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Nirmatrelvir, filed under the brand name Paxlovid, is part of Pfizer’s new Covid-19 pill combo. The other part is a “repurposed” old HIV (AIDS) drug, Ritonavir, known to have serious side-effects, such as irregular heartbeat, diabetes, liver failure, and more. As with so many drugs, the side-effects appear as bad, or worse, than the disease. They even sound similar to the disease.

“Pfizer says it’s ready to start delivery of the drug immediately in the U.S. and will produce 120 million courses in 2022. The U.S. government has a contract with the company for 10 million courses priced at $530 per course. The drug will be sold under the name Paxlovid and will have to be taken every 12 hours for five days once COVID-19 symptoms appear. Potential users of the new drug will have to show a positive virus test.” https://www.voanews.com/a/fda-gives-emergency-authorization-to-pfizer-covid-pill/6365311.html Will governments lay off of the forced vaccinations now, since this is clearly more lucrative for Pfizer? And, Pfizer-BioNTech batches appear to expire in February, though the US and Canada extended use by several months. Who owns the Ritonavir patent? Does this extend it in some way?

While it is claimed that Pfizer’s Covid pill is for high risk individuals, their clinical trials appear to have excluded some types of high risk individuals. Furthermore, it includes ritonavir, which is known to cause irregular heartbeat, among other serious problems.

When Pfizer initiated clinical trials of this drug, it was for IV use (NCT04535167) and they had the following clinical trial Exclusions: “known medical history of ischemic heart disease, heart failure, dysrhythmia or other pre-existing cardiac condition… recurrent seizures, history of venous thromboembolic event, including deep venous thrombosis or pulmonary embolism, pre-existing moderate to severe cardiovascular disease, uncontrolled diabetes, or severe asthma or severe COPD…. recent acute or chronic liver disease (other than NASH), chronic or active hepatitis B or C infection, or primary biliary cirrhosis.
.. HIV infection, acute or chronic history of hepatitis B or C…cancer, unless in remission and untreated…Other medical or psychiatric condition including recent or active suicidal ideation/behavior or laboratory abnormality that may increase the risk of study participation…Females who are pregnant or breastfeeding…”.

Is the pill form that different? Or are most of these contraindications placed under this new description? “History of hypersensitivity or other contraindication to any of the components of the study intervention”. The pill clinical trial also excluded: “active liver disease, Receiving dialysis or have known moderate to severe renal impairment, Known human immunodeficiency virus (HIV) infection with a viral load greater than 400 copies/mL or taking prohibited medications for HIV treatment… Females who are pregnant or breastfeeding”

While it’s not totally clear to us, it appears that the IV form didn’t include the apparently highly toxic Ritonavir, suggesting the drug may be very bad even without Ritonavir:
IV Form: PF-07304814 vs Oral Form: PF-07321332/Ritonavir: “Pfizer also leveraged previous work on SARS-CoV-1, making the most of an antiviral called PF-00835231. This antiviral is based on rupintrivir… Pfizer had modified rupintrivir to make it a better fit for SARS-CoV-1’s Mpro… SARS-CoV-2 Mpro and SARS-CoV-1 Mpro are highly homologous, a 96% match. Pfizer was therefore able to quickly advance both oral and intravenous SARS-CoV-2 Mpro inhibitors. PF-07304814, the intravenous contender, is the phosphate prodrug form of PF-00835231. PF-07321332, the oral candidate, has added substructures from the HCV protease inhibitor boceprevir and additional optimizations for oral bioavailability. To make paxlovid, Pfizer combined PF-07321332 with ritonavir, an HIV drug that inhibits cytochrome P450 and slows the metabolism of protease inhibitors.” See: “A tale of two antiviral targets — and the COVID-19 drugs that bind them: The FDA is considering authorizations for Pfizer’s paxlovid and Merck & Co.’s molnupiravir, the first two oral COVID-19 antivirals.”, 2 Dec. 2021 By Megan Cully, Nature: http://web.archive.org/web/20211203095936/https://www.nature.com/articles/d41573-021-00202-8

It’s supposed to be for diabetics, according to the NYT, yet can increase blood sugar levels and even cause diabetes. So, who is it for? Healthy elderly and healthy obese people? If so, how will Pfizer make its money? Oh, yes. Now being over 60 is considered a pre-existing condition, based on the FDA news release, further below. You know, those folks eligible, or soon eligible, for retirement and social security. Trying hard to resist calling this a name that rhymes with pill and begins with k. “F.D.A. Clears Pfizer’s Covid Pill for High-Risk Patients 12 and Older: The first-of-its-kind treatment, Paxlovid, has been found to be highly protective against severe illness. It could be available within a few days” By Rebecca Robbins and Carl Zimmer Dec. 22, 2021, 1:41 p.m. ET “The Food and Drug Administration on Wednesday authorized the first pill for Covid-19… is authorized for Covid patients age 12 and over who are vulnerable to becoming severely ill because they are older or have medical conditions such as obesity or diabetes…”https://web.archive.org/web/20211222185025/https://www.nytimes.com/2021/12/22/health/pfizer-covid-pill-fda-paxlovid.html

“New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during postmarketing surveillance in HIV-infected patients receiving protease inhibitor therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between protease inhibitor therapy and these events has not been established. Consider monitoring for hyperglycemia, new onset diabetes mellitus, or an exacerbation of diabetes mellitus in patients treated with NORVIR.”https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209512lbl.pdf#page9

Factsheet with some warnings here: https://www.fda.gov/media/155050/download

“PAXLOVID is comprised of nirmatrelvir, a SARS-CoV-2 main protease (Mpro: also referred to as 3CLpro or nsp5 protease) inhibitor, co-packaged with ritonavir, an HIV-1 protease inhibitor and CYP3A inhibitor… PAXLOVID is not approved for any use, including for use for the treatment of COVID-19.” https://www.fda.gov/media/155049/download Emergency Use Authorization isn’t the same as approval.

The FDA admits that: “Possible side effects of Paxlovid include impaired sense of taste, diarrhea, high blood pressure and muscle aches. Using Paxlovid at the same time as certain other drugs may result in potentially significant drug interactions. Using Paxlovid in people with uncontrolled or undiagnosed HIV-1 infection may lead to HIV-1 drug resistance. Ritonavir may cause liver damage, so caution should be exercised when giving Paxlovid to patients with preexisting liver diseases, liver enzyme abnormalities or liver inflammation…. Paxlovid is not recommended in patients with severe kidney or severe liver impairment. In patients with moderate renal impairment, a reduced Paxlovid dose is needed.”
https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-first-oral-antiviral-treatment-covid-19

One of the warnings for the old HIV drug from 1996, NORVIR (ritonavir), which is being “repurposed”: “Ritonavir prolongs the PR interval in some patients. Post marketing cases of second or third degree atrioventricular block have been reported in patients. NORVIR should be used with caution in patients with underlying structural heart disease, preexisting conduction system abnormalities, ischemic heart disease, cardiomyopathies, as these patients may be at increased risk for developing cardiac conduction abnormalities. The impact on the PR interval of co-administration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers, beta-adrenergic blockers, digoxin and atazanavir) has not been evaluated. As a result, co-administration of ritonavir with these drugs should be undertaken with caution, particularly with those drugs metabolized by CYP3A. Clinical monitoring is recommended [see Drug Interactions (7) and Clinical Pharmacology (12.3)].”https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209512lbl.pdf

Nirmatrelvir “is an antiviral drug developed by Pfizer which acts as an orally active 3CL protease inhibitor…. Pfizer submitted an application to the U.S. Food and Drug Administration (FDA) for emergency use authorization for nirmatrelvir in combination with ritonavir in November 2021.” https://en.wikipedia.org/wiki/Nirmatrelvir

As for Nirmatrelvir, it is a 3CLpro inhibitor:
“3CLpro inhibitors commonly target host proteases, which presents a potential liability for unexpected side effects.” (“Considerations for the discovery and development of 3-chymotrypsin-like cysteine protease inhibitors targeting SARS-CoV-2 infection.” By Vandyck K1, Deval J2 Current Opinion in Virology, 27 Apr 2021, 49:36-40)

“Paxlovid combines two protease inhibitors for its virus attack. Ritonavir is an existing drug used to combat HIV. Nirmatrelvir is the brand name given to the experimental molecule PF-07321332, which was developed to specifically attack the protease of the COVID-19 virus.2

While Nirmatrelvir attacks the protease of COVID-19, ritonavir attacks the enzymes that would take on Nirmatrelvir, operating as a team to slow the replication of the virus.” http://web.archive.org/web/20211215174526/https://www.verywellhealth.com/merck-pfizer-covid-pill-comparison-5212924

Ritonavir serious side effects include irregular heartbeat, and yellowing of the skin or eyes (apparently meaning drug induced jaundice).
http://web.archive.org/web/20171222154416/https://medlineplus.gov/druginfo/meds/a696029.html https://medlineplus.gov/druginfo/meds/a696029.html

“Nirmatrelvir, filed under the brand name Paxlovid[2], is an antiviral drug developed by Pfizer which acts as an orally active 3CL protease inhibitor. The combination of nirmatrelvir with ritonavir is in phase III trials for the treatment of COVID-19 since September 2021.[3][4][5] After promising results preventing hospitalization and death if given within the first three days of symptoms, Pfizer submitted an application to the U.S. Food and Drug Administration (FDA) for emergency use authorization for nirmatrelvir in combination with ritonavir in November 2021.[6]” https://en.wikipedia.org/wiki/Nirmatrelvir

Below are some of the side-effects of Ritonavir, as well as the currently approved HIV protease inhibitors, as a general class of drugs.
“RITONAVIR

Ritonavir is a PI that was previously used at high doses as an independent antiretroviral medication, but due to side effects it is no longer used as a PI.  It inhibits the liver enzyme CYP450 3A (CYP3A) and now is used exclusively at lower doses for its boosting effect. The main symptoms associated with ritonavir consist of gastrointestinal effects, including diarrhea, nausea, vomiting, and abdominal pain. These side effects are greater with higher doses of ritonavir….

PROTEASE INHIBITORS
There are currently 10 FDA-approved HIV protease inhibitors (PIs), but in the Adult and Adolescent ARV Guidelines none are designated in the category of Recommended Initial Regimens for Most People with HIV.[2] The following discussion pertains to PIs used to treat HIV infection, not the PIs used to treat hepatitis C virus.

Gastrointestinal Adverse Effects

Gastrointestinal side effects (mainly diarrhea but also nausea, vomiting, and abdominal pain) were common with early PIs, particularly nelfinavir and PIs given with high doses of ritonavir for pharmacokinetic boosting; these adverse effects are less frequent and less severe with more recently developed PIs and when lower doses of ritonavir are used for boosting (100 mg/day versus 200 mg/day).[1] In several trials, boosted darunavir and boosted atazanavir demonstrated lower rates of gastrointestinal side effects compared with the combination of lopinavir-ritonavir.[135,136,137] Nevertheless, PIs overall are linked to higher rates of gastrointestinal side effects than other drug classes, such as the INSTIs or NNRTIs, and even modern PIs can cause some gastrointestinal intolerability.[138,139,140]

Cardiovascular Risk

Protease inhibitors have been associated with dyslipidemia, insulin resistance, premature atherosclerosis, and myocardial infarction.[141] The large, prospective observational D:A:D study found that the incidence of myocardial infarction increased from 1.53 per 1000 person-years in those not exposed to PIs to 6.01 per 1000 person-years in those exposed to PIs for longer than 6 years, with much of this risk attributable to elevated lipid levels.[142] When the D:A:D study results were stratified according to exposure to individual drugs, only indinavir and lopinavir-ritonavir were associated with a statistically significant increased risk of myocardial infarction.[73]

Cardiac Conduction Abnormalities

Several studies have revealed prolonged PR interval as a potential complication of both boosted and unboosted PIs, with the effect being more pronounced with ritonavir-boosted atazanavir, lopinavir, and saquinavir.[143] Although all ritonavir-boosted PIs may potentially prolong the QTc interval, this effect is generally considered minimal, except with the combination of saquinavir with ritonavir.[144]  Some persons taking PIs have developed symptomatic atrioventricular (AV) block. Accordingly, ritonavir-boosted PIs should be used with caution in persons who have underlying conduction defects or in patients taking other medications that can prolong the PR interval.

Bleeding Risk in Persons with Hemophilia

Several case studies and case series have reported an increased risk of spontaneous bleeding episodes among persons with hemophilia and HIV who take HIV PIs.[145,146] In some of these cases, the bleeding was severe. The biologic mechanism remains unknown but may involve platelet dysfunction.[147] Reports have documented individuals with HIV and hemophilia who have safely taken HIV PIs without bleeding complications.[148] In addition, clinical experience has shown that most persons with HIV infection with hemophilia can be safely treated with HIV PIs. Thus, the use of PIs in persons with hemophilia is not contraindicated, but those started on protease inhibitors should be warned about this potential complication and monitored closely.

Lipoaccumulation

Prior use of some first-generation protease inhibitors, particularly indinavir and saquinavir, in combination with thymidine analog NRTIs, has been associated with the development of abnormal central fat accumulation, most often from excessive visceral fat.[45,149] Clinically, the abnormal fat accumulation has manifested as marked increases in abdominal girth, breast enlargement, and development of a dorsocervical fat pad—often referred to as a buffalo hump (Figure 15) and (Figure 16).[149] The risk of developing lipoaccumulation has markedly declined in the current antiretroviral era since regimens now rarely include thymidine analogs (stavudine or zidovudine) or first-generation PIs”https://www.hiv.uw.edu/go/antiretroviral-therapy/adverse-effects/core-concept/all

The so-called boosting impacts appear to be related to its slowing down the processing of the drug in the liver, which is apparently related to the liver toxicity/liver failure-drug contraindication risks. Your liver is supposed to clean drugs and (other) toxins from your system: “PAXLOVID is comprised of nirmatrelvir, a SARS-CoV-2 main protease (Mpro: also referred to as 3CLpro or nsp5 protease) inhibitor, co-packaged with ritonavir, an HIV-1 protease inhibitor and CYP3A inhibitor. Ritonavir, which has no activity against SARS-CoV-2 on its own, is included to inhibit the CYP3A-mediated metabolism of nirmatrelvir and consequently increase nirmatrelvir plasma concentrations to levels anticipated to inhibit SARS-CoV-2 replication. PAXLOVID is not approved for any use, including for use for the treatment of COVID-19.” https://www.fda.gov/media/155049/download

Why do they appear so hell-bent to repurpose this old, apparently unsafe, HIV drug? It didn’t work against Covid so Pfizer threw it in with another drug.
“Repurposing of known drugs can provide an accelerated route to approval, which is likely the only option to address the current COVID-19 crisis. Small molecules like ebselen or carmofur are Mpro inhibitors with anti-SARS-CoV-2 activity in cells;79 however, their thiol reactivity might prove challenging.

Repurposing approved protease inhibitors is an alternative approach.102 Attempts to repurpose the approved combination of HIV protease inhibitors, ritonavir and lopinavir, was unsuccessful in clinical studies, which is not entirely unexpected, given the differences between the proteases of HIV and SARS-CoV-2.107…” (Ullrich, Sven, and Christoph Nitsche. “The SARS-CoV-2 main protease as drug target.” Bioorganic & medicinal chemistry letters vol. 30,17 (2020): 127377. doi:10.1016/j.bmcl.2020.12737 )

INCLUSION AND EXCLUSION CRITERIA FOR CLINICAL TRIAL, WHEN IT WAS TO BE GIVEN INTRAVENOUSLY (IV):
“Ages Eligible for Study: 18 Years to 79 Years   (Adult, Older Adult)
Sexes Eligible for Study: All
Accepts Healthy Volunteers: No
Criteria
* Inclusion Criteria:
1. Male or female participants between the ages of 18 and 79 years.
2. Confirmed SARS-CoV-2 infection.
3. Hospitalized for COVID-19.
4. Symptoms consistent with COVID-19 indicated by at least 1 of the following: fever, cough, sore throat, malaise, headache, muscle pain, shortness of breath, new loss of taste and smell, nausea, chills, fatigue, rhinorrhea, diarrhea, vomiting or radiographic infiltrates by imaging consistent with COVID-19
5. Total body weight >=50 kg (110 lb), BMI <40 kg/m2; BMI <35 kg/m2 for 76- 79 years.

* Exclusion Criteria:
1. Evidence of critical illness, defined by at least one of the following: Respiratory failure, Multi-organ dysfunction/failure, Cardiac failure or septic shock
2. Participants that are anticipated by the study Investigator to progress to critical disease, including mechanical ventilation, within 24 hours of enrolment
3. Participants with pre-existing moderate to severe cardiovascular disease, uncontrolled diabetes, or severe asthma or severe COPD.
* 3.Participants with a known medical history of recent acute or chronic liver disease (other than NASH), chronic or active hepatitis B or C infection, or primary biliary cirrhosis.

* 4. Participants with a known medical history of ischemic heart disease, heart failure, dysrhythmia or other pre-existing cardiac condition.
* 
5. Participants with known HIV infection, acute or chronic history of hepatitis B or C.
* 
6.Participants with a known medical history of recurrent seizures.
*
* 7. Participants with history of venous thromboembolic event, including deep venous thrombosis or pulmonary embolism
*
* 8.Confirmed concurrent active systemic infection other than COVID-19.
9.Current diagnosis of cancer, unless in remission and untreated.
* 10.Other medical or psychiatric condition including recent or active suicidal ideation/behavior or laboratory abnormality that may increase the risk of study participation
* 11.Females who are pregnant or breastfeeding…”
https://clinicaltrials.gov/ct2/show/NCT04535167
https://clinicaltrials.gov/ct2/history/NCT04535167?V_8=View
http://web.archive.org/web/20210725161727/https://clinicaltrials.gov/ct2/show/NCT04535167 (Yes, the original has 3 twice.)

Notice that they increased the age to include the frail elderly:
SHIFTED FROM IV TO ORAL (PILL FORM)

ORAL INCLUSION-EXCLUSION CRITERIA:

“Ages Eligible for Study: 18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study: All
Accepts Healthy Volunteers: No
Criteria

Inclusion Criteria:
* Confirmed SARS-CoV-2 infection within 5 days prior to randomization
* Initial onset of COVID-19 signs/symptoms within 5 days prior to the day of randomization and at least 1 of the specified COVID-19 signs/symptoms present on the day of randomization
* Fertile participants must agree to use a highly effective method of contraception
* Has at least 1 characteristic or underlying medical condition associated with an increased risk of developing severe illness from COVID-19

Exclusion Criteria:
* History of or need for hospitalization for the medical treatment of COVID-19
* Prior to current disease episode, any confirmed SARS-CoV-2 infection
* Known medical history of active liver disease
* Receiving dialysis or have known moderate to severe renal impairment
* Known human immunodeficiency virus (HIV) infection with a viral load greater than 400 copies/mL or taking prohibited medications for HIV treatment
* Suspected or confirmed concurrent active systemic infection other than COVID-19
* History of hypersensitivity or other contraindication to any of the components of the study intervention
* Current or expected use of any medications or substances that are highly dependent on CYP3A4 for clearance or are strong inducers of CYP3A4
* Has received or is expected to receive convalescent COVID-19 plasma
* Has received or is expected to receive any dose of a SARS-CoV-2 vaccine before the Day 34 visit
* Participating in another interventional clinical study with an investigational compound or device, including those for COVID-19 through the long-term follow-up visit
* Known prior participation in this trial or other trial involving PF-07321332
* Oxygen saturation of <92% on room air, or on their standard home oxygen supplementation for those who regularly receive chronic supplementary oxygen for an underlying lung condition
* Females who are pregnant or breastfeeding”
Ca December 1 update: https://www.clinicaltrials.gov/ct2/show/NCT04960202
September update: https://archive.md/aW338#selection-4249.0-4411.31

https://en.wikipedia.org/wiki/CYP3A4

“Considerations for the discovery and development of 3-chymotrypsin-like cysteine protease inhibitors targeting SARS-CoV-2 infection.” By Vandyck K1, Deval J2 Current Opinion in Virology, 27 Apr 2021, 49:36-40
DOI: 10.1016/j.coviro.2021.04.006 PMID: 34029993 PMCID: PMC8075814
“Abstract : Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the COVID-19 pandemic. The coronavirus 3-chymotrypsin-like protease (3CLpro) controls virus replication and is therefore considered a major target and promising opportunity for rational-based antiviral discovery with direct acting agents. Here we review first-generation SARS-CoV-2 3CLpro inhibitors PF-07304814, GC-376, and CDI-45205 that are being delivered either by injection or inhalation due to their low intrinsic oral bioavailability. In addition, PF-07321332 is now emerging as a promising second-generation clinical candidate for oral delivery. A key challenge to the development of novel 3CLpro inhibitors is the poor understanding of the predictive value of in vitro potency toward clinical efficacy, an issue complicated by the involvement of host proteases in virus entry. Further preclinical and clinical validation will be key to establishing 3CLpro inhibitors as a bona fide class for future SARS-CoV-2 therapeutics for both hospitalized and outpatient populations.”
Excerpt: “At the time of the publishing of this manuscript, Pfizer announced the launch of a Phase 1 clinical study (NCT04756531) with the second-generation orally available 3CLpro inhibitor PF-07321332 (https://cen.acs.org/acs-news/acs-meeting-news/Pfizer-unveils-oral-SARS-CoV/99/i13). PF-07321332 contains a nitrile warhead and was optimized for oral delivery by the reduction of the number of H-bond donors and application of a trifluoroacetyl capping group in P4 (Figure 1).

Pitfalls and challenges in assessing the preclinical antiviral potency of 3CLpro inhibitors

The need to discover and develop second-generation 3CLpro inhibitors with improved potency and/or bioavailability is high. In addition, 3CLpro inhibitors commonly target host proteases, which presents a potential liability for unexpected side effects. Therefore, increased target specificity might be critical for future development. However, preclinical evaluation of antiviral potency remains challenging for this class of compounds. Conflicting results of protease inhibitor testing emerged during the early months of the COVID-19 pandemic due to non-standardized assay conditions among research laboratories. For example, the three drugs shikonin, disulfiram, and ebselen previously approved for other indications were reported to inhibit SARS-CoV-2 3CLpro in enzymatic and antiviral assays [26••]. However, enzyme inhibition was only achieved in the absence of physiologically relevant reducing agents, and the reported antiviral effect in cells infected with SARS-CoV-2 could not be reproduced and was therefore suspected to be an indirect consequence of cell death [15•]. Similar lack of reproducibility in SARS-CoV-2 inhibition due to cytotoxicity artefacts have been reported with HIV protease inhibitors nelfinavir and atazanavir [27]. These issues highlight the importance of proper assay conditions and controls to ensure correct interpretation of in vitro protease inhibitor testing results. Additional challenges in assessing 3CLpro inhibition potency in infected cells arose from the role of host proteases in virus entry.

SARS-CoV-2 uses human ACE2 as its entry receptor and human proteases as entry activators including cell surface transmembrane protease/serine (TMPRSS) proteases, furin, cathepsins, plasmin, elastase, and trypsin (for reviews: Refs. [28,29]). Although the relevance of individual host proteases at the site of infection remains subject to debate, the consensus is that SARS-CoV-2 enters cells mainly through direct membrane fusion by TMPRSS2 protease activation [30••]. In addition to the TMPRSS2-facilitated direct entry from the cell membrane, SARS-CoV-2 can also enter cells through the endosomal pathway, where spike proteins are proteolytically activated by the lysosomal cathepsin L and/or B proteases [31]. Therefore, optimizing and developing protease inhibitors for SARS-CoV-2 face distinctive challenges due to the multiple host proteases and their level of redundancy for viral entry. In vitro, the antiviral activity of protease inhibitors largely depends on the mechanism of SARS-CoV-2 cellular entry and is driven by the levels of host protease expression in the cells. For example, the rhinovirus inhibitor rupintrivir and the cathepsin inhibitor K11777 block SARS-CoV-2 replication in A549 lung epithelial cells, but their antiviral effect was greatly diminished when TMRPSS2 was overexpressed [32•]. These examples highlight the difficulty of establishing physiologically relevant antiviral assays due to the influence of host protease expression on the mechanism of virus entry. For these reasons, cellular assays risk overpredicting the true potential antiviral effect of broad-spectrum 3CLpro inhibitors that also target cathepsin L and/or other host proteases involved in virus entry [7]….

Conflict of interest statement
The authors of this manuscript have the following competing interests: JD is current employee of Aligos Therapeutics, Inc., and KV is current employee of Aligos Belgium BV.” Excerpted from: “Considerations for the discovery and development of 3-chymotrypsin-like cysteine protease inhibitors targeting SARS-CoV-2 infection.” By Vandyck K1, Deval J2 Current Opinion in Virology, 27 Apr 2021, 49:36-40 DOI: 10.1016/j.coviro.2021.04.006 

“Repurposing of known drugs can provide an accelerated route to approval, which is likely the only option to address the current COVID-19 crisis. Small molecules like ebselen or carmofur are Mpro inhibitors with anti-SARS-CoV-2 activity in cells;79 however, their thiol reactivity might prove challenging.

Repurposing approved protease inhibitors is an alternative approach.102 Attempts to repurpose the approved combination of HIV protease inhibitors, ritonavir and lopinavir, was unsuccessful in clinical studies, which is not entirely unexpected, given the differences between the proteases of HIV and SARS-CoV-2.107

It is likely that SARS-CoV-2 is not the last human coronavirus emerging from animals. It is therefore important to closely monitor virus populations to understand their replication mechanism early on and investigate druggable targets. A sharp decline in research funding had been noted a few years after the first SARS epidemic.61 Given the long-term nature of drug discovery projects, this has proven disastrous with respect to the current crisis. Now is the best time to progress protease inhibitors to anti-coronaviral drugs.” Excerpted from Ullrich, Sven, and Christoph Nitsche. “The SARS-CoV-2 main protease as drug target.” Bioorganic & medicinal chemistry letters vol. 30,17 (2020): 127377. doi:10.1016/j.bmcl.2020.12737

The FDA’s News Release:
“Today, the U.S. Food and Drug Administration issued an emergency use authorization (EUA) for Pfizer’s Paxlovid (nirmatrelvir tablets and ritonavir tablets, co-packaged for oral use) for the treatment of mild-to-moderate coronavirus disease (COVID-19) in adults and pediatric patients (12 years of age and older weighing at least 40 kilograms or about 88 pounds) with positive results of direct SARS-CoV-2 testing, and who are at high risk for progression to severe COVID-19, including hospitalization or death. Paxlovid is available by prescription only and should be initiated as soon as possible after diagnosis of COVID-19 and within five days of symptom onset. 

“Today’s authorization introduces the first treatment for COVID-19 that is in the form of a pill that is taken orally — a major step forward in the fight against this global pandemic,” said Patrizia Cavazzoni, M.D., director of the FDA’s Center for Drug Evaluation and Research. “This authorization provides a new tool to combat COVID-19 at a crucial time in the pandemic as new variants emerge and promises to make antiviral treatment more accessible to patients who are at high risk for progression to severe COVID-19.” 

Paxlovid is not authorized for the pre-exposure or post-exposure prevention of COVID-19 or for initiation of treatment in those requiring hospitalization due to severe or critical COVID-19. Paxlovid is not a substitute for vaccination in individuals for whom COVID-19 vaccination and a booster dose are recommended.

The FDA has approved one vaccine and authorized others to prevent COVID-19 and serious clinical outcomes associated with a COVID-19 infection, including hospitalization and death. The FDA urges the public to get vaccinated and receive a booster if eligible. Learn more about FDA-approved or -authorized COVID-19 vaccines.

Paxlovid consists of nirmatrelvir, which inhibits a SARS-CoV-2 protein to stop the virus from replicating, and ritonavir, which slows down nirmatrelvir’s breakdown to help it remain in the body for a longer period at higher concentrations. Paxlovid is administered as three tablets (two tablets of nirmatrelvir and one tablet of ritonavir) taken together orally twice daily for five days, for a total of 30 tablets. Paxlovid is not authorized for use for longer than five consecutive days.
 
The issuance of an EUA is different than an FDA approval. In determining whether to issue an EUA, the FDA evaluates the totality of scientific evidence available and carefully balances any known or potential risks with any known or potential benefits of the product. Based on the FDA’s review of the totality of the scientific evidence available, the agency has determined that it is reasonable to believe that Paxlovid may be effective for the treatment of mild-to-moderate COVID-19 in authorized patients. The agency has also determined that the known and potential benefits of Paxlovid, when used consistent with the terms and conditions of the authorization, outweigh the known and potential risks of the product. There are no adequate, approved and available alternatives to Paxlovid for the treatment of COVID-19. 

The primary data supporting this EUA for Paxlovid are from EPIC-HR, a randomized, double-blind, placebo-controlled clinical trial studying Paxlovid for the treatment of non-hospitalized symptomatic adults with a laboratory confirmed diagnosis of SARS-CoV-2 infection.

Patients were adults 18 years of age and older with a prespecified risk factor for progression to severe disease or were 60 years and older regardless of prespecified chronic medical conditions. All patients had not received a COVID-19 vaccine and had not been previously infected with COVID-19. The main outcome measured in the trial was the proportion of people who were hospitalized due to COVID-19 or died due to any cause during 28 days of follow-up. Paxlovid significantly reduced the proportion of people with COVID-19 related hospitalization or death from any cause by 88% compared to placebo among patients treated within five days of symptom onset and who did not receive COVID-19 therapeutic monoclonal antibody treatment. In this analysis, 1,039 patients had received Paxlovid, and 1,046 patients had received placebo and among these patients, 0.8% who received Paxlovid were hospitalized or died during 28 days of follow-up compared to 6% of the patients who received placebo. The safety and effectiveness of Paxlovid for the treatment of COVID-19 continue to be evaluated.

Possible side effects of Paxlovid include impaired sense of taste, diarrhea, high blood pressure and muscle aches. Using Paxlovid at the same time as certain other drugs may result in potentially significant drug interactions. Using Paxlovid in people with uncontrolled or undiagnosed HIV-1 infection may lead to HIV-1 drug resistance. Ritonavir may cause liver damage, so caution should be exercised when giving Paxlovid to patients with preexisting liver diseases, liver enzyme abnormalities or liver inflammation.  

Because Paxlovid works, in part, by inhibiting a group of enzymes that break down certain drugs, Paxlovid is contraindicated with certain drugs that are highly dependent on those enzymes for metabolism and for which elevated concentrations of certain drugs are associated with serious and/or life-threatening reactions. Paxlovid is also contraindicated with drugs that, conversely, strongly induce those same enzymes, leading to the faster breakdown of nirmatrelvir or ritonavir, as reduced concentrations of nirmatrelvir or ritonavir may be associated with potentially losing virologic response and developing viral resistance. Paxlovid cannot be started immediately after discontinuing such medications because the effects of those medications remain after discontinuation. For a complete list of drugs that should not be taken in combination with Paxlovid, see the fact sheet for healthcare providers.

Paxlovid is not recommended in patients with severe kidney or severe liver impairment. In patients with moderate renal impairment, a reduced Paxlovid dose is needed. Patients with kidney or liver problems should discuss with their healthcare provider whether Paxlovid is right for them. 

Under the EUA, fact sheets that provide important information about using Paxlovid in the treatment of COVID-19 as authorized must be made available to healthcare providers and to patients and caregivers. These fact sheets include dosing instructions, potential side effects, drug interactions and information about who is able to prescribe Paxlovid.”
https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-first-oral-antiviral-treatment-covid-19
Notice the FDA news release sounds like a Pharma ad: “Patients with kidney or liver problems should discuss with their healthcare provider whether Paxlovid is right for them.”

“Doctors without Borders” claims that this product is unpatented and they urgently want this questionable experimental treatment available for cheap in the so-called poorer countries, previously called the Third World: https://www.doctorswithoutborders.org/what-we-do/news-stories/news/msf-responds-fda-approval-first-oral-antiviral-covid-19-treatment

Disclaimer: This post does not constitute medical advice. Only you can make your own medical decisions. You are unique. Hopefully you are lucky enough to have a trusted medical professional to help you make the best decision for you.