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Title:Development and Validation of a High- Performance Liquid Chromatography– Tandem Mass Spectrometry Method for the Simultaneous Determination of Irinotecan and Its Main Metabolites in Human Plasma and Its Application in a Clinical Pharmacokinetic Study
Authors:ID Posocco, Bianca, CRO, National Cancer Institute, Aviano (PN), Italy (Author)
ID Mazzega, Elisa, CRO, National Cancer Institute, Aviano (PN), Italy (Author)
ID Marangon, Elena, CRO, National Cancer Institute, Aviano (PN), Italy (Author)
ID Toffoli, Giuseppe, CRO, National Cancer Institute, Aviano (PN), Italy (Author)
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Language:English
Work type:Not categorized
Typology:1.01 - Original Scientific Article
Organization:UNG - University of Nova Gorica
Abstract:Irinotecan is currently used in several cancer regimens mainly in colorectal cancer (CRC). This drug has a narrow therapeutic range and treatment can lead to side effects, mainly neutropenia and diarrhea, frequently requiring discontinuing or lowering the drug dose. A wide inter-individual variability in irinotecan pharmacokinetic parameters and pharmacodynamics has been reported and associated to patients’ genetic background. In particular, a polymorphism in the UGT1A1 gene (UGT1A1*28) has been linked to an impaired detoxification of SN-38 (irinotecan active metabolite) to SN-38 glucuronide (SN-38G) leading to increased toxicities. Therefore, therapeutic drug monitoring of irinotecan, SN-38 and SN-38G is recommended to personalize therapy. In order to quantify simultaneously irinotecan and its main metabolites in patients’ plasma, we developed and validated a new, sensitive and specific HPLC–MS/MS method applicable to all irinotecan dosages used in clinic. This method required a small plasma volume, addition of camptothecin as internal standard and simple protein precipitation. Chromatographic separation was done on a Gemini C18 column (3 μM, 100 mm x 2.0 mm) using 0.1% acetic acid/bidistilled water and 0.1% acetic acid/acetonitrile as mobile phases. The mass spectrometer worked with electrospray ionization in positive ion mode and selected reaction monitoring. The standard curves were linear (R20.9962) over the concentration ranges (10–10000 ng/mL for irinotecan, 1–500 ng/mL for SN-38 and SN-38G and 1–5000 ng/mL for APC) and had good back-calculated accuracy and precision. The intra- and inter-day precision and accuracy, determined on three quality control levels for all the analytes, were always <12.3% and between 89.4% and 113.0%, respectively. Moreover, we evaluated this bioanalytical method by re-analysis of incurred samples as an additional measure of assay reproducibility. This method wassuccessfully applied to a pharmacokinetic study in metastatic CRC patients enrolled in a genotype-guided phase Ib study of irinotecan administered in combination with 5-fluorouracil/ leucovorin and bevacizumab.
Keywords:Pharmacokinetic, pharmacodynamics, phase I clinical study, colorectal cancer, Mass spectrometry, pharmacogenetics
Publication version:Version of Record
Year of publishing:2015
Number of pages:18
Numbering:February 17
PID:20.500.12556/RUNG-3026-8a0d3099-ce90-a6b4-39f0-2acc94b793fc New window
COBISS.SI-ID:4724219 New window
DOI:DOI:10.1371/journal.pone.0118194 New window
NUK URN:URN:SI:UNG:REP:QU7X8ELA
Publication date in RUNG:21.03.2017
Views:4744
Downloads:0
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Record is a part of a journal

Title:PLoS ONE
Publisher:Public Library of Science
Year of publishing:2015
ISSN:1932-6203

Licences

License:CC BY-NC-ND 4.0, Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
Link:http://creativecommons.org/licenses/by-nc-nd/4.0/
Description:The most restrictive Creative Commons license. This only allows people to download and share the work for no commercial gain and for no other purposes.
Licensing start date:20.03.2017

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