PMID- 21691746
OWN - NLM
STAT- MEDLINE
DCOM- 20120217
LR  - 20220409
IS  - 1432-0843 (Electronic)
IS  - 0344-5704 (Linking)
VI  - 69
IP  - 1
DP  - 2012 Jan
TI  - A phase I ascending single-dose study of the safety, tolerability, and 
      pharmacokinetics of bosutinib (SKI-606) in healthy adult subjects.
PG  - 221-7
LID - 10.1007/s00280-011-1688-7 [doi]
AB  - PURPOSE: 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.
FAU - Abbas, Richat
AU  - Abbas R
AD  - Department of Clinical Pharmacology, Pfizer Inc, 500 Arcola Road, Collegeville, 
      PA 19426, USA. richat.abbas-borhan@pfizer.com
FAU - Hug, Bruce A
AU  - Hug BA
FAU - Leister, Cathie
AU  - Leister C
FAU - Gaaloul, Myriam El
AU  - Gaaloul ME
FAU - Chalon, Stephan
AU  - Chalon S
FAU - Sonnichsen, Daryl
AU  - Sonnichsen D
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20110621
PL  - Germany
TA  - Cancer Chemother Pharmacol
JT  - Cancer chemotherapy and pharmacology
JID - 7806519
RN  - 0 (Aniline Compounds)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Nitriles)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Quinolines)
RN  - 5018V4AEZ0 (bosutinib)
RN  - EC 2.7.10.2 (Proto-Oncogene Proteins c-abl)
RN  - EC 2.7.10.2 (src-Family Kinases)
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Aniline Compounds/*administration & dosage/adverse effects/pharmacokinetics
MH  - Antineoplastic Agents/*administration & dosage/adverse effects/pharmacokinetics
MH  - Area Under Curve
MH  - Chromatography, Liquid
MH  - Dose-Response Relationship, Drug
MH  - Double-Blind Method
MH  - Female
MH  - Food-Drug Interactions
MH  - Half-Life
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Nitriles/*administration & dosage/adverse effects/pharmacokinetics
MH  - Protein Kinase Inhibitors/*administration & dosage/adverse 
      effects/pharmacokinetics
MH  - Proto-Oncogene Proteins c-abl/antagonists & inhibitors
MH  - Quinolines/*administration & dosage/adverse effects/pharmacokinetics
MH  - Tandem Mass Spectrometry
MH  - Tissue Distribution
MH  - Young Adult
MH  - src-Family Kinases/antagonists & inhibitors
EDAT- 2011/06/22 06:00
MHDA- 2012/02/18 06:00
CRDT- 2011/06/22 06:00
PHST- 2010/12/23 00:00 [received]
PHST- 2011/06/01 00:00 [accepted]
PHST- 2011/06/22 06:00 [entrez]
PHST- 2011/06/22 06:00 [pubmed]
PHST- 2012/02/18 06:00 [medline]
AID - 10.1007/s00280-011-1688-7 [doi]
PST - ppublish
SO  - Cancer Chemother Pharmacol. 2012 Jan;69(1):221-7. doi: 10.1007/s00280-011-1688-7. 
      Epub 2011 Jun 21.