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

• Published in: European journal of clinical pharmacology 2017, Vol.73 (1), p.49-56
• Main Authors: Hsyu, Poe-Hirr, Pignataro, Daniela Soriano, Matschke, Kyle
• Format: Article
• Language: English
• Subjects: Administration, Oral; Adult; Aniline Compounds - blood; Aniline Compounds - pharmacokinetics; Antiemetics - pharmacology; Antineoplastic Agents - blood; Antineoplastic Agents - pharmacokinetics; Area Under Curve; Biomedical and Life Sciences; Biomedicine; Cross-Over Studies; Cytochrome P-450 CYP3A Inhibitors - pharmacology; Drug Interactions; Female; Healthy Volunteers; Humans; Kinases; Kinetics; Male; Middle Aged; Morpholines - pharmacology; Nitriles - blood; Nitriles - pharmacokinetics; Pharmacokinetics and Disposition; Pharmacology; Pharmacology/Toxicology; Protein Kinase Inhibitors - blood; Protein Kinase Inhibitors - pharmacokinetics; Quinolines - blood; Quinolines - pharmacokinetics; Young Adult
• ISSN: 0031-6970; 1432-1041
• DOI: 10.1007/s00228-016-2108-z

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).