Simulation of Remdesivir Pharmacokinetics and Its Drug Interactions.
Purpose: Remdesivir, a drug originally developed against Ebola virus, is currently recommended for patients hospitalized with coronavirus disease of 2019 (COVID-19). In spite of United States Food and Drug Administration's recent assent of remdesivir as the only approved agent for COVID-19, there is...
| Publicado en: | Journal of Pharmacy & Pharmaceutical Sciences Vol. 24; pp. 277 - 292 |
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| Autores principales: | , |
| Formato: | Journal Article |
| Publicado: |
Frontiers Media S.A.
2021
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=150996089&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 150996089 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 14821826 1CUO jtl: Journal of Pharmacy & Pharmaceutical Sciences issn: 14821826 maglogo: N pubinfo: dt: 2021 vid: 24 pid: 40038 pub: Frontiers Media S.A. artinfo: ui: 150996089 150996089 NLM34107241 10.18433/jpps32011 NLM34107241 150996089 ppf: 277 ppct: 15 formats: tig: atl: Simulation of Remdesivir Pharmacokinetics and Its Drug Interactions. aug: au: Deb, Subrata Reeves, Anthony Allen affil: Department of Pharmaceutical Sciences, College of Pharmacy, Larkin University, Miami, FL, USA. sug: ab: Purpose: Remdesivir, a drug originally developed against Ebola virus, is currently recommended for patients hospitalized with coronavirus disease of 2019 (COVID-19). In spite of United States Food and Drug Administration's recent assent of remdesivir as the only approved agent for COVID-19, there is limited information available about the physicochemical, metabolism, transport, pharmacokinetic (PK), and drug-drug interaction (DDI) properties of this drug. The objective of this in silico simulation work was to simulate the biopharmaceutical and DDI behavior of remdesivir and characterize remdesivir PK properties in special populations which are highly affected by COVID-19.Methods: The Spatial Data File format structures of remdesivir prodrug (GS-5734) and nucleoside core (GS-441524) were obtained from the PubChem database to upload into the GastroPlus software 9.8 version (Simulations Plus Inc., USA). The Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) Predictor and PKPlus modules of GastroPlus were used to simulate physicochemical and PK properties, respectively, in healthy and predisposed patients. Physiologically based pharmacokinetic (PBPK) modeling of GastroPlus was used to simulate different patient populations based on age, weight, liver function, and renal function status. Subsequently, these data were used in the Drug-Drug Interaction module to simulate drug interaction potential of remdesivir with other COVID-19 drug regimens and with agents used for comorbidities.Results: Remdesivir nucleoside core (GS-441524) is more hydrophilic than the inactive prodrug (GS-5734) with nucleoside core demonstrating better water solubility. GS-5734, but not GS-441524, is predicted to be metabolized by CYP3A4. Remdesivir is bioavailable and its clearance is achieved through hepatic and renal routes. Differential effects of renal function, liver function, weight, or age were observed on the PK profile of remdesivir. DDI simulation study of remdesivir with perpetrator drugs for comorbidities indicate that carbamazepine, phenytoin, amiodarone, voriconazole, diltiazem, and verapamil have the potential for strong interactions with victim remdesivir, whereas agents used for COVID-19 treatment such as chloroquine and ritonavir can cause weak and strong interactions, respectively, with remdesivir.Conclusions: GS-5734 (inactive prodrug) appears to be a superior remdesivir derivative due to its hepatic stability, optimum hydrophilic/lipophilic balance, and disposition properties. Remdesivir disposition can potentially be affected by different physiological and pathological conditions, and by drug interactions from COVID-19 drug regimens and agents used for comorbidities. pubtype: Academic Journal doctype: Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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