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

Abstract

Purpose

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.

Methods

Nineteen healthy, fed adults received bosutinib (100 mg × 5) alone or coadministered with aprepitant (125 mg × 1) in each treatment period (with a ≥14-day washout); serial blood samples were analyzed. Safety was evaluated.

Results

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 ng•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.

Conclusion

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).

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