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Randomized Controlled Trial
. 2012 May;97(5):731-8.
doi: 10.3324/haematol.2011.045666. Epub 2012 Feb 7.

Plasma Exposure of Imatinib and Its Correlation With Clinical Response in the Tyrosine Kinase Inhibitor Optimization and Selectivity Trial

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Free PMC article
Randomized Controlled Trial

Plasma Exposure of Imatinib and Its Correlation With Clinical Response in the Tyrosine Kinase Inhibitor Optimization and Selectivity Trial

François Guilhot et al. Haematologica. .
Free PMC article

Abstract

Background: 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.

Design and methods: 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.

Results: 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 http://www.clinicaltrials.gov as NCT00124748.

Figures

Figure 1.
Figure 1.
Imatinib Cmin over time for the 400 mg/day and 800 mg/day protocol dose groups. Box plots show the median, 25th percentile, 75th percentile, and joined mean values. The whiskers extend up to 1.5 times the interquartile range from the boxes. #: values which exceed 1.5 times the interquartile range; Δ: values > 7500 ng/mL.
Figure 2.
Figure 2.
Cmin (mean ± SD)-dose relationship for imatinib (upper panel) and its metabolite CGP74588 (lower panel) over the actual imatinib dose administered in the first 12-month period (pooled analysis of patients from both arms). Dashed line represents the linear regression line forced to the origin to test the dose-to-Cmin proportionality.
Figure 3.
Figure 3.
Time to MMR by imatinib Cmin at Day 29 (pooled analysis of patients from both arms; Kaplan-Meier analyses). Patients without MMR were censored at last assessment on study treatment. MMR: major molecular response.

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