TY - JOUR
T1 - Plasma exposure of imatinib and its correlation with clinical response in the Tyrosine Kinase Inhibitor OPtimization and Selectivity trial
AU - Guilhot, François
AU - Hughes, Timothy P.
AU - Cortes, Jorge
AU - Druker, Brian J.
AU - Baccarani, Michele
AU - Gathmann, Insa
AU - Hayes, Michael
AU - Granvil, Camille
AU - Wang, Yanfeng
PY - 2012/5/1
Y1 - 2012/5/1
N2 - 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.
AB - 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.
KW - Chronic myeloid leukemia
KW - Imatinib
KW - Pharmacokinetics
KW - Tyrosine kinase inhibitor
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U2 - 10.3324/haematol.2011.045666
DO - 10.3324/haematol.2011.045666
M3 - Article
C2 - 22315495
AN - SCOPUS:84860549849
SN - 0390-6078
VL - 97
SP - 731
EP - 738
JO - Haematologica
JF - Haematologica
IS - 5
ER -