Development and validation of LC-MS/MS method for imatinib and norimatinib monitoring by finger-prick DBS in gastrointestinal stromal tumor patients

被引:26
作者
Iacuzzi, Valentina [1 ,2 ]
Posocco, Bianca [1 ]
Zanchetta, Martina [1 ,3 ]
Montico, Marcella [4 ]
Marangon, Elena [1 ]
Poetto, Ariana Soledad [1 ,5 ]
Buzzo, Mauro [1 ]
Gagno, Sara [1 ]
Buonadonna, Angela [6 ]
Guardascione, Michela [1 ]
Casetta, Bruno [1 ,7 ]
Toffoli, Giuseppe [1 ]
机构
[1] Ctr Riferimento Oncol Aviano CRO IRCCS, Expt & Clin Pharmacol Unit, Aviano, Italy
[2] Univ Trieste, Doctoral Sch Nanotechnol, Trieste, Italy
[3] Univ Trieste, Dept Chem & Pharmaceut Sci, Trieste, Italy
[4] Ctr Riferimento Oncol Aviano CRO IRCCS, Sci Directorate, Aviano, Italy
[5] Univ Padua, Doctoral Sch Pharmacol Sci, Padua, Italy
[6] Ctr Riferimento Oncol CRO IRCCS, Med Oncol Dept, Aviano, Italy
[7] Polo Tecnol Pordenone, Pordenone, Italy
关键词
DRIED BLOOD SPOTS; MAIN METABOLITE; DRUG; BENEFIT;
D O I
10.1371/journal.pone.0225225
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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 C-min 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 (R-2 > 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 mu L 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 mu m, 2x50 mm) while the trapping column was a POROS R1/20 (20 mu m, 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.
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页数:18
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