Article

Trough plasma concentration of imatinib reflects BCR-ABL kinase inhibitory activity and clinical response in chronic-phase chronic myeloid leukemia: a report from the BINGO study.

Department of Infectious Diseases, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Cancer Science (Impact Factor: 3.48). 10/2010; 101(10):2186-92. DOI: 10.1111/j.1349-7006.2010.01643.x
Source: PubMed

ABSTRACT Pharmacokinetic (PK) factors have been suggested to be involved in the unfavorable clinical responses of chronic myeloid leukemia (CML) patients treated with imatinib. The purpose of this study was to clarify prognostic implications of PK factors in CML patients treated with imatinib. The plasma trough (C(min)) level of imatinib and serum α(1)-acid glycoprotein (AGP) level were measured on two different days in 65 CML patients treated with imatinib for more than 12 months. We further examined whether the C(min) level of imatinib actually reflects inhibitory activity against BCR-ABL kinase using the plasma inhibitory activity (PIA) assay. Since the differences of five patients were statistically rejected by the Smirnov-Grubbs' test, we excluded them for further analysis. The C(min) level was strongly associated with the achievement of MMR at the 12th month, and ROC analysis demonstrated C(min) levels and their discrimination potential for major molecular response (MMR) with the best sensitivity (63.2%) and specificity (68.2%) at a C(min) threshold of 974 ng/mL. The α(1)-Acid glycoprotein (AGP) level was within the normal range in 57 of 60 patients, indicating little impact of AGP on our study. There was a weak correlation between PIA against phospho (P)-BCR-ABL and the C(min) level of imatinib (r(2) = 0.2501, P = 0.0007), and patient plasma containing >974 ng/mL imatinib sufficiently inhibited P-BCR-ABL. These results collectively indicated that maintaining ∼1000 ng/mL of C(min) was clinically and biologically important for the optimal response in CML patients treated with imatinib. A prospective intervention study is required to establish PK-based management in CML patients treated with imatinib.

0 Bookmarks
 · 
66 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: The aim of the study was to investigate any possible influence of polymorphisms of transmembrane transporters human organic cation transporter 1 (hOCT1), ABCB1, ABCG2 on imatinib pharmacokinetics in 33 men and 27 women (median age and range, 56 and 27-79 years, respectively) affected by chronic myeloid leukemia. A population pharmacokinetic analysis was performed to investigate imatinib disposition in every patient and the role of transporter polymorphisms. Results showed that the α1-acid glycoprotein and the c.480C>G genotype of hOCT1 had a significant effect on apparent drug clearance (CL/F) being responsible, respectively, for a 20% and 10% decrease in interindividual variability (IIV) of CL/F (from 50.1 up to 19.6%). Interestingly, 25 patients carrying at least one polymorphic c.480 G allele had a significant lower CL/F value with respect to the 35 c.480CC individuals (mean±s.d., 9.6±1.6 vs 12.1±2.3 l h(-1), respectively; P<0.001). In conclusion, the hOCT1 c.480C>G SNP may significantly influence imatinib pharmacokinetics, supporting further analyses in larger groups of patients.The Pharmacogenomics Journal advance online publication, 4 March 2014; doi:10.1038/tpj.2014.7.
    The Pharmacogenomics Journal 03/2014; · 5.13 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Abstract Our study aimed to determine the correlation between mean trough Imatinib plasma levels and molecular response in 131 Chronic Myeloid Leukemia (CML) patients. Imatinib plasma levels were also compared in patients who were on Glivec versus those on generic/biosimilar imatinib . Plasma Imatinib trough levels were estimated by high-performance liquid chromatography (HPLC). A receiver operating characteristic curve was constructed to estimate a plasma imatinib threshold level that correlates with a favorable response. Patients were divided into Responders and Non Responders. The mean trough imatinib plasma level in the responders was significantly higher (2.10±1.18µg/ml)/ (3.56±2.0µM) than in the non responders (1.31±0.72µg/ml)/ (2.22±1.22 µM) (p value= 0.001). The area under ROC curve was 0.733, with best sensitivity (51.85%) and specificity (89.42%) at a plasma threshold of 0.988 µg/ml /1.675 µM. There was no significant difference between the mean trough levels of the patients who were on Glivec vs on generic / biosimilar imatinib (p value > 0.05). Trough levels may be a marker for suboptimal response to Imatinib and may identify patients in whom increase of drug dose or change in therapy may be indicated.
    Leukemia & lymphoma 01/2014; · 2.40 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: This observational study analyzed imatinib pharmacokinetics and response in 2478 chronic myeloid leukemia (CML) patients. Data was obtained through centralized therapeutic drug monitoring (TDM) at median treatment duration of ≥2years. First, individual initial trough concentrations under 400 mg/day imatinib starting dose were estimated. Second, their correlation (Ĉmin(400mg)) with reported treatment response was verified. Low imatinib levels were predicted in young male patients and those receiving P-gp/CYP3A4 inducers. These patients had also lower response rates (7% lower 18-months MMR in male, 17% lower 1-year CCyR in young patients, Kaplan-Meier estimates). Time-point independent multivariate regression confirmed a correlation of individual Ĉmin(400mg) with response and adverse events. Possibly due to confounding factors (e.g. dose modifications, patient selection bias), the relationship seemed however flatter than previously reported from prospective controlled studies. Nonetheless, these observational results strongly suggest that a subgroup of patients could benefit from early dosage optimization assisted by TDM, because of lower imatinib concentrations and lower response rates.
    Leukemia Research. 01/2014;