title: Effect of aprepitant, a moderate CYP3A4 inhibitor, on bosutinib exposure in healthy subjects.
abstract: OBJECTIVE
  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 (AUCinf) and maximum plasma concentration (Cmax) were higher than in bosutinib alone (AUCinf, 4719 and 2268 ng•h/mL; Cmax, 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 Cmaxwas 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 AUCinfand Cmaxfor bosutinib with aprepitant relative to bosutinib alone were 199 % (90 % confidence interval, 167-237 %) and 153 % (127-184 %), respectively. Both treatments were well tolerated.
  
  
  CONCLUSIONS
  In healthy volunteers, administering a single dose of aprepitant increased the AUC and Cmaxfollowing 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).
authors.affiliation: Pfizer Inc, 10646 Science Center Drive, La Jolla, CA, 92121, USA. Poe-Hirr.Hysu@pfizer.com.
authors.forename: Poe-Hirr
authors.initials: PH
authors.lastname: Hsyu
authors.affiliation: Pfizer Inc, Walton Oaks, Dorking Road, Tadworth, Surrey, KT20 7NS, UK.
authors.forename: Daniela Soriano
authors.initials: DS
authors.lastname: Pignataro
authors.affiliation: Pfizer Inc, 500 Arcola Road, Collegeville, PA, 19426, USA.
authors.forename: Kyle
authors.initials: K
authors.lastname: Matschke
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000814:Aniline Compounds / Q000097:blood / Q000493:pharmacokinetics*; D000932:Antiemetics / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics*; D000077608:Aprepitant; D019540:Area Under Curve; D018592:Cross-Over Studies; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000494:pharmacology*; D004347:Drug Interactions; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D009025:Morpholines / Q000494:pharmacology*; D009570:Nitriles / Q000097:blood / Q000493:pharmacokinetics*; D047428:Protein Kinase Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D011804:Quinolines / Q000097:blood / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D000814:Aniline Compounds; D000932:Antiemetics; D000970:Antineoplastic Agents; D065692:Cytochrome P-450 CYP3A Inhibitors; D009025:Morpholines; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011804:Quinolines; D000077608:Aprepitant; C471992:bosutinib
keywords: Aprepitant; Bosutinib; Cytochrome P450 3A4; Drug-drug interactions; Pharmacokinetics; Tyrosine kinase inhibitor