@article{François Guilhot_Timothy P. Hughes_Jorge Cortes_Brian J. Druker_Michele Baccarani_Insa Gathmann_Michael Hayes_Camille Granvil_Yanfeng Wang_2012, place={Pavia, Italy}, title={Plasma exposure of imatinib and its correlation with clinical response in the Tyrosine Kinase Inhibitor Optimization and Selectivity Trial}, volume={97}, url={https://haematologica.org/article/view/6299}, DOI={10.3324/haematol.2011.045666}, abstractNote={<strong>Background</strong> This study evaluates the correlation between imatinib trough plasma concentrations (C<sub>min</sub>) 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.<strong>Design and Methods</strong> Patients were randomized 1:2 to 400 mg/day or 800 mg/day imatinib. Imatinib C<sub>min</sub> levels were collected at pre-dose before treatment, and at the end of months 1 (day 29), 6, 9, and 12.<strong>Results</strong> Imatinib C<sub>min</sub> 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<sub>min</sub> 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<sub>min</sub> levels at Day 29 (<1165 ng/mL, 25<sup>th</sup> percentile). There was an apparent association between high imatinib C<sub>min</sub> and the occurrence of grade 3/4 neutropenia and all-grade rash, diarrhea, arthralgia/myalgia, and all-cause edema.<strong>Conclusions</strong> Imatinib C<sub>min</sub> levels were relatively stable over time and proportional to the dose administered. Patients with an imatinib C<sub>min</sub> 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<sub>min</sub> and the frequency of some adverse events. <em>This trial was registered at <a href="http://www.clinicaltrials.gov">http://www.clinicaltrials.gov</a> as <a class="external-ref external-ref-type-clintrialgov" href="/lookup/external-ref?link_type=CLINTRIALGOV&amp;access_num=NCT00124748&amp;atom=%2Fhaematol%2F97%2F5%2F731.atom">NCT00124748</a>.</em&gt;}, number={5}, journal={Haematologica}, author={François Guilhot and Timothy P. Hughes and Jorge Cortes and Brian J. Druker and Michele Baccarani and Insa Gathmann and Michael Hayes and Camille Granvil and Yanfeng Wang}, year={2012}, month={May}, pages={731-738} }