Development and validation of a multiplex UHPLC-MS/MS method for the determination of the investigational antibiotic against multi-resistant tuberculosis macozinone (PBTZ169) and five active metabolites in human plasma
Rattachement africain : ch, ru. Niveau de preuve : code pays fourni par la source.
Le résumé fourni par la source
The emergence of Mycobacterium tuberculosis strains resistant to current first-line antibiotic regimens constitutes a major global health threat. New treatments against multidrug-resistant tuberculosis (MDR-TB) are thus eagerly needed in particular in countries with a high MDR-TB prevalence. In this context, macozinone (PBTZ169), a promising drug candidate with an unique mode of action and highly potent in vitro tuberculocidal properties against MDR Mycobacterium strains, has now reached the clinical phase and has been notably tested in healthy male volunteers in Switzerland. To that endeavor, a multiplex UHPLC-MS/MS method has been developed for the sensitive and accurate human plasma levels determination of PBTZ169 along with five metabolites retaining in vitro anti-TB activity. Plasma protein precipitation with methanol was carried out as a simplified sample clean-up procedure followed by direct injection of the undiluted supernatant for the bioanalysis of the six analytes within 5 min, using 1.8 μm reversed-phase chromatography coupled to triple quadrupole mass spectrometry employing electrospray ionization in the positive mode. Stable isotopically-labelled PBTZ169 was used as internal standard (ISTD), while metabolites could be reliably quantified using two unlabeled chemical analogues selected as ISTD from a large in-house analogous compounds library. The overall methodology was fully validated according to current recommendations (FDA, EMEA) for bioanalytical methods, which include selectivity, carryover, qualitative and quantitative matrix effect, extraction recovery, process efficiency, trueness, precision, accuracy profiles, method and instrument detection limits, integrity to dilution, anticoagulant comparison and short- and long-term stabilities. Stability studies on the reduced metabolite H2-PBTZ169 have shown no significant impact on the actual PBTZ169 concentrations determined with the proposed assay. This simplified, rapid, sensitive and robust methodology has been applied to the bioanalysis of human plasma samples collected within the frame of a phase I clinical study in healthy volunteers receiving PBTZ169.
Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.
Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Development and validation of a multiplex UHPLC-MS/MS method for the determination of the investigational antibiotic against multi-resistant tuberculosis macozinone (PBTZ169) and five active metabolites in human plasma
- Date Crossref
- 31/05/2019
- Éditeur
- Public Library of Science (PLoS)
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Centre Hospitalier Universitaire Vaudois pays non établi dans la noticeÉtablissement de santé
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University of Lausanne Laboratory & Service of Clinical Pharmacology pays non établi dans la noticeUniversité ou école supérieure
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École Polytechnique Fédérale de Lausanne pays non établi dans la noticeUniversité ou école supérieure
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Innovative Medicines for Tuberculosis Foundation pays non établi dans la noticeInstitution
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Federal Research Centre «Fundamentals of Biotechnology» of the Russian Academy of Sciences pays non établi dans la noticeStructure de recherche
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School of Life Sciences Global Health Institute pays non établi dans la noticeUniversité ou école supérieure
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Innovative Medicines for Tuberculosis (IM4TB) pays non établi dans la noticeInstitution
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Federal Research Center "Fundamentals of Biotechnology RAS" pays non établi dans la noticeStructure de recherche
Centre Hospitalier Universitaire Vaudois, Laboratory & Service of Clinical Pharmacology — University of Lausanne et École Polytechnique Fédérale de Lausanne, avec 5 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.