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

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 (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. This trial was registered at http://www.clinicaltrials.gov as NCT00124748.