Abstract

BACKGROUND: Bosutinib is a third-generation dual tyrosine kinase inhibitor (TKI) inhibiting Abl and Src kinases. It was developed to act on up-regulated tyrosine kinases (TKs) like BCR-ABL in Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML) when resistance to first- and second-generation TKIs developed. However, first- and second-generation TKIs show off-target effects on bone metabolism, whereas studies on skeletal adverse effects of bosutinib are still lacking. Therefore, it was the aim of this study to continuously expose juvenile rats to bosutinib and to analyze its influence on the growing bone.

MATERIAL AND METHODS: Starting after weaning, 4-week-old Wistar rats were chronically exposed over a 28-day period to varying concentrations of bosutinib, which were continuously administered subcutaneously via implanted Alzet® micro-osmotic pumps. After necropsy, the length of the femora and tibiae were analyzed.

RESULTS: Continuous administration of bosutinib by micro-osmotic pumps led to serum drug levels in the lower therapeutic range, was well tolerated, and exhibited only minor adverse effects on the growing skeleton.

CONCLUSIONS: Micro-osmotic pumps represent a convenient system for continuous TKI release in young growing rats. Compared to first- and second-generation TKIs, bosutinib seems to exert fewer adverse effects on the growing bone.

Keywords: Aniline Compounds - pharmacology, Aging, Bone Development - drug effects, Drug Delivery Systems - instrumentation, Femur - drug effects, Infusion Pumps, Implantable, Nitriles - pharmacology, Osmosis - drug effects, Protein Kinase Inhibitors - pharmacology, Quinolines - pharmacology, Rats, Wistar, Tibia - drug effects, Weight Gain - drug effects