title: A phase I ascending single-dose study of the safety, tolerability, and pharmacokinetics of bosutinib (SKI-606) in healthy adult subjects.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Clinical Pharmacology, Pfizer Inc, 500 Arcola Road, Collegeville, PA 19426, USA. richat.abbas-borhan@pfizer.com
authors.forename: Richat
authors.initials: R
authors.lastname: Abbas
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Hug
authors.forename: Cathie
authors.initials: C
authors.lastname: Leister
authors.forename: Myriam El
authors.initials: ME
authors.lastname: Gaaloul
authors.forename: Stephan
authors.initials: S
authors.lastname: Chalon
authors.forename: Daryl
authors.initials: D
authors.lastname: Sonnichsen
mesh_terms: D000293:Adolescent; D000328:Adult; D000814:Aniline Compounds / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D019540:Area Under Curve; D002853:Chromatography, Liquid; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D018565:Food-Drug Interactions; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D009570:Nitriles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors; D011804:Quinolines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D053719:Tandem Mass Spectrometry; D014018:Tissue Distribution; D055815:Young Adult; D019061:src-Family Kinases / Q000037:antagonists & inhibitors
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011804:Quinolines; C471992:bosutinib; D016315:Proto-Oncogene Proteins c-abl; D019061:src-Family Kinases