Plasma exposure of imatinib and its correlation with clinical response in the Tyrosine Kinase Inhibitor OPtimization and Selectivity trial

François Guilhot, Timothy P. Hughes, Jorge Cortes, Brian J. Druker, Michele Baccarani, Insa Gathmann, Michael Hayes, Camille Granvil, Yanfeng Wang

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66 Citations (Scopus)


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, 25 th 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.

Original languageEnglish
Pages (from-to)731-738
Number of pages8
Issue number5
Publication statusPublished or Issued - 1 May 2012


  • Chronic myeloid leukemia
  • Imatinib
  • Pharmacokinetics
  • Tyrosine kinase inhibitor

ASJC Scopus subject areas

  • Hematology

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