Simultaneous Determination of Major Molnupiravir Metabolite (β-D-N4-hydroxycytidine) and Favipiravir in Human Plasma by HPLC-MS/MS

Komarov, T. N.; Карнакова, П. К.; Archakova, O. A.; Щелгачева, Д. С.; Bagaeva, N. S.; Шохин, И. Е.; Zaslavskaya, K. Ya.; Bely, P. A.

doi:10.33380/2305-2066-2023-12-1-215-226

Cited by 5 publications

(6 citation statements)

References 17 publications

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“…Since Molnupiravir in human plasma is metabolized to β-D-N4-hydroxycytidine, which does not bind to plasma proteins [ 5 , 11 , 12 , 13 ], its quantitative determination as the main metabolite in human plasma is carried out [ 5 ].…”

Section: Resultsmentioning

confidence: 99%

“…Several studies have recently been published on the quantification of the NHC molnupiravir metabolite in human bodily fluids, aimed at investigating pharmacokinetic parameters. To this end, high-performance liquid chromatography with tandem mass spectrometric detection (HPLC-MS/MS), along with ultra-high-performance liquid chromatography with tandem mass spectrometric detection (UPLC-MS/MS), is used [ 5 ]. Here, sample preparation involves protein precipitation with acetonitrile, as well as ultrafiltration.…”

Section: Resultsmentioning

confidence: 99%

“…Although vaccination has played a significant role in reducing viral spreading, some populations remain unvaccinated. In addition, the emergence of new variants of SARS-CoV-2 and a decrease in the effectiveness of current vaccines have led to a rise in the incidence of COVID-19 cases [ 5 , 6 , 7 , 8 ]. Oral antiviral therapy can prevent the progression of the disease and stop the spread of the virus [ 1 ].…”

Section: Introductionmentioning

confidence: 99%

“…Subsequently, NHC is metabolized to ribonucleoside triphosphate under the action of the kinase. Ribonucleoside triphosphate is an active metabolite that, following the incorporation into the RNA of the SARS-CoV-2 virus, acts on the enzyme of RNA-dependent RNA polymerase and leads to the accumulation of mutations and suppression of viral replication [ 1 , 5 , 11 , 12 , 13 , 14 , 15 ]. The scheme of metabolic alteration of molnupiravir is shown in Figure 1 .…”

Section: Introductionmentioning

confidence: 99%

“…In the latter case, the antiviral activity of molnupiravir against SARS-CoV-2 was shown to increase [ 22 ]. Thus, a study into the combined application of molnupiravir with favipiravir [ 23 ] demonstrated their enhanced antiviral action, allowing molnupiravir to be used in lower doses [ 5 ]. The use of molnupiravir in combination with sotrovimab was shown to reduce the risk of severe COVID-19 outcomes [ 24 ].…”

Section: Introductionmentioning

confidence: 99%

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Development and Validation of a High-Performance Liquid Chromatography with Tandem Mass Spectrometry (HPLC-MS/MS) Method for Quantification of Major Molnupiravir Metabolite (β-D-N4-hydroxycytidine) in Human Plasma

Komarov,

Karnakova,

Archakova

et al. 2023

Biomedicines

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Molnupiravir is an antiviral drug against viral RNA polymerase activity approved by the FDA for the treatment of COVID-19, which is metabolized to β-D-N4-hydroxycytidine (NHC) in human blood plasma. A novel method was developed and validated for quantifying NHC in human plasma within the analytical range of 10–10,000 ng/mL using high-performance liquid chromatography with tandem mass spectrometry (HPLC-MS/MS) to support pharmacokinetics studies. For sample preparation, the method of protein precipitation by acetonitrile was used, with promethazine as an internal standard. Chromatographic separation was carried out on a Shim-pack GWS C18 (150 mm × 4.6 mm, 5 μm) column in a gradient elution mode. A 0.1% formic acid solution in water with 0.08% ammonia solution (eluent A, v/v) and 0.1% formic acid solution in methanol with 0.08% ammonia solution mixed with acetonitrile in a 4:1 ratio (eluent B, v/v) were used as a mobile phase. Electrospray ionization (ESI) was used as an ionization source. The developed method was validated in accordance with the Eurasian Economic Union (EAEU) rules, based on the European Medicines Agency (EMA) and Food and Drug Administration (FDA) guidelines for the following parameters and used within the analytical part of the clinical study of molnupiravir drugs: selectivity, suitability of standard sample, matrix effect, calibration curve, accuracy, precision, recovery, lower limit of quantification (LLOQ), carryover, and stability.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Development and Validation of a High-Performance Liquid Chromatography with Tandem Mass Spectrometry (HPLC-MS/MS) Method for Quantification of Major Molnupiravir Metabolite (β-D-N4-hydroxycytidine) in Human Plasma

Komarov,

Karnakova,

Archakova

et al. 2023

Biomedicines

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Graphene Multiplexed Sensor for Point-of-Need Viral Wastewater-Based Epidemiology

Geiwitz,

Page,

Marello

et al. 2024

ACS Appl. Bio Mater.

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Wastewater-based epidemiology (WBE) can help mitigate the spread of respiratory infections through the early detection of viruses, pathogens, and other biomarkers in human waste. The need for sample collection, shipping, and testing facilities drives up the cost of WBE and hinders its use for rapid detection and isolation in environments with small populations and in lowresource settings. Given the ubiquitousness and regular outbreaks of respiratory syncytial virus, SARS-CoV-2, and various influenza strains, there is a rising need for a low-cost and easy-to-use biosensing platform to detect these viruses locally before outbreaks can occur and monitor their progression. To this end, we have developed an easy-to-use, cost-effective, multiplexed platform able to detect viral loads in wastewater with several orders of magnitude lower limit of detection than that of mass spectrometry. This is enabled by wafer-scale production and aptamers preattached with linker molecules, producing 44 chips at once. Each chip can simultaneously detect four target analytes using 20 transistors segregated into four sets of five for each analyte to allow for immediate statistical analysis. We show our platform's ability to rapidly detect three virus proteins (SARS-CoV-2, RSV, and Influenza A) and a population normalization molecule (caffeine) in wastewater. Going forward, turning these devices into hand-held systems would enable wastewater epidemiology in low-resource settings and be instrumental for rapid, local outbreak prevention.

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Determination of Favipiravir in Human Blood Plasma by HPLC-MS/MS

Komarov,

Karpova,

Archakova

et al. 2023

Razrabotka i registraciâ lekarstvennyh sredstv

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Introduction. Favipiravir is one of the most well-known broad-spectrum drugs against many RNA viruses, including the severe acute respiratory syndrome virus 2 [severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)]. Due to its structure, favipiravir is embedded in the RNA of the virus and blocks its further replication in the cell of the human body. Favipiravir is also included in the list of vital and essential medicines, which confirms the importance for Russian healthcare of this drug in the fight against common RNA viruses. We have already published bioanalytical methods for determining favipiravir in human blood plasma by high-performance liquid chromatography with an ultraviolet detector (HPLC–UV) in order to study the pharmacokinetics of favipiravir with parenteral administration (the analytical range of the technique was 0.25–200.00 µg/ ml for the dosage of favipiravir 400 mg in 1 vial of lyophilizate for the preparation of concentrate for the preparation of solution for infusions) and by HPLC with tandem mass-selective detection (HPLC-MS/MS) in order to study the pharmacokinetics of β-D-N4-hydroxycytidine and favipiravir in their joint determination in blood plasma with oral administration (the analytical range of the technique was 250.00–20000.00 ng/ml for the dosage of favipiravir 400 mg in 1 tablet). The expectation of low favipiravir’s concentrations (the dosage of favipiravir in the drugs in question is 200 mg in 1 tablet in this study) and, in this regard, the expansion of the range by reducing the value of the lower limit of quantitative determination (LLOQ) used in this study necessitates the development of another method. Therefore, this study is given the development and validation of a method for determining favipiravir in human blood plasma by HPLC-MS/MS with an analytical range of 50.00–15000.00 ng/ml.Aim. The aim of this study is to develop a method for quantitative determination of favipiravir in human blood plasma by HPLC-MS/MS for further for further researches of pharmacokinetics and bioequivalence of drugs.Materials and methods. In the process of sample preparation, a method of proteins precipitation with methanol was used. A solution labeled with stable isotopes of favipiravir-13C3 was used as an internal standard, the mobile phase was a 0.1 % solution of formic acid in water (eluent A) and methanol (eluent B). Chromatographic column – Phenomenex Kinetex C18, 100×3.0 mm. The determination of favipiravir in human blood plasma was carried out by HPLC using a tandem mass spectrometric detector with a triple quadrupole. The analytical range for favipiravir is 50.00– 15000.00 ng/ml in human blood plasma.Results and discussion. This method was validated by selectivity, calibration curve, accuracy, precision, matrix effect, spike recovery, carry-over effect, the lower limit of quantification and stability.Conclusion. A method of quantitative favipiravir’s determination in human blood plasma by HPLC-MS/MS with a confirmed analytical range of 50.00–15000.00 ng/ml in human blood plasma has been developed and validated. This method allows using it for the analytical part of pharmacokinetics and bioequivalence studies of drugs containing favipiravir in order to expand their range in the domestic pharmaceutical market.

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Simultaneous Determination of Major Molnupiravir Metabolite (β-D-N4-hydroxycytidine) and Favipiravir in Human Plasma by HPLC-MS/MS

Cited by 5 publications

References 17 publications

Development and Validation of a High-Performance Liquid Chromatography with Tandem Mass Spectrometry (HPLC-MS/MS) Method for Quantification of Major Molnupiravir Metabolite (β-D-N4-hydroxycytidine) in Human Plasma

Development and Validation of a High-Performance Liquid Chromatography with Tandem Mass Spectrometry (HPLC-MS/MS) Method for Quantification of Major Molnupiravir Metabolite (β-D-N4-hydroxycytidine) in Human Plasma

Graphene Multiplexed Sensor for Point-of-Need Viral Wastewater-Based Epidemiology

Determination of Favipiravir in Human Blood Plasma by HPLC-MS/MS

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