Simultaneous quantification of seven repurposed COVID-19 drugs remdesivir (plus metabolite GS-441524), chloroquine, hydroxychloroquine, lopinavir, ritonavir, favipiravir and azithromycin by a two-dimensional isotope dilution LC-MS/MS method in human serum.
Adenosine
/ analogs & derivatives
Adenosine Monophosphate
/ analogs & derivatives
Alanine
/ analogs & derivatives
Amides
/ blood
Antiviral Agents
/ blood
Azithromycin
/ blood
COVID-19
/ blood
Chloroquine
/ blood
Chromatography, Liquid
/ methods
Furans
/ blood
Humans
Hydroxychloroquine
/ blood
Isotopes
/ chemistry
Lopinavir
/ blood
Pandemics
/ prevention & control
Pyrazines
/ blood
Pyrroles
/ blood
Ritonavir
/ blood
SARS-CoV-2
/ drug effects
Tandem Mass Spectrometry
/ methods
Triazines
/ blood
COVID-19 Drug Treatment
Antiviral therapy
Isotope dilution liquid chromatography tandem mass spectrometry (ID-LC–MS/MS)
Therapeutic drug monitoring
Journal
Journal of pharmaceutical and biomedical analysis
ISSN: 1873-264X
Titre abrégé: J Pharm Biomed Anal
Pays: England
ID NLM: 8309336
Informations de publication
Date de publication:
20 Mar 2021
20 Mar 2021
Historique:
received:
09
10
2020
revised:
30
12
2020
accepted:
24
01
2021
pubmed:
7
2
2021
medline:
27
2
2021
entrez:
6
2
2021
Statut:
ppublish
Résumé
The present COVID-19 pandemic has prompted worldwide repurposing of drugs. The aim of the present work was to develop and validate a two-dimensional isotope-dilution liquid chromatrography tandem mass spectrometry (ID-LC-MS/MS) method for accurate quantification of remdesivir and its active metabolite GS-441524, chloroquine, hydroxychloroquine, lopinavir, ritonavir, favipiravir and azithromycin in serum; drugs that have gained attention for repurposing in the treatment of COVID-19. Following protein precipitation, samples were separated with a two-dimensional ultra-high performance liquid chromatography (2D-UHPLC) setup, consisting of an online solid phase extraction (SPE) coupled to an analytical column. For quantification, stable isotope-labelled analogues were used as internal standards for all analytes. The method was validated on the basis of the European Medicines Agency bioanalytical method validation protocol. Detuning of lopinavir and ritonavir allowed simultaneous quantification of all analytes with different concentration ranges and sensitivity with a uniform injection volume of 5 μL. The method provided robust validation results with inaccuracy and imprecision values of ≤ 9.59 % and ≤ 11.1 % for all quality controls. The presented method is suitable for accurate and simultaneous quantification of remdesivir, its metabolite GS-441525, chloroquine, hydroxychloroquine, lopinavir, ritonavir, favipiravir and azithromycin in human serum. The quantitative assay may be an efficient tool for the therapeutic drug monitoring of these potential drug candidates in COVID-19 patients in order to increase treatment efficacy and safety.
Sections du résumé
BACKGROUND
BACKGROUND
The present COVID-19 pandemic has prompted worldwide repurposing of drugs. The aim of the present work was to develop and validate a two-dimensional isotope-dilution liquid chromatrography tandem mass spectrometry (ID-LC-MS/MS) method for accurate quantification of remdesivir and its active metabolite GS-441524, chloroquine, hydroxychloroquine, lopinavir, ritonavir, favipiravir and azithromycin in serum; drugs that have gained attention for repurposing in the treatment of COVID-19.
METHODS
METHODS
Following protein precipitation, samples were separated with a two-dimensional ultra-high performance liquid chromatography (2D-UHPLC) setup, consisting of an online solid phase extraction (SPE) coupled to an analytical column. For quantification, stable isotope-labelled analogues were used as internal standards for all analytes. The method was validated on the basis of the European Medicines Agency bioanalytical method validation protocol.
RESULTS
RESULTS
Detuning of lopinavir and ritonavir allowed simultaneous quantification of all analytes with different concentration ranges and sensitivity with a uniform injection volume of 5 μL. The method provided robust validation results with inaccuracy and imprecision values of ≤ 9.59 % and ≤ 11.1 % for all quality controls.
CONCLUSION
CONCLUSIONS
The presented method is suitable for accurate and simultaneous quantification of remdesivir, its metabolite GS-441525, chloroquine, hydroxychloroquine, lopinavir, ritonavir, favipiravir and azithromycin in human serum. The quantitative assay may be an efficient tool for the therapeutic drug monitoring of these potential drug candidates in COVID-19 patients in order to increase treatment efficacy and safety.
Identifiants
pubmed: 33548872
pii: S0731-7085(21)00047-9
doi: 10.1016/j.jpba.2021.113935
pmc: PMC7843035
pii:
doi:
Substances chimiques
Amides
0
Antiviral Agents
0
Furans
0
Isotopes
0
Pyrazines
0
Pyrroles
0
Triazines
0
GS-441524
1BQK176DT6
Lopinavir
2494G1JF75
remdesivir
3QKI37EEHE
Adenosine Monophosphate
415SHH325A
Hydroxychloroquine
4QWG6N8QKH
Azithromycin
83905-01-5
Chloroquine
886U3H6UFF
favipiravir
EW5GL2X7E0
Adenosine
K72T3FS567
Ritonavir
O3J8G9O825
Alanine
OF5P57N2ZX
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
113935Informations de copyright
Copyright © 2021 Elsevier B.V. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Competing Interest The authors have no conflict of interest to declare.
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