Authorization for emergency use of remdesivir for the treatment of COVID19 (letter). Takahashi T., Luzum J.A., Nicol M.R., Jacobson P.A. Drugs.com provides accurate and independent information on more than 24,000 prescription drugs, over-the-counter medicines and natural products. 5 In addition, several commonly used diet and natural health supplements taken by the COVID-19 patients can influence its outcome. -. This indicates that COVID-19 patients will be on additional medications (e.g., antihypertensives such as amlodipine, nifedipine, irbesartan, losartan, verapamil, and diltiazem; antidiabetic agents such as glimepiride, glipizide, glyburide; cholesterol lowering drugs such as statins) to manage their comorbidities [41,42]. Indeed, our recent simulation work predicted that COVID-19 regimen related other drugs (e.g., ritonavir) and agents for comorbidities (e.g., voriconazole, diltiazem) have the potential to interact with remdesivir [27]. , Drug-drug or drug-herb interactions, which will be generically termed as DDI in this discussion, can have at least two major perspectives of perpetrator and victim. Remdesivir has broad antiviral activity against RNA viruses, including filoviruses (Ebola and Marburg) and coronaviruses, such as severe acute respiratory syndrome coronavirus (SARSCoV), Middle East respiratory syndrome coronavirus (MERSCoV), and SARSCoV2. Inhaled administration will likely be for less serious COVID-19 patients since it would be for local treatment [21]. 1 National Library of Medicine Anim Dis. However, the GS-441524 and GS-704277 were somewhat different between day 1 and day 7 or day 14. The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak. Following i.v. Special populations with hepatic and renal dysfunction have demonstrated indications of differential pharmacokinetics and have the potential for toxicity from remdesivir. Varis T., Kivisto K.T., Backman J.T., Neuvonen P.J. Liverpool Drug Interactions Group University of Liverpool The clearance and volume of distribution ranged from 755 mL/min to 719 mL/min and 45.1 L to 66.5 L, respectively. Paxlovid, molnupiravir, Actemra, Lagevrio, nirmatrelvir / ritonavir, Olumiant. Available at: Gliga S, Luebke N, Killer A, et al. Remdesivir has demonstrated in vitro and in vivo activity against SARS-CoV-2.1 Remdesivir retains in vitro neutralization activity against the Omicron variant and its subvariants.2-5. Remdesivir (Veklury) [package insert]. The intravenous administration of remdesivir affords patients to achieve therapeutically meaningful plasma concentrations. Drug Class: Remdesivir is a prodrug that undergoes intracellular conversion to an active analogue of adenosine triphosphate to inhibit viral RNA polymerase. Dick R.A. Refinement of In Vitro Methods for Identification of Aldehyde Oxidase Substrates Reveals Metabolites of Kinase Inhibitors. CYP, cytochrome P450, CES, carboxylesterase. [54] is a classic example that drugs used with remdesivir should be assessed for possible ADME interactions before, during, and after treatment for COVID-19. Biomimetic SARS-CoV-2 Spike Protein Nanoparticles. As a library, NLM provides access to scientific literature. Gotte, M. The antiviral compound remdesivir potently inhibits RNAdependent RNA polymerase from Middle East respiratory syndrome coronavirus, Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019nCoV) in vitro, Discovery and synthesis of a phosphoramidate prodrug of a Pyrrolo[2,1f][triazin4amino] adenine CNucleoside (GS5734) for the treatment of Ebola and emerging viruses. 2014. In Vitro and In Vivo Drug-Drug Interaction Study of the Effects of Ivermectin and Oxantel Pamoate on Tribendimidine. 15 HHS Vulnerability Disclosure, Help Rodriguez-Morales A.J., Cardona-Ospina J.A., Gutirrez-Ocampo E., Villamizar-Pea R., Holguin-Rivera Y., Escalera-Antezana J.P., Alvarado-Arnez L.E., Bonilla-Aldana D.K., Franco-Paredes C., Henao-Martinez A.F., et al. Gandhi S, Klein J, Robertson AJ, et al. Overall, remdesivir is an adenosine nucleotide analog prodrug which is metabolically activated to a nucleoside triphosphate metabolite (GS-443902). doi: 10.7759/cureus.36247. Best Pract Res Clin Endocrinol Metab. Profiles Drug Subst Excip Relat Methodol. The recommendations from the COVID-19 Treatment Guidelines Panel (the Panel) are based on the results of these studies. Monogue, M.L. Written by Cerner Multum. Unauthorized use of these marks is strictly prohibited. HHS Vulnerability Disclosure, Help KALETRA (Lopinavir and Ritonavir) Package Insert. There was no increased risk of renal toxicity at Day 5 among the individuals who received remdesivir when compared with those who received standard of care. Remdesivir disposition appears to be affected by P-gp modulators. In respiratory epithelial cells, GS441524 is further converted by intracellular esterases into the pharmacologically active nucleoside triphosphate (GS443902), which competes with naturally occurring adenosine phosphate and functions as a delayed RNAdependent RNA polymerase inhibitor. There are 369 drugs known to interact with remdesivir, along with 2 disease interactions, and 1 alcohol/food interaction. Gordon, C.J. CYP3A4. Travel Med. The clinical relevance of lower RDV levels is unknown. Pharmacokinetics and tissue distribution of remdesivir and its metabolites nucleotide monophosphate, nucleotide triphosphate, and nucleoside in mice. Efficacy of antiviral agents against the SARS-CoV-2 Omicron subvariant BA.2. Epub 2023 Feb 9. Intracellular metabolic pathway of remdesivir, Intracellular metabolic pathway of remdesivir (GS-5734), Mean (standard deviation) of remdesivir (RDV), GS-704277, and GS-441524 plasma concentration vs time, MeSH Zhu W., Song L., Zhang H., Matoney L., LeCluyse E., Yan B. Dexamethasone differentially regulates expression of carboxylesterase genes in humans and rats. Kasarla SS, Borse SP, Kumar Y, Sharma N, Dikshit M. Front Pharmacol. Moderately clinically significant. Inside the cell, remdesivir undergoes metabolic activation to form the intracellular active triphosphate metabolite, GS-443902 (detected in peripheral blood mononuclear cells), and ultimately, the renally eliminated plasma metabolite GS-441524. This site needs JavaScript to work properly. [(accessed on 15 March 2021)]; Amiodarone Package Insert. Notable adverse events include rash (8%) and abnormal liver function tests (523%). 2 Online ahead of print. A post hoc analysis was done for 59 patients with a baseline eGFR of <30 mL/min; 15 of these patients were on dialysis. On April 21, 2020, the National Institutes of Health (NIH) released their own COVID19 treatment guidelines. Remdesivir is an investigational drug, now in clinical trials in the US. The interaction between antiviral agents and hepatic transporters may result in hepatotoxicity and adverse drug . Coronavirus disease 2019 treatment: a review of early and emerging options. Cheng M, Fowler R, Murthy S, et al. Experience at a large tertiary urban medical center. Effect of ivermectin on activities of cytochrome P450 isoenzymes in mouflon (. [54] reported that remdesivir can induce liver toxicity when it is co-administered with amiodarone and administered nine days after chloroquine dosing. With the recent announcement of the FDA EUA for remdesivir, Gilead Sciences has pledged to donate its existing supply of remdesivir of 1.5 million dosesenough to treat ~140,000 patients worldwide. 2 are major, and 367 are moderate. However, the liver and small intestine are the main organs responsible for bulk of the drug metabolism in vivo [35]. 2022 Oct 12;13:973768. doi: 10.3389/fphar.2022.973768. Gently invert the bag 20 times to mix the solution in the bag; do not shake. Remdesivir is an antiviral drug.In the United States, remdesivir may also be . There are 369 drugs known to interact with PMC Remdesivir (Veklury) [package insert]. BSEP, bile acid export pump; COVID19, coronavirus disease 2019; CYP, cytochrome; EUA, Emergency Use Authorization; MRP4, multidrug resistanceassociated protein 4; NIH, National Institutes of Health; NTCP, Na+taurocholate cotransporting polypeptide; OATP, organic anion transporting polypeptide; Pgp, Pglycoprotein; RDV, remdesivir; SIDP, Society of Infectious Diseases Pharmacists. The global pandemic of severe acute respiratory syndrome coronavirus 2 (SARSCoV2) has resulted in a critical need to rapidly develop new pharmacologic interventions and disseminate information. Currently, no clinical drug-drug interaction studies of remdesivir have been conducted. Dhama K., Sharun K., Tiwari R., Dadar M., Malik Y.S., Singh K.P., Chaicumpa W. COVID-19, an emerging coronavirus infection: Advances and prospects in designing and developing vaccines, immunotherapeutics, and therapeutics. There is an urgent need for mechanistic experimental work on drug-drug interactions using rodent models, cell culture models, and human tissues. Online ahead of print. The role of combination antiviral therapy in the treatment of COVID-19 is not yet known. h/mL, respectively [26]. Topline results from the openlabel phase III SIMPLE trial showed that patients with severe COVID19 manifestations taking a 10day treatment course of remdesivir achieved similar improvement in clinical status compared with patients taking a 5day course of therapy (odds ratio 0.75; 95% confidence interval 0.511.12). official website and that any information you provide is encrypted Inclusion in an NLM database does not imply endorsement of, or agreement with, government site. Results: The main interactions between COVID-19 drugs and antipsychotics are the risk of QT-prolongation and TdP, and cytochromes P450 interactions. Patients should be monitored during the infusion and observed for at least 1 hour after the infusion as clinically appropriate. It binds to the viral RNA-dependent RNA polymerase and inhibits viral replication by terminating RNA transcription prematurely. Adverse events were similar in both studies, ranging from 6066% of patient receiving remdesivir (compared with 64% patients receiving placebo). 8600 Rockville Pike A Review on Remdesivir: A Broad-spectrum Antiviral Molecule for Possible COVID-19 Treatment. Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by Coronavirus-19 (COVI-19 or SARS-CoV-2): Anti-inflammatory strategies. Food and Drug Administration. Metabolism is mediated predominantly by hydrolases with 74% and 18% of remdesivir recovered in urine and feces. The case report outlined by Leegwater et al. Route of elimination. Likewise, drugs used to manage COVID-19 comorbidities such as cardiovascular diseases (e.g., telmisartan, carvedilol, diltiazem, nitrendipine, procainamide, quinidine) and hyperlipidemia (e.g., simvastatin, fenofibrate) can inhibit CES1 [62,63] and block the conversion of remdesivir to its intermediate and active metabolites. Comparison of cytochrome P450 (CYP) genes from the mouse and human genomes, including nomenclature recommendations for genes, pseudogenes and alternative-splice variants. Each 100-mg vial of remdesivir lyophilized powder contains 3 g of sulfobutylether beta-cyclodextrin sodium (SBECD), and each 100-mg/20-mL vial of remdesivir solution contains 6 g of SBECD.6 SBECD is a vehicle that is primarily eliminated through the kidneys. Nonetheless, the current knowledge of remdesivir ADME and PK shall allow the healthcare professionals to identify DDI and toxicity situations in a limited manner. Remdesivir has been granted approvals in several countries for use in adults and children hospitalized with severe coronavirus disease 2019 (COVID-19). 2023 May 8;24(5):2030-2041. doi: 10.1021/acs.biomac.2c01465. For the treatment of COVID19, remdesivir is given as a 200mg i.v. Published reports of remdesivir have shown mixed efficacy. Bookshelf As of April 30, 2020, the global pandemic of SARSCoV2 infections has resulted in >3.4 million cases of coronavirus disease 2019 (COVID19) and almost 240,000 deaths worldwide. COVID-19: a promising cure for the global panic. These drugs should not be coadministered. Profiles Drug Subst Excip Relat Methodol. & CYP3A4 is a critical enzyme that is responsible for about 70% of the drugs available in the clinic [37]. 2022 Dec;43(12):1041-1054. doi: 10.1016/j.tips.2022.09.005. -. The use of RDV with known inducers of Pgp (e.g., rifampin) is not recommended. It has been postulated that plasma concentrations of remdesivir increased due to the inhibition of P-gp by amiodarone [54]. Nebert D.W., Wikvall K., Miller W.L. 9 Because this is not an FDA-approved drug, fully-developed US package insert information is unfortunately not available. Our analyses of COVID-19 treatment guidelines from three different agencies such as the Infectious Diseases Society of America (ISDA), the World Health Organization (WHO), and the National Institutes of Health (NIH) suggest that a host of drugs are prescribed in combination during different stages of COVID-19 [4,13]. Remdesivir in patients with acute or chronic kidney disease and COVID-19. This is even more critical because of the ability of remdesivir to act as victim or perpetrator in drug interaction scenarios. As such, there are 57 isoforms of human CYP enzymes that are responsible for the biotransformation of endobiotic and xenobiotic substances including COVID-19 medications [36]. Mathematical drug-drug interaction liability predictions, based on in vitro and phase I data, suggest RDV has low potential for drug-drug interactions, as the impact of inducers or inhibitors on RDV disposition is minimized by the parenteral route of administration and extensive extraction. Thirty-four patients received the lyophilized powder formulation of remdesivir for a median duration of 10 days, while 25 patients received standard of care. -. Tchesnokov, E.P. The substrate profile of remdesivir with P-gp and OATP1B1 also offers reasonable possibility of mechanisms through which its plasma concentrations can be affected [18]. ; resources, S.D. 11 An official website of the United States government. U.S. Food and Drug Administration Fact Sheet for Health Care Providers Emergency Use Authorization (EUA) of Veklury (Remdesivir) for Pediatric Patients. [(accessed on 9 April 2021)]; Eastman R.T., Roth J.S., Brimacombe K.R., Simeonov A., Shen M., Patnaik S., Hall M.D. The journey of remdesivir: from Ebola to COVID-19. It is also an inhibitor of CYP3A4, OATP1B1, OATP1B3, and multidrug and toxin extrusion protein (MATE) 1.6 See Table 4e for more information. Would you like email updates of new search results? Since the inception of the pandemic, treatment options have been either limited or ineffective. The authors declare no conflict of interest. Last Updated: December 1, 2022 Remdesivir is a nucleotide prodrug of an adenosine analog. Then an older drug, remdesivir, emerged as an effective option. official website and that any information you provide is encrypted Prevalence of comorbidities and its effects in patients infected with SARS-CoV-2: A systematic review and meta-analysis. Yang J., Zheng Y., Gou X., Pu K., Chen Z., Guo Q., Ji R., Wang H., Wang Y., Zhou Y. Available at: Takashita E, Yamayoshi S, Simon V, et al. eCollection 2023 Mar. Federal government websites often end in .gov or .mil. Because COVID -19 is a RNA virus and remdesivir resembles an RNA subunit, incorporation of this drug into the viral RNA halts replication. Gilead Sciences. Although there was no evidence for CYP induction by either the intermediate metabolite, GS7042277, or the active nucleoside metabolite, GS441524, it is unclear if either of these metabolites are substrates or inhibitors of P450s or affected by transporters. Careers. Regulation of hepatic cytochrome P-450 during infectious disease. Using physiologically based pharmacokinetic modeling, RDV is not predicted to be a clinically significant inhibitor of drug-metabolizing enzymes or transporters in patients infected with COVID-19 at therapeutic RDV doses. There were also no statistically significant differences between the arms in the need for new dialysis, the need for new mechanical ventilation, or mortality. Official websites use .govA .gov website belongs to an official government organization in the United States. Drug Des Devel Ther. Tomaszewski, K. Since the start of the pandemic, information on potential therapeutic options have been rapidly disseminated on an almost daily basis, often with incomplete or conflicting results and without adequate peer review. The medications can be broadly classified into several groups including antivirals (e.g., remdesivir, lopinavir, ritonavir, umifenovir, favipiravir), antiprotozoal drugs (e.g., hydroxychloroquine, ivermectin), convalescent plasma, anti-bacterial agents (e.g., azithromycin), anti-inflammatory/immunosuppressants (e.g., corticosteroids, anakinra, interferon beta, monoclonal antibodies such as tocilizumab, cocktail to neutralize inflammatory proteins), and supportive agents (e.g., propofol, famotidine, benzodiazepine) [4,12,13,40]. Hospitalized patients should receive remdesivir for 5 days or until hospital discharge, whichever comes first.6 See Table 4e for more information. FOIA Disclaimer. The potential drug-drug interactions could complicate the treatment outcomes of COVID-19. Though CYP3A4 is reported to have about 10% contribution in the metabolism of remdesivir [65], depending on the relative status of non-CYP metabolizing enzyme activities, CYP3A4 may contribute to a higher extent. Subscribe to Drugs.com newsletters for the latest medication news, new drug approvals, alerts and updates. 2 disease interactions, and 1 alcohol/food interaction. The role of human carboxylesterases in drug metabolism: Have we overlooked their importance? To date, there are only limited in vitro transporter and enzymemediated drug interaction studies on remdesivir. sharing sensitive information, make sure youre on a federal Of the total drug interactions, 2 are major, and 367 are moderate. This will require further study to determine the full clinical impact of drugdrug interactions with remdesivir therapy. Over the past year and a half, the drug sold in the U.S. under the brand Veklury had been used in hospitals to treat very . In this narrative review, we have evaluated the currently available ADME, PK, and DDI information about remdesivir and have discussed the potential of DDIs between remdesivir and different COVID-19 drug regimens and agents used for comorbidities. This approach also assumes that increased remdesivir levels, and potentially increased levels of the active metabolite, GS441524, will not lead to increased toxicity, which may or may not be warranted given the short plasma halflife and safety profile of remdesivir and clinical studies are needed to validate this approach. 1. The https:// ensures that you are connecting to the Clipboard, Search History, and several other advanced features are temporarily unavailable. Front Pharmacol. 1 Bakheit AH, Darwish H, Darwish IA, Al-Ghusn AI. Remdesivir (3 mg to 225 mg) was given as an IV infusion for 2 h and generated a linear kinetics profile [23]. Simulation of Remdesivir Pharmacokinetics and Its Drug Interactions. The .gov means its official. Epub 2020 Jun 9. 1 Chemical structures of remdesivir (GS5734) and the nucleoside metabolite, GS441524. J Pharm Pharm Sci. , doi: 10.1111/cts.12840. Epub 2021 Sep 7. The brand name is Veklury. & However, the focus of the clinical analyses should be on drugs used to treat COVID . Remdesivir, a drug originally designed to be used for Ebola virus, has antiviral activity against SARS-CoV-2 and has been included in the COVID-19 treatment regimens. Understandably, while the focus of these investigations has centered on therapeutic efficacy, attention should also be paid to the clinical pharmacology and potential for drugdrug interactions, which is often lacking published data. ; writingreview and editing, S.D. SBECD has been shown to accumulate in moderate to severe renal dysfunction and, in preclinical studies, has resulted in renal vacuolation. This suggests that P-gp inducers (e.g., phenytoin, rifampin, St. Johns wort) and inhibitors (e.g., amiodarone, lopinavir, ritonavir) have the potential to affect the movement of victim remdesivir in the hepatic and other tissue compartments [52]. In-vitro, remdesivir is a substrate for various drug metabolising enzymes, e.g., CYP2C8, CYP2D6 and CYP3A4, and P- glycoprotein (P-gp) transporters and an inhibitor of various other enzymes, e.g. 2023 Feb 9;14:1053814. doi: 10.3389/fphar.2023.1053814. Differential effect of IFNalpha-2b on the cytochrome P450 enzyme system: A potential basis of IFN toxicity and its modulation by other drugs. Evaluation of sulfobutylether-beta-cyclodextrin (SBECD) accumulation and voriconazole pharmacokinetics in critically ill patients undergoing continuous renal replacement therapy. Brand name: Veklury Dosage forms: intravenous powder for injection (100 mg), intravenous solution (5 mg/mL) Drug class: Purine nucleosides Medically reviewed by Drugs.com on May 12, 2022. Publishers Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Kim K.-A., Park J.-Y., Lee J.-S., Lim S. Cytochrome P450 2C8 and CYP3A4/5 are involved in chloroquine metabolism in human liver microsomes. It binds to the viral RNA-dependent RNA polymerase and inhibits viral replication by terminating RNA transcription prematurely. and A.A.R. There is 1 alcohol/food interaction with remdesivir. Remdesivir is a nucleotide prodrug of an adenosine analog. Keywords: Grein J., Ohmagari N., Shin D., Diaz G., Asperges E., Castagna A., Feldt T., Green G., Green M.L., Lescure F.X., et al. Luke, D.R. Dis. Remdesivir, molnupiravir and nirmatrelvir remain active against SARS-CoV-2 Omicron and other variants of concern. An official website of the United States government. Kale A, Shelke V, Dagar N, Anders HJ, Gaikwad AB. Results showed high intracellular concentrations of GS-443902 suggestive of efficient conversion from RDV into the triphosphate form, and further supporting this clinical dosing regimen for the treatment of COVID-19. World Health Organization (WHO) R&D Blueprint and COVID-19. 2023 Mar 16;15(3):e36247. on days 210. Inside the cell, remdesivir undergoes metabolic activation to form the intracellular . [(accessed on 15 March 2021)]; Leegwater E., Strik A., Wilms E.B., Bosma L.B.E., Burger D.M., Ottens T.H., van Nieuwkoop C. Drug-induced liver injury in a COVID-19 patient: Potential interaction of remdesivir with P-glycoprotein inhibitors. [(accessed on 21 March 2021)]; Conti P., Ronconi G., Caraffa A., Gallenga C.E., Ross R., Frydas I., Kritas S.K. The clinical . In this light, the remdesivir has an interesting ADME profile that makes it a good candidate for DDI as victim as well as perpetrator (Table 2). Porter, D.P. Remdesivir is 74% eliminated in the urine and 18% eliminated in the feces. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. CYP, cytochrome P450,, MeSH being able to get an erection, but not having it last long enough for sex. Human cytochromes P450 in health and disease. This research received no external funding. [(accessed on 15 March 2021)]; Jean S.-S., Lee P.-I., Hsueh P.-R. This review discusses the pre-clinical pharmacology of RDV, clinical pharmacokinetics, pharmacodynamics/concentration-QT analysis, rationale for dose selection for treatment of patients with COVID-19, and drug-drug interaction potential based on available in vitro and clinical data in healthy volunteers. ; writingoriginal draft preparation, A.A.R., R.H., R.B. Remdesivir should be administered in a setting where severe hypersensitivity reactions, such as anaphylaxis, can be managed. Epub 2023 Feb 9. This has led to an urgency to develop new pharmacologic treatment options. 2020;13(5):896906. 2020;34:101623. doi: 10.1016/j.tmaid.2020.101623. Caution should be exercised when coadministered with other parenteral medications formulated in SBECD (e.g., voriconazole and amiodarone), particularly in patients with creatinine clearance <30mL/minute. Remdesivir is metabolized by both cytochrome P450 (CYP) and non-CYP enzymes such as carboxylesterases. being able to get an erection sometimes, but not every time you want to have sex. Based upon these data, the US Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) for use of remdesivir for the treatment of hospitalized patients with COVID19 on May 1, 2020. Schlamm, H.T. Nelson D.R., Zeldin D.C., Hoffman S.M.G., Maltais L.J., Wain H.M., Nebert D.W. 8600 Rockville Pike Potential drug-drug interactions involving remdesivir, either as victim or perpetrator. Department of Pharmaceutical Sciences, College of Pharmacy, Larkin University, Miami, FL 33169, USA; Received 2021 May 29; Accepted 2021 Jun 28. Pharmacokinetics of remdesivir have not been evaluated in patients with renal dysfunction. Following multiple doses of RDV 150 mg once daily for 7 or 14 days, major metabolite GS-441524 accumulates approximately 1.9-fold in plasma. World Health Organization (WHO) Coronavirus Disease (COVID-19) Pandemic. Patients who are severely immunocompromised may have a prolonged duration of SARS-CoV-2 replication, which may lead to rapid viral evolution. Please see Special Considerations in Children, Therapeutic Management of Nonhospitalized Children With COVID-19, and Therapeutic Management of Hospitalized Children With COVID-19. 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