinib alone and with the last dose of a 200 mg twice daily, 11-dose itraconazole regimen. DDI study 2: Strong CYP3A inducer: Subjects (N=24) received 100 mg acalabrutinib alone and with the first and last dose of a 600 mg daily, 9-dose rifampin regimen. DDI study 3: Grapefruit juice-CYP3A inhibitor: Subjects (N=12) received 100 mg acalabrutinib. Grapefruit juice (240 mL) was given twice, 12 hours before and with the 100 mg acalabrutinib dose. In all studies, plasma PK and geometric mean ratio (GMR) (90% CI) of acalabrutinib Cmax and AUC were evaluated, along with PK of concomitant itraconazole and rifampin. Results: In the presence of steady-state itraconazole, geometric mean (GM) acalabrutinib AUC and Cmax increased by 5.1-fold (90%CI 4.5-5.8) and 3.9-fold (3.2-4.7), respectively, relative to acalabrutinib given alone. In the presence of steady-state rifampin, acalabrutinib AUC decreased by 4.3-fold (GMR 0.23 [90%CI 0.19-0.29]), relative to acalabrutinib given alone. Cmax decreased by 3.1-fold (GMR 0.32 (90%CI 0.24-0.42)), relative to acalabrutinib given alone. In the presence of grapefruit juice, acalabrutinib AUC decreased by 1.2-fold (GMR 0.83 [90%CI 0.72-0.97]) relative to acalabrutinib given alone. Cmax decreased by 1.5-fold (GMR 0.65 [90%CI 0.45-0.93]) relative to acalabrutinib given alone. Overall, acalabrutinib was safe and well tolerated by the healthy subjects in these studies, when administered alone or when coadministered with itraconazole, rifampin, or grapefruit juice. Conclusions: In healthy subjects, coadministration of strong CYP3A inhibitor, itraconazole, increased acalabrutinib AUC by 5.1-fold and strong CYP3A inducer, rifampin, decreased acalabrutinib AUC by 4.3-fold. Grapefruit juice resulted in a 1.2-fold decrease in acalabrutinib AUC. Disclosures Izumi: Acerta Pharma: Employment, Equity Ownership. Pearson: Acerta Pharma: Consultancy; Pearson Pharma Partners: Consultancy. Hamdy: Acerta Pharma: Employment, Equity Ownership, Patents & Royalties: Acalabrutinib related patents. Rodriquez: Acerta Pharma: Employment. Yang: Acerta Pharma: Employment, Equity Ownership. Ulrich: Acerta Pharma BV: Equity Ownership, Membership on an entity9s Board of Directors or advisory committees, Patents & Royalties: EP3076974 A1 Therapeutic combination of a pi3k inhibitor and a btk inhibitor. No royalties.. Podoll: Acerta Pharma: Employment; Astra Zeneca: Equity Ownership. Andrew: Acerta Pharma: Employment; Astra Zeneca: Equity Ownership. Krejsa: Acerta Pharma: Employment, Equity Ownership; Astra Zeneca: Equity Ownership. Ingallinera: Astra Zeneca: Equity Ownership; Acerta Pharma: Employment, Equity Ownership. Slatter: Acerta Pharma: Employment; Astra Zeneca: Equity Ownership.