title: Micro-osmotic pumps for continuous release of the tyrosine kinase inhibitor bosutinib in juvenile rats and its impact on bone growth.
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.
  
  
  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.
authors.affiliation: Division of Pediatric Hematology and Oncology, Department of Pediatrics, University Hospital "Carl Gustav Carus", Technical University, Dresden, Germany.
authors.forename: Josephine Tabea
authors.initials: JT
authors.lastname: Tauer
authors.forename: Lorenz C
authors.initials: LC
authors.lastname: Hofbauer
authors.forename: Rolang
authors.initials: R
authors.lastname: Jung
authors.forename: Reinhold G
authors.initials: RG
authors.lastname: Erben
authors.forename: Meinolf
authors.initials: M
authors.lastname: Suttorp
mesh_terms: D000375:Aging; D000814:Aniline Compounds / Q000008:administration & dosage* / Q000097:blood / Q000494:pharmacology*; D000818:Animals; D001846:Bone Development / Q000187:drug effects*; D016503:Drug Delivery Systems / Q000295:instrumentation*; D005269:Femur / Q000033:anatomy & histology / Q000187:drug effects; D015918:Infusion Pumps, Implantable; D008297:Male; D009570:Nitriles / Q000008:administration & dosage* / Q000097:blood / Q000494:pharmacology*; D009995:Osmosis / Q000187:drug effects*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D011804:Quinolines / Q000008:administration & dosage* / Q000097:blood / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013977:Tibia / Q000033:anatomy & histology / Q000187:drug effects; D015430:Weight Gain / Q000187:drug effects
chemical_list: D000814:Aniline Compounds; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011804:Quinolines; C471992:bosutinib