Universität zu Köln

Mueller, Carsten, Fietz, Cornelia, Koehler, Philipp ORCID: 0000-0002-7386-7495, Sibley, Graham, Nforbugwe, Achu Che Awah ORCID: 0000-0002-9403-8522, Streichert, Thomas and Wiesen, Martin H. J. (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 (11). WASHINGTON: AMER SOC MICROBIOLOGY. ISSN 1098-6596

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Abstract

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 isotopelabeled analogue of F901318 was employed as an internal standard. Chromatographic separation was achieved using a 50-mm by 2.1-mm, 1.9-mu m, polar Hypersil Gold C-18 column and isocratic mobile phase consisting of 0.1% formic acid-acetonitrile (60%-40%, vol/vol) at a flow rate of 330 mu l/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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Mueller, Carsten UNSPECIFIED UNSPECIFIED UNSPECIFIED Fietz, Cornelia UNSPECIFIED UNSPECIFIED UNSPECIFIED Koehler, Philipp UNSPECIFIED orcid.org/0000-0002-7386-7495 UNSPECIFIED Sibley, Graham UNSPECIFIED UNSPECIFIED UNSPECIFIED Nforbugwe, Achu Che Awah UNSPECIFIED orcid.org/0000-0002-9403-8522 UNSPECIFIED Streichert, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Wiesen, Martin H. J. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-166664
DOI:	10.1128/AAC.01356-18
Journal or Publication Title:	Antimicrob. Agents Chemother.
Volume:	62
Number:	11
Date:	2018
Publisher:	AMER SOC MICROBIOLOGY
Place of Publication:	WASHINGTON
ISSN:	1098-6596
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language DIHYDROOROTATE DEHYDROGENASE Multiple languages Microbiology; Pharmacology & Pharmacy Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/16666