Effect of aprepitant, a moderate CYP3A4 inhibitor, on bosutinib exposure in healthy subjects

Bosutinib is an oral, dual Src and Abl tyrosine kinase inhibitor (TKI) approved for the treatment of Philadelphia chromosome-positive chronic myeloid leukemia resistant or intolerant to prior TKI therapy. Bosutinib is primarily metabolized by cytochrome P450 (CYP) 3A4, suggesting drug interaction potential with other CYP3A4 modulators. This open-label, randomized, 2-sequence, 2-period crossover study assessed the effect of single-dose aprepitant, a moderate CYP3A4 inhibitor, on the single-dose pharmacokinetic profile of oral bosutinib 500 mg. Nineteen healthy, fed adults received bosutinib (100 mg x 5) alone or coadministered with aprepitant (125 mg x 1) in each treatment period (with a ae14-day washout); serial blood samples were analyzed. Safety was evaluated. Following coadministration of aprepitant with bosutinib, the area under the concentration-time curve from time zero extrapolated to infinity (AUC(inf)) and maximum plasma concentration (C (max)) were higher than in bosutinib alone (AUC(inf), 4719 and 2268 ngaEuro cent h/mL; C (max), 146.0 and 94.94 ng/mL). For bosutinib with aprepitant versus bosutinib alone, mean terminal elimination half-life was similar (25.99 vs 27.79 h), time to C (max) was longer (6.02 vs 4.15 h), and apparent oral clearance (CL/F) was decreased (105.9 vs 220.4 L/h). The ratio of adjusted geometric means of AUC(inf) and C (max) for bosutinib with aprepitant relative to bosutinib alone were 199 % (90 % confidence interval, 167-237 %) and 153 % (127-184 %), respectively. Both treatments were well tolerated. In healthy volunteers, administering a single dose of aprepitant increased the AUC and C (max) following a single dose of bosutinib by 99 and 53 %, respectively. These results are consistent with a moderate CYP3A4 inhibitor effect of aprepitant on bosutinib (Trial Registration: ClinicalTrials.gov NCT02058277).