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Validation of LC-MS/MS methods for determination of remdesivir and its metabolites GS-441524 and GS-704277 in acidified human plasma and their application in COVID-19 related clinical studies.
Xiao, Deqing; John Ling, Kah Hiing; Tarnowski, Thomas; Humeniuk, Rita; German, Polina; Mathias, Anita; Chu, Jasper; Chen, Yuan-Shek; van Ingen, Eric.
  • Xiao D; Department of Clinical Pharmacology, Gilead Sciences, Foster City, CA, USA. Electronic address: deqing.xiao@gilead.com.
  • John Ling KH; Department of Clinical Pharmacology, Gilead Sciences, Foster City, CA, USA.
  • Tarnowski T; Department of Clinical Pharmacology, Gilead Sciences, Foster City, CA, USA.
  • Humeniuk R; Department of Clinical Pharmacology, Gilead Sciences, Foster City, CA, USA.
  • German P; Department of Clinical Pharmacology, Gilead Sciences, Foster City, CA, USA.
  • Mathias A; Department of Clinical Pharmacology, Gilead Sciences, Foster City, CA, USA.
  • Chu J; QPS, LLC, Delaware Technology Park, 3 Innovation Way, Suite 240, Newark, DE, USA.
  • Chen YS; QPS, LLC, Delaware Technology Park, 3 Innovation Way, Suite 240, Newark, DE, USA.
  • van Ingen E; QPS, LLC, Delaware Technology Park, 3 Innovation Way, Suite 240, Newark, DE, USA.
Anal Biochem ; 617: 114118, 2021 03 15.
Article in English | MEDLINE | ID: covidwho-1064675
Semantic information from SemMedBD (by NLM)
1. Metabolite COEXISTS_WITH human plasma
Subject
Metabolite
Predicate
COEXISTS_WITH
Object
human plasma
2. remdesivir COEXISTS_WITH human plasma
Subject
remdesivir
Predicate
COEXISTS_WITH
Object
human plasma
3. remdesivir ADMINISTERED_TO Gaoshan Chinese
Subject
remdesivir
Predicate
ADMINISTERED_TO
Object
Gaoshan Chinese
4. formic acid TREATS Problem
Subject
formic acid
Predicate
TREATS
Object
Problem
5. Metabolite COEXISTS_WITH human plasma
Subject
Metabolite
Predicate
COEXISTS_WITH
Object
human plasma
6. remdesivir COEXISTS_WITH human plasma
Subject
remdesivir
Predicate
COEXISTS_WITH
Object
human plasma
7. remdesivir ADMINISTERED_TO Gaoshan Chinese
Subject
remdesivir
Predicate
ADMINISTERED_TO
Object
Gaoshan Chinese
8. formic acid TREATS Problem
Subject
formic acid
Predicate
TREATS
Object
Problem
ABSTRACT
Remdesivir (RDV) is a phosphoramidate prodrug designed to have activity against a broad spectrum of viruses. Following IV administration, RDV is rapidly distributed into cells and tissues and simultaneously metabolized into GS-441524 and GS-704277 in plasma. LC-MS/MS methods were validated for determination of the 3 analytes in human plasma that involved two key aspects to guarantee their precision, accuracy and robustness. First, instability issues of the analytes were overcome by diluted formic acid (FA) treatment of the plasma samples. Secondly, a separate injection for each analyte was performed with different ESI modes and organic gradients to achieve sensitivity and minimize carryover. Chromatographic separation was achieved on an Acquity UPLC HSS T3 column (2.1 × 50 mm, 1.8 µm) with a run time of 3.4 min. The calibration ranges were 4-4000, 2-2000, and 2-2000 ng/mL, respectively for RDV, GS-441524 and GS-704277. The intraday and interday precision (%CV) across validation runs at 3 QC levels for all 3 analytes was less than 6.6%, and the accuracy was within ±11.5%. The long-term storage stability in FA-treated plasma was established to be 392, 392 and 257 days at -70 °C, respectively for RDV, GS-441524 and GS-704277. The validated method was successfully applied in COVID-19 related clinical studies.
Subject(s)
Keywords

Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Pyrroles / Triazines / Adenosine Monophosphate / Drug Monitoring / Alanine / Tandem Mass Spectrometry / Furans Limits: Humans Language: English Journal: Anal Biochem Year: 2021 Document Type: Article

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Pyrroles / Triazines / Adenosine Monophosphate / Drug Monitoring / Alanine / Tandem Mass Spectrometry / Furans Limits: Humans Language: English Journal: Anal Biochem Year: 2021 Document Type: Article