1. Remdesivir (RDV)
Remdesivir (abbreviation: RDV) is a monophosphoramidate prodrug of an adenosine analog with potent activity against an array of single stranded RNA virus families including Filoviridae, Paramyxoviridae, Pneumoviridae, and Orthocoronavirinae (Brown 2019, Sheehan 2017), through the targeting of the viral RNA dependent RNA polymerase (RdRp) (Cho 2012, Agostini 2018). The drug was initially reported to have in vivo antiviral efficacy against Ebola virus in nonhuman primates (Warren 2016) and it was used during the Kivu Ebola epidemic. However, a randomized controlled trial showed that remdesivir was significantly less effective than the single monoclonal antibody mAb114, or the triple monoclonal antibody REGN-EB3 (Mulangu 2019).
The first Remdesivir COVID-19 studies showed mixed results. Findings of a compassionate use program (Grein 2020) have been judged inconclusive and are being interpreted with caution (Hoffmann 2020, xxx, xxx, xxx, xxx). Results of the first randomised, double-blind, placebo-controlled, multicenter trial reported that RDV use was not associated with a difference in time to clinical improvement (Wang Y 2020). Only patients who received the drug within the first 10 days after the appearance of symptoms seemed to have a faster time to clinical improvement; however, this was statistically not significant.
On 1 May 2020, the FDA granted RDV emergency use authorization for treatment of COVID-19. The drug will still need formal approval if the manufacturer provides additional data of the drug’s safety and effectiveness.
Although Remdesivir is far from being a Penicillin-like watershed in medicine, some studies indicate that SARS-2-CoV could be amenable to drug treatment. More potent drugs are urgently needed.
Brand Name: N/A ™
Drug Class: Nucleotide Analogs
Manufacturer: Gilead Sciences
N/A™ vials: 100 mg.
Remdesivir can be administered only by intravenous injection.
Dose used during trials: Loading dose of 200 mg IV on day 1, followed by 100 mg IV daily for 9 days (Wang Y 2020).
Side effects: Typical side effects include nausea and vomiting, elevated transaminases and infusion site reactions (Mehta 2020). Signs and symptoms of infusion‐related reactions may include low blood pressure, nausea, vomiting, sweating, and shivering (FDA 2020).
Interactions: RDV is not believed to affect other medications; however, some drugs may affect RDV and should probably not be coadministered: rifampicin, rifapentine, carbamazepine, phenobarbital, phenytoin, primidone, St John’s wort, may affect RDV. For more details, consult information provided by the Liverpool Drug Interactions Group at www.covid19-druginteractions.org.
Comments/Warnings: It is unknown whether RDV is safe during pregnancy and whether is passes into breast milk.
Internet sources: xxx
Agostini ML, Andres EL, Sims AC, et al. Coronavirus Susceptibility to the Antiviral Remdesivir (GS-5734) Is Mediated by the Viral Polymerase and the Proofreading Exoribonuclease. mBio. 2018 Mar 6;9(2). pii: mBio.00221-18. PubMed: https://pubmed.gov/29511076. Full-text: https://doi.org/10.1128/mBio.00221-18
Brown AJ, Won JJ, Graham RL, et al. Broad spectrum antiviral remdesivir inhibits human endemic and zoonotic deltacoronaviruses with a highly divergent RNA dependent RNA polymerase. Antiviral Res. 2019 Sep;169:104541. PubMed: https://pubmed.gov/31233808. Full-text: https://doi.org/10.1016/j.antiviral.2019.104541
Grein J, Ohmagari N, Shin D, et al. Compassionate Use of Remdesivir for Patients with Severe Covid-19. N Engl J Med. 2020 Apr 10. PubMed: https://pubmed.gov/32275812. Full-text: https://doi.org/10.1056/NEJMoa2007016
FDA. Frequently Asked Questions on the Emergency Use Authorization for Remdesivir for Certain Hospitalized COVID‐19 Patients”. U.S. Food and Drug Administration (FDA). 1 May 2020. https://www.fda.gov/media/137574/download. Retrieved 3 May 2020.
Mehta N, Mazer-Amirshahi M, Alkindi N, Ali Pourmand. Pharmacotherapy in COVID-19; A narrative review for emergency providers. Am J Emerg Med. 2020 Apr 15. pii: S0735-6757(20)30263-1. PubMed: https://pubmed.gov/32336586. Full-text: https://doi.org/10.1016/j.ajem.2020.04.035
Mulangu S, Dodd LE, Davey RT Jr, et al. A Randomized, Controlled Trial of Ebola Virus Disease Therapeutics. N Engl J Med. 2019 Dec 12;381(24):2293-2303. PubMed: https://pubmed.gov/31774950. Full-text: https://doi.org/10.1056/NEJMoa1910993
Sheahan TP, Sims AC, Graham RL, et al. Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses. Sci Transl Med. 2017 Jun 28;9(396). pii: 9/396/eaal3653. PubMed: https://pubmed.gov/28659436. Full-text: https://doi.org/10.1126/scitranslmed.aal3653
Warren TK, Jordan R, Lo MK, et al. Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys. Nature. 2016 Mar 17;531(7594):381-5. PubMed: https://pubmed.gov/26934220. Full-text: https://doi.org/10.1038/nature17180
Cho A, Saunders OL, Butler T, et al. Synthesis and antiviral activity of a series of 1´-substituted 4-aza-7,9-dideazaadenosine C-nucleosides. Bioorg Med Chem Lett. 2012 Apr 15;22(8):2705-7. PubMed: https://pubmed.gov/22446091. Full-text: https://doi.org/10.1016/j.bmcl.2012.02.105
Wang Y, Zhang D, Du G, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet, April 29, 2020. Full-text: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31022-9/fulltext
Lopinavir is an HIV protease inhibitors (PI) first approved in 2000. It is today out of fashion for HIV treatment because of side effects (diarrhea, dyslipidemia), interactions and inconvenient dosage (high number of pills). Today, better HIV regimes are available (Madruga 2007, Riddler 2008, De Meyer 2009).
To achieve appropriate plasma levels, lopinavir must be boosted with another PI called ritonavir (usually indicated by “/r”: lopinavir/r. As with all HIV PIs, one must be aware of drug-drug interactions. Ritonavir is a strong pharmacoenhancer and cannot be used with a variety of other drugs (see the contraindications below). For example, tacrolimus has to be reduced by 10-100 fold to maintain concentration within the therapeutical range (Bartiromo 2020).
For lopinavir/r, at least two case-control studies on SARS (Chan 2003, Chu 2004) and one prophylactic study on MERS (Park 2019) indicated a beneficial effect. When used 10 to 17 days after onset of COVID-19, a randomized open-lable trial in 199 adults hospitalized with severe illness did not find any clinical benefit beyond standard care (Cao 2020). There is one retrospective study on 280 cases in which early initiation of lopinavir/r and/or ribavirin showed some benefits (Wu 2020).
Lopinavir/r will continue to be tested in WHO’s huge SOLIDARITY trial. There is currently no reason to believe that the drug will have an important impact on the COVID-19 pandemic.
Brand Name: Kaletra™
Drug Class: Protease inhibitor
Manufacturer: AbbeVie. Generic drugs are available.
Kaletra® film-coated tablets with 200 mg lopinavir + 50 mg ritonavir.
Kaletra® film-coated tablets with 100 mg lopinavir + 25 mg ritonavir.
Kaletra® solution with 80 mg lopinavir + 20 mg ritonavir per ml.
Indications: HIV infection, adults and children over 2 years.
Dose: 1x 4 tablets (800 mg lopinavir / 200 mg ritonavir) regardless of meals.
Side effects: especially diarrhea, nausea, dyslipidemia. Abdominal pain, asthenia, headache, vomiting and, particularly in children, rash, are less frequent.
Note: The solution contains ethanol, it should be kept in the refrigerator.
Interactions: Drugs that are metabolised by CYP3A or CYP2D6 are contraindicated: Flecainide, propafenone, terfenadine, ergotamine, cisapride, midazolam, triazolam. Rifampicin and St. John’s wort reduce the effectiveness of lopinavir. Be careful with lovastatin, simvastatin (rhabdomyolysis), carbamazepine, phenobarbital, phenytoin or sildenafil (drop in blood pressure), amiodarone, marcumar, lidocaine, tricyclic antidepressants, quinidine, cyclosporin, tacrolimus. Measure serum levels in patients with impaired liver function, transaminase elevations. Sometimes, methadone dosage needs to be increased.
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