title: A neuropharmacokinetic assessment of bafetinib, a second generation dual BCR-Abl/Lyn tyrosine kinase inhibitor, in patients with recurrent high-grade gliomas.
abstract: OBJECTIVE
  The primary objective of this study was to use intracerebral microdialysis (ICMD) to determine the neuropharmacokinetics of bafetinib, a dual BCR-Abl/Lyn tyrosine kinase inhibitor that may have activity against gliomas.
  
  
  METHODS
  A microdialysis catheter was placed into either peritumoural or enhancing brain tissue of seven patients at the time of tumour resection or biopsy. Twenty-four hours later, bafetinib was administered, 240 or 360 mg po, repeating the same dose 12 h later. Dialysate samples were continuously collected for 24h, with plasma samples obtained in parallel. One to two weeks after finishing ICMD, patients were allowed to resume taking bafetinib continuously while being observed for toxicity and tumour response.
  
  
  RESULTS
  Twenty-six dialysate samples per patient were collected (n=6) and analysed for bafetinib by tandem mass spectrometry. Bafetinib concentrations in the brain were below the lower limit of detection of the assay (0.1 ng/ml) in all samples except one from a single subject that was 0.52 ng/ml. The mean plasma bafetinib maximum concentrations after dose 1 and 2 were 143±99 and 247±73 ng/ml, respectively. Only one patient remained on treatment past two cycles, and no radiographic responses were seen.
  
  
  CONCLUSIONS
  Bafetinib does not sufficiently cross intact or disrupted blood-brain barrier, and therefore, systemic administration of bafetinib is not recommended when investigating this drug as a treatment for brain tumours. ICMD can be a valuable research tool in early drug development. Lead-in ICMD studies can be performed relatively quickly, requiring only a small number of patients, and without significantly disrupting standard cancer care.
authors: Department of Medical Oncology, City of Hope/Beckman Research Institute, Duarte, CA 91010, USA. jportnow@coh.org
authors: Jana
authors: J
authors: Portnow
authors: Behnam
authors: B
authors: Badie
authors: Susan
authors: S
authors: Markel
authors: An
authors: A
authors: Liu
authors: Massimo
authors: M
authors: D'Apuzzo
authors: Paul
authors: P
authors: Frankel
authors: Rahul
authors: R
authors: Jandial
authors: Timothy W
authors: TW
authors: Synold
mesh_terms: D000328:Adult; D000368:Aged; D019540:Area Under Curve; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001932:Brain Neoplasms / Q000188:drug therapy*; D002851:Chromatography, High Pressure Liquid; D015314:Dialysis Solutions / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors; D005910:Glioma / Q000188:drug therapy*; D006801:Humans; D017567:Karnofsky Performance Status; D008297:Male; D013058:Mass Spectrometry; D016920:Meningitis, Bacterial / Q000139:chemically induced; D008657:Metabolic Clearance Rate; D017551:Microdialysis / Q000379:methods; D010865:Pilot Projects; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D016896:Treatment Outcome; D019061:src-Family Kinases / Q000037:antagonists & inhibitors
chemical_list: D015314:Dialysis Solutions; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; C506918:bafetinib
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