PMID- 21148045
OWN - NLM
STAT- MEDLINE
DCOM- 20120325
LR  - 20181211
IS  - 1552-4604 (Electronic)
IS  - 0091-2700 (Linking)
VI  - 51
IP  - 12
DP  - 2011 Dec
TI  - Effect of ketoconazole on the pharmacokinetics of oral bosutinib in healthy 
      subjects.
PG  - 1721-7
LID - 10.1177/0091270010387427 [doi]
AB  - Bosutinib (SKI-606), a dual inhibitor of Src and Abl tyrosine kinases, is being 
      developed for the treatment of chronic myelogenous leukemia. The effect of 
      coadministration of ketoconazole on the pharmacokinetic (PK) profile of bosutinib 
      was evaluated in an open-label, randomized, 2-period, crossover study. Healthy 
      subjects (fasting) received a single dose of oral bosutinib 100 mg alone and with 
      multiple once-daily doses of oral ketoconazole 400 mg. PK sampling occurred 
      through 96 hours. The least square geometric mean treatment ratios (90% 
      confidence interval [CI]) of C(max(bosutinib+ketoconazole))/C(max(bosutinib 
      alone)), AUC(T(bosutinib+ketoconazole))/AUC(T(bosutinib alone)), and 
      AUC((bosutinib+ketoconazole))/AUC((bosutinib alone)) were assessed. Compared with 
      bosutinib administered alone, coadministration with ketoconazole increased 
      bosutinib C(max) 5.2-fold, AUC(T) 7.6-fold, and AUC 8.6-fold. Ketoconazole 
      coadministration decreased the mean apparent clearance of bosutinib approximately 
      9-fold and increased the mean (SD) terminal half-life from 46.2 (16.4) hours to 
      69.0 (29.1) hours. The incidence of adverse events (AEs) was comparable between 
      the 2 treatments. The most common AEs were headache, nausea, and increased blood 
      creatinine. No safety-related discontinuations or serious AEs occurred. These PK 
      results indicate that bosutinib is susceptible to interaction with potent CYP3A4 
      inhibitors.
FAU - Abbas, Richat
AU  - Abbas R
AD  - Pfizer Inc, Collegeville, PA 19426, USA. Richat.Abbas-Borhan@pfizer.com
FAU - Hug, Bruce A
AU  - Hug BA
FAU - Leister, Cathie
AU  - Leister C
FAU - Burns, Jaime
AU  - Burns J
FAU - Sonnichsen, Daryl
AU  - Sonnichsen D
LA  - eng
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20101208
PL  - England
TA  - J Clin Pharmacol
JT  - Journal of clinical pharmacology
JID - 0366372
RN  - 0 (Aniline Compounds)
RN  - 0 (Antifungal Agents)
RN  - 0 (Cytochrome P-450 CYP3A Inhibitors)
RN  - 0 (Nitriles)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Quinolines)
RN  - 5018V4AEZ0 (bosutinib)
RN  - EC 1.14.14.1 (Cytochrome P-450 CYP3A)
RN  - EC 1.14.14.55 (CYP3A4 protein, human)
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
RN  - R9400W927I (Ketoconazole)
SB  - IM
MH  - Administration, Oral
MH  - Adult
MH  - Aniline Compounds/administration & dosage/adverse effects/*pharmacokinetics
MH  - Antifungal Agents/pharmacology
MH  - Area Under Curve
MH  - Cross-Over Studies
MH  - Cytochrome P-450 CYP3A
MH  - *Cytochrome P-450 CYP3A Inhibitors
MH  - Drug Interactions
MH  - Humans
MH  - Ketoconazole/*pharmacology
MH  - Male
MH  - Middle Aged
MH  - Nitriles/administration & dosage/adverse effects/*pharmacokinetics
MH  - Protein Kinase Inhibitors/administration & dosage/adverse 
      effects/*pharmacokinetics
MH  - Protein-Tyrosine Kinases/*antagonists & inhibitors
MH  - Quinolines/administration & dosage/adverse effects/*pharmacokinetics
MH  - Young Adult
EDAT- 2010/12/15 06:00
MHDA- 2012/03/27 06:00
CRDT- 2010/12/15 06:00
PHST- 2010/12/15 06:00 [entrez]
PHST- 2010/12/15 06:00 [pubmed]
PHST- 2012/03/27 06:00 [medline]
AID - 0091270010387427 [pii]
AID - 10.1177/0091270010387427 [doi]
PST - ppublish
SO  - J Clin Pharmacol. 2011 Dec;51(12):1721-7. doi: 10.1177/0091270010387427. Epub 
      2010 Dec 8.