key: cord-0799555-wyrbmbjn
authors: Ali, Ahmed S; Ibrahim, Ibrahim M; Burzangi, Abdulhadi S; Ghoneim, Ragia H.; Aljohani, Hanin S; Alsamhan, Hamoud A; Barakat, Jehan
title: Scoping Insight on Antiviral Drugs Against COVID-19
date: 2021-08-16
journal: Arabian journal of chemistry
DOI: 10.1016/j.arabjc.2021.103385
sha: 9bcd4e8bef90e1157811d69bb7fd7a15e7df84fa
doc_id: 799555
cord_uid: wyrbmbjn

Background COVID-19 is an ongoing viral pandemic produced by SARS-CoV-2. In light of in vitro efficacy, several medications were repurposed for its management. During clinical use, many of these medications produced inconsistent results or had varying limitations. Objective The purpose of this literature review is to explain the variable efficacy or limitations of Lopinavir/Ritonavir, Remdesivir, Hydroxychloroquine, and Favipiravir in clinical settings. Method A study of the literature on the pharmacodynamics (PD), pharmacokinetics (PK), safety profile, and clinical trials through academic databases using relevant search terms. Results & Discussion The efficacy of an antiviral drug against COVID-19 is associated with its ability to achieve therapeutic concentration in the lung and intestinal tissues. This efficacy depends on the PK properties, particularly protein binding, volume of distribution, and half-life. The PK and PD of the model drugs need to be integrated to predict their limitations. Conclusion Current antiviral drugs have varying pharmacological constraints that may associate with limited efficacy, especially in severe COVID-19 patients, or safety concerns. Disclaimer What was mentioned in this paper is a scientific view and information relating to general principles which should not be construed as specific instructions to change or criticize any protocols. But rather an academic discussion to push further research and development of these drugs for better achievements.

Coronavirus disease 2019 (COVID-19) is a global pandemic caused by a highly infectious respiratory virus, SARS-CoV-2. It resulted in significant human and economic losses. About 181 million cases had been confirmed as of June 29, 2021, and 3.92 million verified deaths [1] [2] [3] [4] . Drug repurposing is the process of providing new uses for currently approved drugs. Some repurposed FDA-approved drugs were subjected to in vitro testing and showed promising results against SARS-CoV-2 [5, 6] . However, clinical trials of most antiviral drugs demonstrated inconsistent results or limitations [7, 8] . Limited publications were concerned with integrating pharmacokinetics/pharmacodynamics (PK/PD) parameters to predict their efficacy in clinical settings [9, 10] . For an antiviral drug to be effective in treating COVID-19, it must achieve sufficient concentrations that suppress viral replication in multiple sites, primarily the cells of the upper and lower respiratory tract [11] . Wang; et al. suggested antiviral drugs, which showed activity against the virus in vitro and have high lung distributions, might benefit COVID-19

patients by reducing viral load (Table 1) . The low concentration of unbound lopinavir (LPV) in the lung tissues limits its efficacy in COVID-19 patients [12] . The present review aims to provide a deeper understanding of the reasons behind variable efficacy or limitations of some antiviral drugs through the integration of their PK/PD and safety profiles. Four drugs were selected: Remdesivir (RDV), Lopinavir/ritonavir (LPV/r), Hydroxychloroquine (HCQ), and Favipiravir (FPV).

RDV (Veklury) is a broad-spectrum antiviral drug RNA polymerase inhibitor (Fig 1) . It was initially developed in the United States to treat hepatitis C, but it was directed toward Ebola viral infection treatment. It is currently the first FDA approved antiviral drug against COVID- 19 . Only intravenous injection formulation is available, which needs patients to be hospitalized for administration. It is a prodrug that is expected to enable better intracellular delivery of an adenosine analog (GS-441524) monophosphate, which is then biotransformed into the active triphosphate intracellular metabolite (GS-443902) (Fig 2) [14] [15] [16] . 

RDV is an adenosine analog prodrug; within the cells, it is transformed into its active triphosphate metabolite that competes endogenous adenosine triphosphate to inhibit SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) ultimately inhibiting viral replication [17] .

Studies in VeroE6 cells demonstrated selectivity and high potency against SARS-CoV-2 demonstrated by its IC 50 of 0.77 µM and an IC 90 of 1.760 µM [18] . However, a higher IC 50 value of 23.15 µM was reported [19] .

In monkeys, RDV demonstrated widespread tissue distribution and transformation into the final active metabolite (GS-443902) in both peripheral blood mononuclear cells and respiratory tissues [20] . Animal PK studies revealed that renal and biliary excretion were the primary routes of elimination [21] . PK parameters of RDV and its major metabolite in humans are summarized in Tabel.2 [17, [22] [23] [24] . RDV should be given by slow IV infusion, over 60 min. At the end of the infusion, peak concentration of RDV in the blood was reached; however, disappeared after 1 hr. due to its rapid metabolism and distribution [26] . RDV has a high ability to bind to plasma proteins (88-93.6% bound). In contrast, the plasm protein binding of GS-441524 is as low as 2%. RDV is extensively metabolized in the liver and blood. The nucleoside metabolite GS-441524 is mainly excreted in the urine and most of the dose recovered in urine was as GS-441524 (48.6%) and about 10% of the RDV dose was recovered in the urine unchanged.

The intracellular activation of RDV was assumed to involve several steps that end up by forming the final active nucleoside triphosphate (GS-443902) (Fig 2) .

In vivo bioactivation pathway of RDV [27] In the presence of serum enzymes, the phosphate prodrugs are hydrolyzed prematurely to the nucleoside. GS-441524, which after access to the cells activated to the triphosphate. Other pathway (not shown) involves access of RDV into the cells, its metabolism to GS-441524 monophosphate, then to GS-441524 triphosphate.

The following data (Fig 3) were based on RDV PK study in two severe COVID-19 patients, one of them has moderate renal dysfunction. On the first day, RDV was given as 200 mg loading dose then 100 mg daily. On days 3 through 9, blood samples were taken (after the end of IV infusion) immediately (C 0 ), 1hr. (C 1 ), and 24 hr. (C 24 ). RDV serum concentration reached a peak (C 0 ), then began to decline to almost undetectable after 1 hr. In contrast, the plasma concentrations of the metabolite GS-441524 peaked at C 1 and remained measurable until the next dose. (Left RDV, Right GS-441524. Patient 1: with renal impairment. Patient 2: normal renal function. Data are shown as mean ± SD; at 3-9 days after RDV initiation from [28] .

Some early reports and meta-analyses suggested that RDV is not sufficient on its own for the management of COVID-19 in hospitalized patients [29] [30] [31] . Later several meta-analyses suggested favorable benefit-risk profiles for RDV compared with placebo effects [32] [33] [34] [35] [36] [37] . A recent metaanalysis concluded that RDV attenuates disease progression, leading to lower odds of MV/ECMO and greater odds of hospital discharge for COVID-19 patients. However, RDV does not affect the odds of mortality [38] .

On the other hand, the WHO Solidarity Trial, which included 11,330 in-patients with COVID-19 who were randomized to receive HCQ (n=954), LPV (n=1411), RDV (n=2750), interferon regimens (n=2063), or none of these drugs (n=4088), found that all these investigated drugs had little to no effect on overall mortality [39] . However, RDV becomes the 1 st FDA approved drug for the management of COVID-19 [40] .

Many adverse effects were reported for RDV during COVID-19 clinical trials, severe bradycardia being of particular concern, which is consistent with RDV's PD properties, [41], changes in ECG, anaphylaxis, infusion-related reactions, nephrotoxicity, and hepatic toxicity [42] .

The oral bioavailability of GS-441524 in beagle dogs was investigated, and it was discovered that plasma concentrations up to 24-fold greater than the EC 50 against SARS-CoV-2 could be maintained readily and safely. These findings support the development of GS-441524 as an oral COVID-19 treatment [43] . Furthermore, GS-441524 effectively inhibited SARS-CoV-2 infection in mouse models [44] .

RDV (EC 50 = 0.47-1.09 M), according to cell-based research [45] .

Moreover, there is evidence of fast metabolism of RDV in the blood into the parent molecule, nucleoside analog GS-441524. Moreover, the enzymes required for RDV metabolism and activation were more expressed in liver and kidney cells than in type ll pneumocytes in the lungs.

Given these emerging data, it seemed logical to speculate that the anti-COVID-19 effect of RDV in vivo is mainly mediated through its parent compound GS-441524. Yan and Muller concluded that GS-441524 is thought to be superior to RDV in the management of COVID-19.

In addition, GS-441524 has a simplified synthesis method, easier to formulate as IV or inhalation [27] . Moreover, RDV solution contains 6% sulfobutylated beta-cyclodextrin, which is likely to accumulate in patients with severe renal impairment [17] .

LPV is an antiretroviral protease inhibitor (Fig 4) indicated for the treatment of HIV-1 infection and has been repurposed to manage COVID-19. It is available as a fixed combination with ritonavir, a potent inhibitor of cytochrome P450-3A4, which allows LPV to be effective orally [46, 47] .

LPV has been found to inhibits SARS-CoV-2 replication by binding to viral main protease 3C-like protease (3CLpro) with an EC 50 of 16.7 µg/ml; however, other values have been reported [48] .

When administered alone, LPV has a low oral bioavailability of 25%; therefore, it is only given in combination with ritonavir, which increases its bioavailability by slowing its metabolism allowing therapeutic LPV concentrations to be obtained. After oral dosing, the maximal plasma LPV is 98% bound to plasma proteins. Both alpha-1-acid glycoprotein and albumin are involved. LPV is mainly metabolized by hepatic CYP3A isozymes. Biotransformation is reduced and plasma levels of the active antiviral drug are enhanced when concomitantly taken with ritonavir, a potent inhibitor of CYP3A enzymes [49] .

A meta-analysis concluded no significant advantage of LPV/r in alleviating symptoms of COVID-19 [50] . Moreover, the WHO published results from the Solidarity Trial showed that LPV was not significantly different from control in reducing mortality or hospitalization. 

At a dose of LPV/r 400 /100 mg twice orally, the steady-state peak (4 hr. post-dose) and

trough (before next dose) LPV concentration was about 18 μg/mL. Recall that its free level (unbound) was only about 1% (protein binding > 98%). Thus, the therapeutic free drug level (active form) is not achievable (Fig 5) . Another critical limitation is that ritonavir, a potent inhibitor of cytochrome P450-3A4 is given in combination with LPV; therefore, a long list of interactions with other medications must be considered in COVID-19 patients [52] . 

FPV (T-705) is a modified pyrazine analogue (Fig 4) . It is a broad-spectrum antiviral RdRp inhibitor. It was developed in Japan and approved by the Pharmaceuticals and Medical Devices Agency (PMDA) to treat influenza. Also, it has been included in COVID-19 treatment guidelines in many countries [54, 55] .

FPV is a modified nucleoside analog that targets RdRp enzymes. It is a prodrug that undergoes intracellular activation to favipiravir-ribofuranosyl-5'-triphosphate (T-705-RTP) that binds to and inhibits RdRp, consequently inhibiting viral transcription and replication [56] . Wang, et al.

reported low potency against SARS-CoV-2 (EC 50 61.88 µM) [57] . However, other in vitro studies showed different EC 50 values.

The drug is administered orally with a bioavailability of about 97%. FPV has non-linear PK demonstrated as a decrease in drug concentration after chronic administration. This may be explained by the auto-induction of certain CYP450 enzymes responsible for its metabolism [58] .

Moreover, there is an ethnic variation in FPV's disposition [59, 60] .

FPV accelerates viral clearance by seven days and contributes to clinical improvement in about fourteen days. Particularly in patients with mild to moderate disease [61] [62] [63] . FVP treatment results in considerable clinical and radiological improvements compared to standard care, with no significant differences in viral clearance, need for oxygen, or side effect profiles. A study reported favorable outcomes when compared with umifenovir or LPV/r [64] . A randomized controlled trial in non-severe COVID-19 patients demonstrated that on day 7, FPV provided a better clinical recovery rate and was more effective than umifenovir in alleviating fever and cough.

FPV is still under evaluation. Its PK/PD profile suggests potential effectiveness, at least, in mild and moderate cases of COVID-19. However, a PK study in critically ill COVID-19 patients who received the recommended dose of FPV demonstrated a low trough level (1 µg/mL) [65] .

Recall low potency against SARS-CoV-2 with EC 50 61.88 µM [57] . The lung-to-tissue level of FPV was estimated to be about 50% of that in the blood. These PK data suggest moderate drug access to lung tissues [66] . The drug did not show life-threatening adverse effects in clinical trials, but it has some adverse effects including a rise in serum uric acid, liver enzymes, diarrhea, nausea, vomiting, and tachycardia [64] . FPV may be teratogenic and has a long list of potential drug-drug interactions [Drug67].

HCQ is a 4-aminoquinoline derivative of chloroquine (CQ) (Fig 4) [68] . It is a low-cost drug that has been used to prevent and treat malaria and manage rheumatoid arthritis, lupus, and porphyria, among other conditions. [69] [70] [71] . It is usually taken orally as HCQ sulfate. The drug received extensive interest and debate due to its potential activity against COVID-19 [72] . Many

African countries have already approved the use of HCQ or CQ to treat COVID-19 at the national level [73] .

In vitro studies showed that HCQ is more potent than CQ against SARS-CoV-2 (EC 50 of 0.72 μM for HCQ and 5.47 μM for CQ). As a result, HCQ was one of the earliest drugs to be tested against COVID-19. Regardless of the antiviral activity, HCQ has immunomodulatory effects [74, 75] , which provided the basis of their utility to prevent cytokine release syndrome (CRS) [76] .

Interestingly, HCQ has been suggested as a valuable drug for prophylaxis against lung thrombosis [77] .

Absorption of HCQ after oral administration is good but extensively variable (~70%;

range: 25 to 100%). HCQ is considered a lysosomotropic drug that accumulates intracellularly at concentrations up to 1000-fold higher than the extracellular concentration. The rise in endosomal pH mediated by HCQ blocks virus/cell fusion. The elevated Golgi apparatus pH impairs the terminal glycosylation of the angiotensin-converting enzyme 2 (ACE2) receptor and reduces its binding affinities to SARS-CoV-2 spike protein [78, 79] . This accumulation in lysosomes is likely to explain the considerable very high volume of distribution of HCQ (Vd = 70 L/kg). The lung/plasma ratio of HCQ was suggested to be high, at least 50. HCQ has a long elimination halflife of about 40 to 50 days. These PK/PD characteristics explain the potential efficacy of HCQ against the novel virus [80, 81] . HCQ is metabolized in the liver through CYP 2C3, 2D6, 2C8, 3A4, and 3A5 into active and inactive metabolites. Therefore, the genetic polymorphism of these enzymes would affect its blood level. About 20% of HCQ dose is excreted in urine as unchanged drugs; hence renal function is likely to affect its clearance [82] . HCQ has a narrow therapeutic range and moderate protein binding (about 50%), primarily with albumin [83] . According to a systemic review, HCQ was found beneficial in hospitalized COVID-19 patients when given early in the outpatient setting. HCQ is consistently effective against COVID-19, has not caused disease deterioration, and is well tolerated [91] In contrast, the WHO published the Solidarity Trial results showing that HCQ was not significantly different from control in reducing mortality or hospitalization [92] . This was in line with RECOVERY trial that concluded: "there is no benefit of using HCQ in COVID-19 patients" [93] .

An in vitro study suggested that HCQ suppresses trained immunity, which is may be counterproductive to the antiviral innate immune response to SARS-CoV-2 [94] . Lung acidosis that can be induced by severe COVID-19 is likely to reduce access of the weakly basic drug to lung tissues [95] . Hence, HCQ has marked reduction in cellular uptake in severely ill patients [96] . Consequently, Ali et al. suggested that HCQ is not likely to provide a potent antiviral effect in severe cases of COVID-19. If indicated, it should be given as early as possible to optimize its use [97] . Another limitation of HCQ is potential QT prolongation and ventricular arrhythmia. Unfortunately, there has been no dose-response relationship study to accurately predict the association of HCQ drug level with cardiac toxicities [93, 98, 99] . Moreover, the drug showed extreme variability in drug levels in COVID-19 patients, as shown in figure 6 . 

To ensure optimal use of medications in management of a disease; the integration of their PK/PD and side effects should be extended to include other variables such as genetic, chronic diseases, drug interactions, immunological status etc. A complex disease-drug-drug interaction is expected in severe COVID-19 [101] . Pathophysiological changes induced by severe COVID-19 include, hyperinflammation, severe hypoxia, acute respiratory distress syndrome (ARDS), encephalopathy, myocardial injury, heart failure, coagulation dysfunction and acute kidney injury [102] are likely to affect drug transporters, and its PK [103] . For example, COVID-19 induced hypoxia and inflammation can reduce the intracellular transport of RDV main metabolite GS-441524 and its activation to GS-441524 monophosphate [104] .

COVID-19 associated complications also predispose the patients for drug induced toxicities [105] . For example, hypokalemia predisposes the patient to tachyarrhythmias, the cytokine storm is also known to prolong QT intervals [106] . This may explain the higher incidence of cardiac toxicity of antiviral drugs such as HCQ.

Pharmacotherapy of COVID-19 in patients with pre-existing comorbidities, especially elderly, is highly challenging due to the use of multiple medications with great potential for drugdrug interactions [107] [108] [109] [110] . The PK properties (e.g., induction or inhibition of cytochrome P450 (CYP) isoenzymes, competition in renal elimination) as well as the PD properties (e.g., QT prolongation) are largely responsible for such drug-drug interactions. In addition to these interactions, COVID-19 patients have a significant pathophysiological changes, which can alter the PK of the medications (e.g., downregulation of CYP isoenzymes, organ failure, modification of plasma protein binding) [111, 112] .

Dosing of drugs used to treat COVID-19 in patients with renal or hepatic impairment requires great attention. Fortunately guidelines for dose adjustment and precautions are available in the drug monograph and some publications [113] . For example, RDV should only be used in adults and children with an eGFR of less than 30 mL/min if the possible benefit justifies the potential danger [114] .

Based on the genetics of COVID-19 patients, pharmacogenetics could explain the interindividual variability in medication response. Variants in genes encoding drug-metabolizing enzymes, transporters, or receptors have been identified, and they may provide the information needed to develop a tailored therapy that optimize the use of pharmacotherapy for COVID-19 [115] [116] [117] .

Using a nebulizer with an inhaled nanoparticle formulation to deliver medications directly to the primary site of infection may allow for more targeted and accessible delivery in hospitalized and non-hospitalized patients, as well as potentially decrease systemic exposure to the drug.

Inhaled nanoformulations of RDV is under development [118] [119] [120] . Inhaled HCQ is also under investigation and showing promising results [121] [122] [123] [124] . To our knowledge, no other medications have been studied for inhalable formulation. Table 4 

In vivo bioactivation pathway of RDV [27] In the presence of serum enzymes, the phosphate prodrugs are hydrolyzed prematurely to the nucleoside. GS-441524, which after access to the cells activated to the triphosphate. Other pathway (not shown) involves, access of RDV into the cells, its metabolism to GS-441524 monophosphate, then to GS-441524 triphosphate. After thorough revision of the manuscript, the authors modified the abstract and the conclusion, accordingly; added some new information; and added some figures for better illustration of the content. All changes are highlighted (yellow) in the revised text. Here is a point-by-point response to the reviewers' comments and concerns.

Comment 1: There are a lot of punctuation mistakes in the manuscript. For example, the semicolon must be used between remdesivir and lopinavir in Keywords part. And the full stop should not use in the manuscript title. "and Methods" in Abstract part must be written as bold. These mistakes should be corrected.

Response: Thanks for pointing these out. I have revised and corrected all spelling and grammatical errors pointed out by the reviewer. Response: We revised the manuscript and made the necessary changes. Fig. 4, Fig. 4 and subtitle were written different font.

Response: Thanks for pointing this out. We revisited all the figures and addressed the reviewer's comments and concerns. We the undersigned declare that this manuscript is original, has not been published before and isnot currently being considered for publication elsewhere.

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Effects of chloroquine on viral infections: an old drug against today's diseases. The Lancet infectious diseases

Subheadings in the manuscript must be written bold such as "Mechanism of Action

Response: Thanks for your comment. We revised the subheadings in the manuscript and made sure they are written bold

In Safety Concern part, why is "anaphylaxis and infusion-related reactions" written in italics, I could not understand

Response: Thanks for pointing this out. Probably it was done by mistake

Comment 10: In Abstract part and in the title of the manuscript, it was written that one of the drugs to be mentioned is lopinavir. However, lopinavir/ritonavir combination was discussed in the manuscript. Similarly, it was written that hydroxychloroquine was one of the drugs to be considered. However, it was given information about hydroxychloroquine and chloroquine in the manuscript so there is incompatibility, and the title of this manuscript is not consistent with the manuscript content

Comment 11: I could not understand that some words were underlined (on page 11 line 45, 49, 52, 53), and some words were written as bold

Probably this was done to highlight some points during revision. We revised the manuscript and corrected the formatting. Comment 12: References should be written for Fig

There are no volume, issue, and page numbers in some references for example

We explored the issue and added missing volume, issue, and page numbers. However, for #40, StatPearls is an online library that publishes peer-reviewed PubMed indexed articles; for #42 and #44, the articles were published in an online library as well. Comment 14: Sometimes long names of journal were written, sometimes abbreviations for journal names were used

Sometimes the first letter of journal name was written as capital, sometimes it was written as lowercase

Similarly, sometimes the first letter of article names was written as capital, sometimes it was written as lowercase. The correction is needed here

We revised the references and made the corrections and changes as per the reviewer's comments. -Journal names are consistently in long form

Comment 18: It has been found that reference 37 and 38 are the same. Response: Thanks for your comment. We checked the references and duplicates are removed. Comment 19: Reference 59 was not written clearly and suitably, and this reference contains wrong words such as

Response: Thanks for pointing this out. The reference (now #67) has been revised and fixed as per the reviewer's comment

We look forward to hearing from you in due time regarding our submission and to respond to any further questions and comments you may have

Non of the authors has a conflict of interest Journal : Arabian J of Chemistry Manuscript : Scoping Insight On Four Antiviral Drugs Against COVID-19 Given Their Pharmacological Profile

The authors acknowledge Miss Asmaa A. Ali, 6th year medical students at Ibn Sina National college for medical studies for designing the figures of this manuscript.Hydroxychloroquine [127] We confirm that the manuscript has been read and approved by all named authors and that thereare no other persons who satisfied the criteria for authorship but are not listed. We further confirm that the order of authors listed in the manuscript has been approved by all of us.We understand that the Corresponding Author is the sole contact for the Editorial process. He/she is responsible for communicating with the other authors about progress, submissions ofrevisions and final approval of proofs

Signed by all authors as follows: Ahmed S. Ali Date 26/ 5/ 2021 Ibrahim M Ibrahim 26-5-2021