Development and validation of a multiplex HPLC-MS/MS assay for the monitoring of JAK inhibitors in patient plasma.

Détails

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Etat: Public
Version: Final published version
Licence: CC BY 4.0
ID Serval
serval:BIB_670CB2162D89
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Development and validation of a multiplex HPLC-MS/MS assay for the monitoring of JAK inhibitors in patient plasma.
Périodique
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences
Auteur⸱e⸱s
Tachet J., Versace F., Mercier T., Buclin T., Decosterd L.A., Choong E., Girardin F.R.
ISSN
1873-376X (Electronic)
ISSN-L
1570-0232
Statut éditorial
Publié
Date de publication
15/11/2023
Peer-reviewed
Oui
Volume
1230
Pages
123917
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: ppublish
Résumé
Janus kinase inhibitors (JAKi) are oral small molecules used in the treatment of a broad spectrum of autoimmune and myeloproliferative diseases. JAKi exhibit significant intra- and inter-individual pharmacokinetic variabilities, due to fluctuations in compliance with oral treatments and their metabolism essentially driven by cytochrome P450 enzymes. Intrinsically, JAKi have dose-response relationship and narrow therapeutic index: therapeutic drug monitoring (TDM) is expected to optimize and adapt their dosage regimen in order to resolve problems of efficacy and tolerance linked to dose and safety. A sensitive analytical method using multiplex high-performance liquid-chromatography coupled to tandem mass spectrometry (HPLC-MS/MS) was developed and validated for the simultaneous quantification in plasma of the 6 major currently used JAKi, namely abrocitinib, baricitinib, fedratinib, ruxolitinib, tofacitinib, and upadacitinib. Plasma samples are subjected to protein precipitation with MeOH, using stable isotopically labelled internal standards. The separation of JAKi in supernatants diluted 1:1 with ultrapure H <sub>2</sub> O was performed using a C <sub>18</sub> column Xselect HSS T3 2.5 µm, 2.1x150 mm using a mobile phase composed of formic acid (FA) 0.2% and acetonitrile (+FA 0.1%) in gradient mode. The analytical run time for the multiplex assay was 7 min. JAKi drugs were monitored by electrospray ionization in the positive mode followed by triple-stage quadrupole MS/MS analysis. The method was validated according to SFSTP and ICH guidelines over the clinically relevant concentration ranges (0.5-200 ng/mL for abrocitinib, baricitinib and upadacitinib; 1-400 ng/mL for tofacitinib; 0.5-400 ng/mL for ruxolitinib, and 10-800 ng/mL for fedratinib). This multiplex HPLC-MS/MS assay achieved good performances in term of trueness (91.1-113.5%), repeatability (3.0-9.9%), and intermediate precision (4.5-11.3%). We developed and validated a highly sensitive method for the multiplex quantification of the JAKi abrocitinib, baricitinib, fedratinib, ruxolitinib, tofacitinib, and upadacitinib in human plasma. The method will be applied for prospective clinical pharmacokinetic studies to determine whether TDM programs for JAKi based on residual drug concentrations can be recommended using disease-specific therapeutic ranges.
Mots-clé
Humans, Chromatography, High Pressure Liquid/methods, Tandem Mass Spectrometry/methods, Janus Kinase Inhibitors, Prospective Studies, Drug Monitoring/methods, Reproducibility of Results, Immunosuppressants, Inflammatory diseases, JAK inhibitors, LC-MS/MS, Targeted therapy, Therapeutic Drug Monitoring
Pubmed
Web of science
Open Access
Oui
Création de la notice
14/11/2023 17:50
Dernière modification de la notice
19/12/2023 7:14
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