Abstract
The introduction of imatinib, an oral tyrosine kinase inhibitor, as first-line standard therapy in patients with unresectable, metastatic, or recurrent gastro-intestinal stromal tumor (GIST), strongly improved their treatment outcomes. However, therapeutic drug monitoring (TDM) is recommended for this drug due to the large inter-individual variability in plasma concentration when standard dose is administered. A Cmin higher than 760 ng/mL was associated with a longer progression free survival. Thus, a LC-MS/MS method has been developed and fully validated to quantify imatinib and its active metabolite, norimatinib, in finger-prick dried blood spot (DBS). The influence of hematocrit, sample homogeneity, and spot size and the correlation between finger-prick and venous DBS measurements were also assessed. The method showed a good linearity (R2 > 0,996) between 50-7500 ng/mL for imatinib and 10-1500 ng/mL for norimatinib. Analytes were extracted from DBS samples by simply adding to 3 mm-discs 150 μL of acidified methanol containing IMA-D8. The collected extract was then injected on a LC Nexera system in-house configured for the on-line cleanup, coupled with an API-4000 QT. The chromatographic separation was conducted on a Synergi Fusion-RP column (4 μm, 2x50 mm) while the trapping column was a POROS R1/20 (20 μm, 2x30 mm). The total run time was 8.5 min. DBSs stored at room temperature in plastic envelopes containing a silica-gel drying bag were stable up to 16 months. The proposed method was applied to 67 clinical samples, showing a good correlation between patients' finger-prick DBS and plasma concentrations, measured by the reference LC-MS/MS method, internally validated. Imatinib and norimatinib concentrations found in finger-prick DBS were adjusted by hematocrit or by an experimental correction factor to estimate the corresponding plasma measurements. At the best of our knowledge, the proposed LC-MS/MS method is the first analytical assay to measure imatinib and norimatinib in DBS samples.
Highlights
IntroductionImatinib (Gleevec or Glivec1), hereinafter referred to as IMA, belongs to the family of tyrosine-kinase inhibitors (TKIs) (Fig 1)
Imatinib (Gleevec1 or Glivec1), hereinafter referred to as IMA, belongs to the family of tyrosine-kinase inhibitors (TKIs) (Fig 1). The introduction of this drug on the market turned out to be a revolution in cancer therapy. It is used as first line-treatment in Philadephia-positive chronic myeloid leukemia (Ph+CML) [1] and it has been approved for the use in metastatic or unresectable gastrointestinal stromal tumors (GISTs) [2] based on the increased progressionfree (PFS) and overall survival (OS) [3]
According to the proposed method, analytes were extracted from dried blood spot (DBS) samples by adding to 3 mm-disc 150 μL of methanol added with 0.1% of formic acid and IMA-D8 as internal standard at the concentration of 10 ng/mL
Summary
Imatinib (Gleevec or Glivec1), hereinafter referred to as IMA, belongs to the family of tyrosine-kinase inhibitors (TKIs) (Fig 1). The introduction of this drug on the market turned out to be a revolution in cancer therapy It is used as first line-treatment in Philadephia-positive chronic myeloid leukemia (Ph+CML) [1] and it has been approved for the use in metastatic or unresectable gastrointestinal stromal tumors (GISTs) [2] based on the increased progressionfree (PFS) and overall survival (OS) [3]. For this drug, like for many other antineoplastic medicines, there is a large inter-individual variability in plasma concentration after administration of the standard dose [4]. Therapeutic drug monitoring (TDM) is recommended to maintain plasma concentrations within the targeted therapeutic window in order to maximize the efficacy and minimize the toxicity of the therapy [5]
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