title: Imatinib pharmacokinetics and its correlation with response and safety in chronic-phase chronic myeloid leukemia: a subanalysis of the IRIS study.
abstract: Imatinib at 400 mg daily is standard treatment for chronic myeloid leukemia in chronic phase. We here describe the correlation of imatinib trough plasma concentrations (C(mins)) with clinical responses, event-free survival (EFS), and adverse events (AEs). Trough level plasma samples were obtained on day 29 (steady state, n = 351). Plasma concentrations of imatinib and its metabolite CGP74588 were determined by liquid chromatography/mass spectrometry. The overall mean (+/- SD, CV%) steady-state C(min) for imatinib and CGP74588 were 979 ng/mL (+/- 530 ng/mL, 54.1%) and 242 ng/mL (+/- 106 ng/mL, 43.6%), respectively. Cumulative estimated complete cytogenetic response (CCyR) and major molecular response (MMR) rates differed among the quartiles of imatinib trough levels (P = .01 for CCyR, P = .02 for MMR). C(min) of imatinib was significantly higher in patients who achieved CCyR (1009 +/- 544 ng/mL vs 812 +/- 409 ng/mL, P = .01). Patients with high imatinib exposure had better rates of CCyR and MMR and EFS. An exploratory analysis demonstrated that imatinib trough levels were predictive of higher CCyR independently of Sokal risk group. AE rates were similar among the imatinib quartile categories except fluid retention, rash, myalgia, and anemia, which were more common at higher imatinib concentrations. These results suggest that an adequate plasma concentration of imatinib is important for a good clinical response. This study is registered at http://clinicaltrials.gov as NCT00333840.
authors.affiliation: University of Chicago, MC-2115, 5841 S Maryland Ave, Chicago, IL 60637, USA. rlarson@medicine.bsd.uchicago.edu
authors.forename: Richard A
authors.initials: RA
authors.lastname: Larson
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Druker
authors.forename: Francois
authors.initials: F
authors.lastname: Guilhot
authors.forename: Stephen G
authors.initials: SG
authors.lastname: O'Brien
authors.forename: Gilles J
authors.initials: GJ
authors.lastname: Riviere
authors.forename: Tillmann
authors.initials: T
authors.lastname: Krahnke
authors.forename: Insa
authors.initials: I
authors.lastname: Gathmann
authors.forename: Yanfeng
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000293:Adolescent; D000328:Adult; D017677:Age Distribution; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001549:Benzamides; D001830:Body Surface Area; D001835:Body Weight; D003710:Demography; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D015466:Leukemia, Myeloid, Chronic-Phase / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D010879:Piperazines / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011379:Prognosis; D011743:Pyrimidines / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; C464561:CGP 74588; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate