Reliable and Easy-To-Use Liquid Chromatography-Tandem Mass Spectrometry Assay for Quantification of Olorofim (F901318), a Novel Antifungal Drug, in Human Plasma and Serum

A fast and easy-to-use liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the determination and quantification of a novel antifungal drug, olorofim (F901318), a member of the novel class of orotomides, in human plasma and serum was developed and validated. Sample preparation was ba...

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Bibliographic Details
Published in:	Antimicrobial agents and chemotherapy Vol. 62; no. 11
Main Authors:	Müller, Carsten, Fietz, Cornelia, Koehler, Philipp, Sibley, Graham, Nforbugwe, Achu Che Awah, Streichert, Thomas, Wiesen, Martin H J
Format:	Journal Article
Language:	English
Published:	United States American Society for Microbiology 01-11-2018
Subjects:	Acetamides Analytical Procedures Antifungal Agents Chromatography, Liquid Piperazines Plasma Pyrimidines Pyrroles Tandem Mass Spectrometry liquid chromatography-coupled tandem mass spectrometry (LC-MS/MS) antifungal agents orotomide antifungal drug therapeutic drug monitoring matrix effects
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Summary:	A fast and easy-to-use liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the determination and quantification of a novel antifungal drug, olorofim (F901318), a member of the novel class of orotomides, in human plasma and serum was developed and validated. Sample preparation was based on protein precipitation with acetonitrile and subsequent centrifugation. An isotope-labeled analogue of F901318 was employed as an internal standard. Chromatographic separation was achieved using a 50-mm by 2.1-mm, 1.9-μm, polar Hypersil Gold C column and isocratic mobile phase consisting of 0.1% formic acid-acetonitrile (60%-40%, vol/vol) at a flow rate of 330 μl/min. The analyte was detected using a triple-stage quadrupole mass spectrometer operated in selected reaction monitoring (SRM) mode with positive heated electrospray ionization (HESI ) within a single runtime of 2.00 min. The present LC-MS/MS method was validated according to the international guidelines of the International Conference on Harmonisation (ICH) and the U.S. Food and Drug Administration (FDA). Linearity of F901318 concentration ranges was verified by the Mandel test. The calibration curve was tested linear across the range and fitted using least-squares regression with a weighting factor of the reciprocal concentration. The limit of detection was 0.0011 mg/liter, and the lower limit of quantitation was 0.0033 mg/liter. Intraday and interday precisions ranged from 1.17% to 3.23% for F901318, and intraday and interday accuracies (percent bias) ranged from 0.75% to 5.01%. In conclusion, a method was established for the rapid quantitation of F901318 concentrations in serum and plasma samples in patient trials, and it optimizes therapeutic drug monitoring in applying an easy-to-use single method.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Citation Müller C, Fietz C, Koehler P, Sibley G, Nforbugwe ACA, Streichert T, Wiesen MHJ. 2018. Reliable and easy-to-use liquid chromatography-tandem mass spectrometry assay for quantification of olorofim (F901318), a novel antifungal drug, in human plasma and serum. Antimicrob Agents Chemother 62:e01356-18. https://doi.org/10.1128/AAC.01356-18.
ISSN:	0066-4804 1098-6596
DOI:	10.1128/AAC.01356-18