| Pharmacokinetic-pharmacodynamic relationship of bosutinib in patients with chronic phase chronic myeloid leukemia. | |
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MedLine Citation:
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PMID: 23070145 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Poe-Hirr Hsyu; Diane R Mould; Richard N Upton; Michael Amantea |
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Publication Detail:
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Type: Journal Article; Meta-Analysis; Research Support, Non-U.S. Gov't Date: 2012-10-16 |
Journal Detail:
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Title: Cancer chemotherapy and pharmacology Volume: 71 ISSN: 1432-0843 ISO Abbreviation: Cancer Chemother. Pharmacol. Publication Date: 2013 Jan |
Date Detail:
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Created Date: 2013-01-03 Completed Date: 2013-02-26 Revised Date: 2013-05-02 |
Medline Journal Info:
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Nlm Unique ID: 7806519 Medline TA: Cancer Chemother Pharmacol Country: Germany |
Other Details:
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Languages: eng Pagination: 209-18 Citation Subset: IM |
Affiliation:
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Pfizer Inc, La Jolla, CA, USA. Poe-Hirr.Hsyu@pfizer.com |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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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:
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0/Aniline Compounds; 0/Antineoplastic Agents; 0/Nitriles; 0/Protein Kinase Inhibitors; 0/Quinolines; 380443-75-4/bosutinib |
| Comments/Corrections | |
Erratum In:
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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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