Klin Padiatr 2013; 225 - A7
DOI: 10.1055/s-0033-1343624

Long-term administration of the tyrosine kinase inhibitor bosutinib via micro-osmotic pumps and resulting skeletal side effects in juvenile rats

JT Tauer 1, R Jung 2, M Suttorp 1
  • 1Dept of Pediatrics, University Hospital, TU Dresden
  • 2Experimental Centre of the Medical Faculty, TU Dresden, Germany

Background: In Ph+ chronic myeloid leukemia the up-regulated BCR-ABL1 tyrosine kinase (TK) is the major target of TK-inhibitors (TKI) like imatinib and dasatinib. Bosutinib is a third generation dual TKI – developed to overcome resistance to first and second generation TKIs – inhibiting Abl and also Src kinases. However, first and second generation TKIs show off-target effects on bone metabolism. Skeletal side effects of bosutinib have not been yet investigated. Therefore, we examined the influence of a continuous exposure of bosutinib on the growing skeleton in juvenile rodents.

Methods: At an age of four weeks male Wistar rats were chronically exposed over a period of four weeks continuously to bosutinib (50µM, 100µM) via subcutaneously implanted Alzet® micro-osmotic pumps. After necropsy bone related parameters were analyzed.

Results: Continuous administration of bosutinib by micro-osmotic pumps was well tolerated and resulted in serum drug levels in the lower therapeutical range. However, contrasting our experience with imatinib and dasatinib, bosutinib exhibited only minor side effects (e.g. a non-significant trend to reduced bone length) on the growing skeleton.

Conclusion: Micro-osmotic pumps represent a suitable system for a continuous exposure of TKI in juvenile growing rats. In comparison to first and second generation TKI bosutinib seems to induce minor side effects on the growing bone.