Effective quantification of ravidasvir (an NS5A inhibitor) and sofosbuvir in rat plasma by validated LC-MS/MS method and its application to pharmacokinetic study

Hefnawy, Mohamed M.; Hammad, Sherif F.; Kadi, Adnan A.; Alsaif, Nawaf A.; Mohammed, Mostafa; Al-Hossaini, Abdullah M.; Jardan, Yousef Bin; Attwa, Mohamed W.; AbouEl-Alamin, Maha M

doi:10.1016/j.arabjc.2020.09.048

Cited by 6 publications

(7 citation statements)

References 24 publications

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“…The calculated pharmacokinetics ( C max , T max , and AUC) were higher than those of the existing method (Hefnawy et al, 2020) (Table 4). These variabilities in results may be attributed to many reasons.…”

Section: Resultsmentioning

confidence: 61%

“…These variabilities in results may be attributed to many reasons. The first reason is the difference in rat species used in the pharmacokinetics experiments; the existing method (Hefnawy et al, 2020) used Wistar rats, whereas we used Sprague–Dawley rats. The second reason is different vehicles used for dissolving ravidasvir before intragastric administration; the existing method (Hefnawy et al, 2020) used 1% DMSO/saline, whereas we used 20% PEG.…”

Section: Resultsmentioning

confidence: 99%

“…The first reason is the difference in rat species used in the pharmacokinetics experiments; the existing method (Hefnawy et al, 2020) used Wistar rats, whereas we used Sprague–Dawley rats. The second reason is different vehicles used for dissolving ravidasvir before intragastric administration; the existing method (Hefnawy et al, 2020) used 1% DMSO/saline, whereas we used 20% PEG. Finally, in the extraction procedure of the drug from the plasma, the existing method (Hefnawy et al, 2020) used acetonitrile as a simple deproteinizing agent.…”

Section: Resultsmentioning

confidence: 99%

“…The second reason is different vehicles used for dissolving ravidasvir before intragastric administration; the existing method (Hefnawy et al, 2020) used 1% DMSO/saline, whereas we used 20% PEG. Finally, in the extraction procedure of the drug from the plasma, the existing method (Hefnawy et al, 2020) used acetonitrile as a simple deproteinizing agent. However, we used the liquid–liquid extraction method, which is superior to the simple deproteinization for cleaning and higher percentage recovery.…”

Section: Resultsmentioning

confidence: 99%

“…The use of this combination with and without ribavirin was well tolerated in patients with and without hepatic cirrhosis (Esmat et al, 2018). Only one LC–MS/MS method is reported in the literature to determine ravidasvir with sofosbuvir in rat plasma (Hefnawy et al, 2020) but not for ravidasvir with its metabolites.…”

Section: Introductionmentioning

confidence: 99%

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Determination and structural characterization of ravidasvir metabolites by LC coupled to triple quadrupole linear ion trap MS: Application to pharmacokinetics and phase I metabolism in rats

Kaddah

Talaat

Demellawy

2021

Biomedical Chromatography

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Hepatitis C virus (HCV) is an infectious disease that has become a global clinical issue because of its significant morbidity and mortality. Novel anti‐hepatitis C drugs are continuously developed to decrease the pervasiveness of the infection globally. A synthetic ravidasvir, benzimidazole‐naphthylene‐imidazole derivatives, has been used as an anti‐HCV drug. This study determined the metabolites of ravidasvir and its pharmacokinetics in rats using information‐dependent acquisition and multiple reaction monitoring scanning modes in linear ion trap LC–MS/MS instrument, respectively. Two time‐programming linear‐gradient chromatographic methods were employed using a Kinetex C18 column (50 × 3 mm, 2.6 μm) and a Luna HILIC column (100 × 4.6 mm, 3 μm) for the qualitative and quantitative determination of ravidasvir and its metabolites, respectively. In silico prediction where sites in a molecule are susceptible to metabolism by cytochrome P450 was implemented, which helped in proposing the metabolic pathway of ravidasvir. The most dominant metabolite in rat liver microsomal samples was oxidative ravidasvir, where one O‐demethylated metabolite and eight isomers of the oxidative ravidasvir metabolites were identified. The study provides essential data for proposing the metabolic pathway and successfully applied it to determine the pharmacokinetics of ravidasvir in rat plasma.

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Section: Resultsmentioning

confidence: 61%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Determination and structural characterization of ravidasvir metabolites by LC coupled to triple quadrupole linear ion trap MS: Application to pharmacokinetics and phase I metabolism in rats

Kaddah

Talaat

Demellawy

2021

Biomedical Chromatography

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Applicable pharmacokinetic study: Development and validation of bioanalytical LC-MS/MS method for the simultaneous quantification of cytarabine and glasdegib used for the treatment of acute myeloid leukemia

Al-Nasser

Hefnawy

Alanazi

et al. 2023

Arabian Journal of Chemistry

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Population pharmacokinetics of ravidasvir in adults with chronic hepatitis C virus infection and impact of antiretroviral treatment

Panjasawatwong,

Avihingsanon,

Menétrey

et al. 2024

Antimicrob Agents Chemother

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Ravidasvir (RDV) is a novel NS5A inhibitor that exhibits potent pan-genotypic inhibition of hepatitis C virus (HCV) replication. Sofosbuvir (SOF) plus RDV was demonstrated to be efficacious and safe in adults with active HCV infection, including those living with HIV (LWHIV), in the STORM-C-1 trial. We assessed the population pharmacokinetics (PK) of RDV in a sub-study nested within STORM-C-1 conducted in Thailand and Malaysia. SOF (400 mg) plus RDV (200 mg) was administered orally once daily for 12 weeks to adults with chronic HCV infection, but without cirrhosis and for 24 weeks to those with compensated cirrhosis. Intensive and sparse PK samples were collected at 4, 8, and 12 weeks after treatment initiation. Population PK parameters of RDV and the impact of covariates were evaluated using nonlinear mixed-effects modeling. Five hundred ninety-four participants were included, 235 (40%) had compensated cirrhosis, and 189 (32%) were LWHIV. RDV plasma concentrations were best described by a two-compartment model with first-order elimination. Oral clearance (CL/F) and volume of distribution (Vd/F) parameters were allometrically scaled on fat-free mass. Concomitant antiretroviral treatment (ART) increased RDV CL/F by 30%–60%, with efavirenz-based ART having the largest impact. Females had 16% lower RDV CL/F than males, and higher albumin levels reduced RDV central volume of distribution. While several covariates impact RDV CL/F and Vd/F, the effect on RDV exposures was not clinically relevant based on the efficacy data reported in this diverse Asian adult population. There were no meaningful drug-drug interactions in adults LWHIV on ART.

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Effective quantification of ravidasvir (an NS5A inhibitor) and sofosbuvir in rat plasma by validated LC-MS/MS method and its application to pharmacokinetic study

Cited by 6 publications

References 24 publications

Determination and structural characterization of ravidasvir metabolites by LC coupled to triple quadrupole linear ion trap MS: Application to pharmacokinetics and phase I metabolism in rats

Determination and structural characterization of ravidasvir metabolites by LC coupled to triple quadrupole linear ion trap MS: Application to pharmacokinetics and phase I metabolism in rats

Applicable pharmacokinetic study: Development and validation of bioanalytical LC-MS/MS method for the simultaneous quantification of cytarabine and glasdegib used for the treatment of acute myeloid leukemia

Population pharmacokinetics of ravidasvir in adults with chronic hepatitis C virus infection and impact of antiretroviral treatment

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