Effect of aprepitant, a moderate CYP3A4 inhibitor, on bosutinib exposure in healthy subjects
| Autor: | Poe-Hirr Hsyu, Kyle Matschke, Daniela Soriano Pignataro |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
Adult
Male medicine.drug_class Morpholines Administration Oral Antineoplastic Agents Pharmacology 030226 pharmacology & pharmacy Tyrosine-kinase inhibitor 03 medical and health sciences Young Adult 0302 clinical medicine Pharmacokinetics Nitriles Medicine Humans Pharmacology (medical) Drug Interactions Protein Kinase Inhibitors Aprepitant Aniline Compounds Cross-Over Studies CYP3A4 business.industry General Medicine Drug interaction Middle Aged Crossover study Confidence interval Healthy Volunteers 030220 oncology & carcinogenesis Area Under Curve Quinolines Antiemetics Cytochrome P-450 CYP3A Inhibitors Female business Bosutinib medicine.drug |
| Zdroj: | European journal of clinical pharmacology. 73(1) |
| ISSN: | 1432-1041 |
| Popis: | 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 × 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. Following coadministration of aprepitant with bosutinib, the area under the concentration-time curve from time zero extrapolated to infinity (AUCinf) and maximum plasma concentration (C max) were higher than in bosutinib alone (AUCinf, 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 AUCinf 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). |
| Databáze: | OpenAIRE |
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