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Erschienen in: Cancer Chemotherapy and Pharmacology 1/2013

01.01.2013 | Original Article

Pharmacokinetic–pharmacodynamic relationship of bosutinib in patients with chronic phase chronic myeloid leukemia

verfasst von: Poe-Hirr Hsyu, Diane R. Mould, Richard N. Upton, Michael Amantea

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 1/2013

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Abstract

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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Metadaten
Titel
Pharmacokinetic–pharmacodynamic relationship of bosutinib in patients with chronic phase chronic myeloid leukemia
verfasst von
Poe-Hirr Hsyu
Diane R. Mould
Richard N. Upton
Michael Amantea
Publikationsdatum
01.01.2013
Verlag
Springer-Verlag
Erschienen in
Cancer Chemotherapy and Pharmacology / Ausgabe 1/2013
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI
https://doi.org/10.1007/s00280-012-1998-4

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