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SARS-CoV-2 and COVID-19
Published in Patricia G. Melloy, Viruses and Society, 2023
In addition to monoclonal antibody therapy, antiviral drugs specific to SARS-CoV-2 are starting to be developed. In late 2021, successful clinical trials were completed on two antiviral drugs given in the form of a pill to fight SARS-CoV-2: Molnupiravir and Paxlovid. Molnupiravir works by causing errors in the viral genome during replication, and Paxlovid works by interfering with the maturing of certain viral proteins to stop SARS-CoV-2 (Jayk Bernal et al. 2021; Gordon et al. 2021; Mahase 2021; Ledford 2021).
Infectious Disease
Published in John S. Axford, Chris A. O'Callaghan, Medicine for Finals and Beyond, 2023
Susanna J. Dunachie, Hanif Esmail, Ruth Corrigan, Maria Dudareva
The mainstay of management is supportive care with oxygen if required to maintain saturations above 92%, and monitoring of end-organ function.Clinical trials continue to reveal beneficial adjuvant therapies for COVID-19, including dexamethasone, antivirals (remdesevir, molnupiravir and Paxlovid), IL-6 blockade (toclizumab) and monoclonal antibodies (Ronapreve and Sotrovimab). Local up-to-date management guidelines should be consulted.
From the Wuhan-Hu-1 strain to the XD and XE variants: is targeting the SARS-CoV-2 spike protein still a pharmaceutically relevant option against COVID-19?
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Matteo Pavan, Davide Bassani, Mattia Sturlese, Stefano Moro
In the face of this increasingly troublesome variant landscape, characterised by a progressive reduction of the efficacy of existing therapeutic options against COVID-19, a light at the end of the tunnel is possibly represented by the development and release on the market of Paxlovid. This therapeutic combination between the active principle Nirmatrelvir (also known as PF-07321332) and the pharmacokinetic enhancer Ritonavir, represents the first orally available drug specifically designed against SARS-CoV-2 virus43. Instead of targeting the Spike protein, this peptidomimetic entity is designed to inhibit the SARS-CoV-2 Main Protease (Mpro) by covalently binding to Cysteine 145, one of the two components of the protease’s catalytic diad44. Clinical studies showed a remarkable therapeutic efficacy of this novel treatment, with Paxlovid being able to lower by 89% the risk of severe complications associated with COVID-19 infection in symptomatic, non-vaccinated, and non-hospitalized adult patients45.
Efficacy and safety of three new oral antiviral treatment (molnupiravir, fluvoxamine and Paxlovid) for COVID-19：a meta-analysis
Published in Annals of Medicine, 2022
Wen Wen, Chen Chen, Jiake Tang, Chunyi Wang, Mengyun Zhou, Yongran Cheng, Xiang Zhou, Qi Wu, Xingwei Zhang, Zhanhui Feng, Mingwei Wang, Qin Mao
The potential mechanism of fluvoxamine for the treatment of COVID-19 is still uncertain; some hypotheses have been proposed. A study reported that fluvoxamine exhibited the strongest activity among all SSRIs with low nanomolar affinity on sigma-1 receptor (S1R), which may reduce the excessive inflammatory state induced by novel coronavirus by regulating S1R [26]. In addition, S1R has other antiviral effects, including reducing platelet aggregation, reducing mast cell degeneration, interfering with endolysosomal virus transport, regulating myositol requiring enzyme 1α driven inflammation and increasing melatonin levels [26], which may be important mechanisms influencing COVID-19 treatment. In addition, Paxlovid is an oral antiviral drug candidate for SARS-CoV-2 protease inhibitors, recently released by Pfizer [20]. Paxlovid is a combination of PF-07321332 and Ritonavir. Paxlovid does not work as well if it is taken on its own. The body’s defence mechanisms will remove anything that it does not recognize, including drugs, which can be digested by the liver enzymes [27]. Among them, Paxlovid is designed to block the activity of SARS-COV-2-3Cl protease, which is needed for the coronavirus to replicate [20]. Use of Paxlovid in combination with a low dose of ritonavir helps slow down the metabolism or breakdown of PF-07321332 so that it remains active in the body for longer at higher concentrations and helps in fighting the virus [20]. Paxlovid™ has been designed with the novel coronavirus-specific protease in mind and is therefore more specific to this coronavirus than molnupiravir [27]. Data obtained from a larger cohort of 1881 patients in EPIC-HR showed that treatment-emergent adverse events were comparable between Paxlovid (19%) and placebo (21%), and most of them were mild in intensity [28].
Monoclonal antibodies for the treatment of COVID-19 infection in children
Published in Expert Review of Anti-infective Therapy, 2022
Small molecule antivirals are more likely than mAbs to have medication interactions and unintentional side effects due to off target binding and drug elimination. For example, Paxlovid is a strong CYP3A inhibitor, and is contraindicated for people taking medications that are either cleared by CYP3A, or strong CYP3A inducers that could reduce the plasma concentrations of Paxlovid [41,42]. If Paxlovid is being considered for use in high-risk pediatric populations, drug interactions for Paxlovid become an important consideration.