Abstract
Purpose
Bosutinib (SKI-606), a dual Src/Abl tyrosine kinase inhibitor, is in clinical development for the treatment of patients with chronic myelogenous leukemia (CML). To support clinical development, we conducted a dose-escalation and food-effect evaluation of safety, tolerability, and pharmacokinetics (PK) of bosutinib in healthy adults.
Methods
This was a randomized, double-blind, placebo-controlled, single-ascending dose, sequential-group study of oral bosutinib. Subjects randomly received bosutinib 200, 400, 600, and 800 mg with food; 200 and 400 mg without food; or placebo. Plasma concentrations were determined by a liquid chromatography-tandem mass spectrometry assay. Non-compartmental PK analyses were performed, and power models assessed dose linearity.
Results
Of 55 enrolled subjects, 33 (81%) subjects had adverse events (AEs) after receiving bosutinib. Common AEs included diarrhea (39%), nausea (29%), and headache (22%). Bosutinib 200–600 mg with food was safe and well tolerated. Bosutinib exposures (C max and AUC) were linear and dose proportional from 200 to 800 mg with food. Absorption was relatively slow; median time to C max was 6 h. Apparent volume of distribution (V z/F) was 131–214 L/kg, mean apparent clearance (CL/F) was 2.25–3.81 L/h/kg, and mean terminal elimination half-life (t 1/2) was 32–39 h. Preliminary food effect assessment showed that exposure to bosutinib increased by ~2.52-fold (P = 0.002) for C max and ~2.28-fold (P = 0.002) for AUC when 200 mg bosutinib was administered with food compared with administration under fasting conditions; administration of 400 mg bosutinib with food increased AUC by ~1.5-fold (P = 0.037). Approximately 1% of administered dose was excreted in urine.
Conclusions
Bosutinib 200–600 mg with food was safe and well tolerated. Under fed conditions, bosutinib exposures were linear and dose proportional, and C max increased by ~1.5-fold. The t 1/2 supported a once-daily dosing regimen.
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Acknowledgments
This study was sponsored by Wyeth Research, which was acquired by Pfizer in October 2009. We thank all the subjects who participated in this study, as well as the study staff of the Kendle Phase 1 Unit, Utrecht, The Netherlands. Editorial/medical writing support was provided by Joseph Ramcharan, PhD, at On Assignment Clinical Research, and Kimberly Brooks, PhD, at MedErgy, and was funded by Pfizer.
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Abbas, R., Hug, B.A., Leister, C. et al. A phase I ascending single-dose study of the safety, tolerability, and pharmacokinetics of bosutinib (SKI-606) in healthy adult subjects. Cancer Chemother Pharmacol 69, 221–227 (2012). https://doi.org/10.1007/s00280-011-1688-7
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DOI: https://doi.org/10.1007/s00280-011-1688-7