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Type: Journal article
Title: Plasma exposure of imatinib and its correlation with clinical response in the Tyrosine Kinase Inhibitor Optimization and Selectivity Trial
Author: Guilhot, F.
Hughes, T.
Cortes, J.
Druker, B.
Baccarani, M.
Gathmann, I.
Hayes, M.
Granvil, C.
Wang, Y.
Citation: Haematologica, 2012; 2012(5):731-738
Publisher: Ferrata Storti Foundation
Issue Date: 2012
ISSN: 0390-6078
Statement of
François Guilhot, Timothy P. Hughes, Jorge Cortes, Brian J. Druker, Michele Baccarani, Insa Gathmann, Michael Hayes, Camille Granvil and Yanfeng Wang
Abstract: <h4>Background</h4>This study evaluates the correlation between imatinib trough plasma concentrations (C(min)) and clinical response and safety in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase in the Tyrosine Kinase Inhibitor OPtimization and Selectivity (TOPS) trial.<h4>Design and methods</h4>Patients were randomized 1:2 to 400 mg/day or 800 mg/day imatinib. Imatinib C(min) levels were collected at pre-dose before treatment, and at the end of months 1 (day 29), 6, 9, and 12.<h4>Results</h4>Imatinib C(min) were stable over time in the 400 mg/day dose arm, but showed a slight decrease in the 800 mg/day arm due to dose adjustments between months 1-6. The overall median imatinib C(min) levels were 1040, 1200, 1935, and 2690 ng/mL for the actual 300, 400, 600, and 800 mg/day doses, respectively. The rates of major molecular response (MMR) at 3, 6, 9, and 12 months, and complete cytogenetic response (CCyR) at 6 and 12 months were significantly lower among patients with the lowest imatinib C(min) levels at Day 29 (<1165 ng/mL, 25th percentile). There was an apparent association between high imatinib C(min) and the occurrence of grade 3/4 neutropenia and all-grade rash, diarrhea, arthralgia/myalgia, and all-cause edema. Conclusions Imatinib C(min) levels were relatively stable over time and proportional to the dose administered. Patients with an imatinib C(min) above 1165 ng/mL on Day 29 achieved MMR faster and had higher MMR and CCyR rates at 12 months. There appeared to be an association between imatinib C(min) and the frequency of some adverse events. This trial was registered at as NCT00124748.
Keywords: imatinib; pharmacokinetics; tyrosine kinase inhibitor; chronic myeloid leukemia.
Rights: Copyright © Ferrata Storti Foundation
RMID: 0020124150
DOI: 10.3324/haematol.2011.045666
Appears in Collections:Medicine publications

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