Drugs Shown to Inhibit SARS-CoV-2 in COVID-19 Disease: Comparative Basic and Clinical Pharmacology of Molnupiravir and Ivermectin

Abstract

The pharmacology of anti-SARS-CoV-2 drugs, Molnupiravir (M) and repurposed Ivermectin (IV) were compared. The IC50 for the inhibition of viral replication were 0.3μM for M and 2.8μM for IV. Both drugs have good oral absorption, with M achieving peak plasma concentrations by 2 hours and IV by 5 hours. The plasma half life were 7 hours for M and 81-91 hours for IV. M inhibits viral replication inducing viral mutagenesis in RdRp, causing viral error catastrophe and viral extinction. IV affects viral cell entry, nuclear transport and inhibits replication via RdRp. IV has additional effect to suppress cytokine production through STAT-3 inhibition. M is a more potent antiviral drug and IV has a longer residence in the body. Their effects on RdRp and cytokine inhibition are potentially complimentary for anti-COVID-19 activity. Both IV and M should be compared in randomized controlled clinical trials, and the possibility of their combination for anti-SARS-CoV-2 antiviral actions, explored further.

Keywords: COVID-19; Antiviral therapeutics; Molnupiravir; Ivermectin; Combination

Introduction

The COVID-19 pandemic caused by SARS-CoV-2, has affected more than 120 million people and resulted in nearly 3 million deaths worldwide. Although vaccine roll out is mitigating the community transmission and enabling a reopening of global economy piecemeal, there are still many nations where vaccines are not yet widely available, and new viral variants are emerging. There is a gradual shift in focus, to antiviral drugs, both for possible adjunctive chemoprophylaxis, as well as for active treatment of patients with new SARS-CoV-2 infections, or post -vaccination breakthrough COVID-19 cases. There have been purposive efforts, to develop novel and specific antiviral drugs for SARS-CoV-2, and to repurpose existing FDA -approved drugs to treat COVID-19. Molnupiravir is the most advanced of the novel antiviral drugs undergoing clinical development and trials, whilst Ivermectin is the most studied “repurposed” medication globally, in randomized clinical trials, retrospective studies and metaanalyses. This mini- review examines and compares their basic and clinical pharmacology and the possible utility of their combination, in treating COVID-19 and future corona virus diseases.

Molnupiravir and Ivermectin Anti-SARSCoV- 2 Mechanisms, Pharmacokinetics and Pharmacodynamics

Molnupiravir (EIDD2801/MK-4482) is a pro-drug of the novel active antiviral nucleoside analogue β-d-N4-hydroxycytidine (NHC, EIDD1931) [1]. It’s a broad spectrum antiviral agent against SARSCoV- 2, SARS-CoV,seasonal or pandemic influenza and MERS corona virus [1]. The basic and clinical pharmacological properties are shown on Table 1. Ivermectin is an FDA-approved, WHO essential drug used as broad spectrum antiparasitic, antibiotic and which has demonstrated broad spectrum antiviral activity against RNA viruses, including HIV, Zika, MERS corona virus. It is being repurposed as a therapeutic agent for COVID-19, after in vitro studies in Vero/hSLAM cells, showed that it caused a 5000-fold inhibition of SARS-CoV-2, (99.98% at 48 hours) with an IC50 of 2.8μM [2]. The corresponding in vitro IC₅₀ of molnupiravir for SARS-CoV-2 is 0.3μM in Vero cells and 0.08μM in Calu-3 Cells [3]. The IC₅₀ of Molnupiravir shows it to be a more potent anti-SARS-CoV-2 agent, compared to Ivermectin in vitro. Both molnupiravir and ivermectin are well absorbed after oral dosing, the Tmax of molnupiravir being 1-1.75 hours , with a half life of 7 hours, 1 whilst the Tmax of ivermectin is 4-6 hours, and a very long half life of 81-91 hours [4]. Ivermectin, being lipophilic has a large volume of distribution (V_d) and the ability to accumulate in the lungs [5], the major target organ of COVID-19. Molnupiravir is given twice daily, and doses of 400 and 800 mg showed viral clearance by RT-PCR [1]. By contrast, the dosing regimen of ivermectin in randomized clinical trials with RCT-PCR SARS-CoV-2 clearance, varied from 12mg daily [6], to 12mg twice a week [7]. The anti-SARS-CoV-2 actions, both of molnupiravir and ivermectin, are dose and concentration dependent [1,7]. Pharmacodynamically, the mechanisms of anti-SARS-CoV-2 action, both of molnupiravir and ivermectin are overlapping and complimentary (Table 1). Molnupiravir active metabolite (NHC-5’ Triphosphate), acts as a competitive alternative substrate for the viral RNA dependent RNA polymerase (RdRp), causing viral mutagenesis or transition mutations, which leads to viral error catastrophe and extinction of replication [8]. There is some concern about the safety of NHC -nucleoside triphosphate, which is also mutagenic to mammalian cells [9]. Ivermectin (Table 1) exhibits multifarious actions, ranging from binding to SARS-CoV-2 spike protein S, reducing cell entry via human ACE2 receptors, inhibition of the nuclear transport of viral proteins, which prevents interference with replication, to binding to RdRP, reducing the activity of the viral transcription -replication complex [10]. Ivermectin has additional effects on Signal Transduction Activation of Transcription (STAT-3) and inhibition of cytokine production and inflammation, which has not yet been shown for molnupiravir.

  

    

    
Molnupiravir
    
Ivermectin
  
  

    
Chemical structure/Name
    
RiboNucleoside analogue. Pro-drug of β-d-N4 Hydroxycytidine    (NHC), EIDD 2801
    
22,23 dihydroavermectin B1a + B1b (80:20) mixture
  
  

    
Pharmacokinetics

      Absorption and F

      Distribution (Vd)

      Metabolism

      Excretion routes

      T ½ (hours)

      Mean Residence Time (hours)

      Tmax (hours)
      
Daily doses
      
SARS-CoV2 IC50
    
 
      
Rapid
      
Prodrug > EIDD1931 (plasma esterases) >    active 5’ATP EIDD (tissue kinases).
      
7 hours
      
?
      
1-1.75 hours
      
2
      
0.3μM (Vero cells) 0.08μM (Calu cells)

        414.6 nM (Syrian Hamster)
    
 
      
Good

        9-12L/Kg

        Hepatic CYP3A4 mainly, 3A5, 2C9, 2D6

        Fecal >99%

        81-91 hours

        84 hours
      
5 hours

        1
      
 
      
2.5-2-8 μM (E, RdRP cell associated virus genes)

        Vero-h/SLAB
  
  

    
Pharmacodynamics

      Antiviral mechanisms
      

        
Cell    viral entry-hACE2 receptor.
      
      

        
Nuclear    transport -importin a/β1
      
      
 
      

        
RNA    dependent, RNA polymerase (RdRp)*
      
      
Viral mutagenesis
      
 
      
Dose/Concentration-anti SARS-CoV-2 response
    
 
      
?
      
?
      
 
      
Competitive alternative substrate for SARS-CoV-2    RdRP viral genome >excessive mutations > viral error catastrophe >    viral extinction.
      
Yes
      
 
      
Dose -Dependent Viral RNA clearance in human    phase 2A study.
    
 
      
Binds to active sites of spike protein S.    Inhibits human cell entrance of virus via h-ACE2.
      
Binds Importin a to prevent link with β1 and    nuclear transport of viral and host proteins.
      
Binds to and inhibits viral RdRp replication and    transcription complex with -9.7Kcal/mol energy
      
 
      
No
      
 
      
Significant dose and concentration dependent    virucidal response seen in humans.
  
  

    
Effects on Cytokines & interleukins (IL)
    
?
    
Inhibits Janus Kinase (JAK) Signal transduction    Activator of Transcription (STAT-3) and IL-6/10
  
  

    
Clinical Trials and Real World Efficacy

      RT-PCR Cases
    
Phase 2A shows dose dependent high anti-SARS-CoV-2    efficacy in COVID-19.
    
Mixed outcomes. Meta-analyses show clinical and    laboratory benefits and mortality reduction.
  
  

    
Adverse effects and Drug-Drug Interactions
    
No Serious Adverse effects compared to placebo.
    
No Serious Adverse Effects. Dizziness
  

Table 1: Comparison of Anti-SARS-CoV-2 pharmacology of Molnupiravir and Ivermectin.