Abstract
Purpose
Bosutinib, a dual Src/Abl kinase inhibitor in development for treatment of chronic myeloid leukemia, is primarily metabolized by the CYP3A4 hepatic enzyme. This study evaluated the pharmacokinetics and safety of bosutinib in patients with chronic hepatic impairment and matched healthy subjects.
Methods
Hepatically impaired patients were aged 18–65 years and of Child-Pugh classes A, B, or C; healthy subjects were matched by age, sex, body mass index, and smoking habits. A single oral dose of bosutinib 200 mg was administered on day 1 within 5 min after completion of breakfast.
Results
Compared with healthy subjects (n = 9), maximal plasma concentration (C max) and area under the curve increased 2.42-fold and 2.25-fold in Child-Pugh A (n = 6), 1.99-fold and 2.0-fold in Child-Pugh B (n = 6), and 1.52-fold and 1.91-fold in Child-Pugh C patients (n = 6). Time to C max decreased from 4 h in healthy subjects to 2.5, 2.0, and 1.5 h in Child-Pugh A, B, and C patients, respectively; the elimination half-life increased from 55 h in healthy subjects to 86, 113, and 111 h in Child-Pugh A, B, and C patients. Bosutinib oral clearance was lower in hepatically impaired patients compared with healthy subjects. Frequently reported adverse events included prolonged QTc interval (37.0 %, n = 10), nausea (11.1 %, n = 3), and vomiting (7.4 %, n = 2).
Conclusions
A single oral dose of bosutinib 200 mg showed acceptable tolerability in healthy subjects and in patients with mild, moderate, or severe chronic hepatic impairment.
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Acknowledgments
We thank the study participants as well as the research personnel at the study site. This study was sponsored by Wyeth Research, which was acquired by Pfizer Inc in October 2009. Richat Abbas is an employee of Pfizer, and Stephan Chalon, Cathie Leister, Myriam El Gaaloul, and Daryl Sonnichsen are former employees of Pfizer; through employment of the authors, the sponsor was involved in all aspects of study design and conduct as well as manuscript preparation. Stephan Chalon, Cathie Leister, and Daryl Sonnichsen additionally own/owned stock in Pfizer. Medical writing support was provided by Kimberly Brooks, PhD, of SciFluent, and was funded by Pfizer.
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Abbas, R., Chalon, S., Leister, C. et al. Evaluation of the pharmacokinetics and safety of bosutinib in patients with chronic hepatic impairment and matched healthy subjects. Cancer Chemother Pharmacol 71, 123–132 (2013). https://doi.org/10.1007/s00280-012-1987-7
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DOI: https://doi.org/10.1007/s00280-012-1987-7