Document Detail


Pharmacokinetic-pharmacodynamic relationship of bosutinib in patients with chronic phase chronic myeloid leukemia.
MedLine Citation:
PMID:  23070145     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
PURPOSE: Bosutinib is an orally active, dual Src/Abl tyrosine kinase inhibitor that has demonstrated manageable safety and high response rates in patients with chronic phase (CP) chronic myeloid leukemia (CML). The current analysis evaluated potential bosutinib pharmacokinetic-pharmacodynamic relationships.
METHODS: Bosutinib exposure metrics at steady state were estimated from a previously developed population pharmacokinetic model. Safety and efficacy metrics were from two clinical studies of bosutinib 500 mg/day in patients with CP CML.
RESULTS: The analysis included 749 patients (aged 18-91 years; mean weight, 75 kg; 54% male). An exposure-response relationship was identified for the pooled incidence (but not severity) of diarrhea, with predicted probability ranging from 0.575 to 0.797 for the lowest and highest area under the curve bins, respectively; a weak relationship was also observed for the incidence of rash (predicted probability, 0.216-0.419). There was no evidence of an exposure-response relationship for nausea, vomiting, neutropenia, thrombocytopenia, or elevated alanine and aspartate aminotransferases. Exposure-response relationships were observed in patients with newly diagnosed CP CML for complete cytogenetic response at 1 year (predicted probability, 0.476-0.650), major molecular response at 1 year (0.238-0.497), and cumulative complete hematologic response (CHR) at 1 year (0.605-0.763). Patients with previously treated CP CML showed no exposure-response relationship for major cytogenetic response at 24 weeks (0.320); for CHR, higher bosutinib exposure was associated with a lower probability of response (0.926-0.743).
CONCLUSIONS: The absence of exposure-response relationships for some safety and efficacy metrics may reflect bosutinib exposure metrics that exceeded the half-maximal inhibitory values and achieved a maximum effect.
Authors:
Poe-Hirr Hsyu; Diane R Mould; Richard N Upton; Michael Amantea
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Publication Detail:
Type:  Journal Article; Meta-Analysis; Research Support, Non-U.S. Gov't     Date:  2012-10-16
Journal Detail:
Title:  Cancer chemotherapy and pharmacology     Volume:  71     ISSN:  1432-0843     ISO Abbreviation:  Cancer Chemother. Pharmacol.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-01-03     Completed Date:  2013-02-26     Revised Date:  2013-05-02    
Medline Journal Info:
Nlm Unique ID:  7806519     Medline TA:  Cancer Chemother Pharmacol     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  209-18     Citation Subset:  IM    
Affiliation:
Pfizer Inc, La Jolla, CA, USA. Poe-Hirr.Hsyu@pfizer.com
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MeSH Terms
Descriptor/Qualifier:
Administration, Oral
Adolescent
Adult
Aged
Aged, 80 and over
Aniline Compounds / administration & dosage*,  pharmacokinetics,  pharmacology
Antineoplastic Agents / administration & dosage*,  pharmacokinetics,  pharmacology
Area Under Curve
Clinical Trials, Phase I as Topic
Clinical Trials, Phase II as Topic
Clinical Trials, Phase III as Topic
Female
Follow-Up Studies
Humans
Leukemia, Myeloid, Chronic-Phase / drug therapy*,  pathology
Male
Middle Aged
Models, Biological*
Nitriles / administration & dosage*,  pharmacokinetics,  pharmacology
Protein Kinase Inhibitors / administration & dosage,  pharmacokinetics,  pharmacology
Quinolines / administration & dosage*,  pharmacokinetics,  pharmacology
Randomized Controlled Trials as Topic
Treatment Outcome
Young Adult
Chemical
Reg. No./Substance:
0/Aniline Compounds; 0/Antineoplastic Agents; 0/Nitriles; 0/Protein Kinase Inhibitors; 0/Quinolines; 380443-75-4/bosutinib
Comments/Corrections
Erratum In:
Cancer Chemother Pharmacol. 2013 Apr;71(4):1105-6

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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