The antiviral therapeutic arsenal against SARS-CoV-2 virus infection has been expanded after the authorization by the United States Food and Drug Administration (FDA), on December 22, of the drug Paxlovid from the Pfizer pharmaceutical company.
The FDA issued a Emergency Use Authorization (USA) for the use of Paxlovid in the treatment of COVID-19 of mild to moderate intensity, in adult subjects and pediatric patients (12 years of age or older weighing at least 40 kilograms), who test positive for SARS-CoV-2 and are at high risk of serious illness, including hospitalization or death.
Previously, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) issued a notice, on December 16, 2021, by virtue of Article 5 (3) of Regulation 726/2004, allowing the authorities of the Member States of the European Union to supply and use Paxlovid, in emergency use contexts, for treat adult COVID-19 patients who do not require supplemental oxygen and are at increased risk of progressing to serious illness.
And on December 31 it was also authorized in the United Kingdom, after a statement of the Health and Medicines Regulatory Agency (MHRA), in which it reported that this drug is "safe and effective", reducing the chances of hospitalization and death in high-risk adult patients.
What is Paxlovid?
Paxlovid is a preparation based on two antivirals: a newly developed one, nirmatrelvir, and a classic one, widely used in other viral infections, ritonavir, packaged together for oral use. This drug will only be dispensed with a prescription and should be taken as soon as possible after the diagnosis of COVID-19, within five days of the onset of symptoms.
It should be borne in mind that Paxlovid is not authorized for the prevention of the disease or for the treatment after exposure to SARS-CoV-2, nor for the initiation of treatment in people who require hospitalization due to a serious condition. And, of course, it is not an alternative to vaccination against COVID-19 either.
How does Paxlovid work?
Nirmatrelvir (PF-07321332) is an antiviral agent that has a high oral bioavailability, as shown in the clinical trial with healthy volunteers NCT04756531.
This antiviral works by inhibiting the 3C protease (3CLPRO), also known as MPRO. This is the main enzyme that participates in the proteolytic maturation of the coronavirus, mediating the cleavage of the polyproteins PP1a and PP1ab (Figure 1).
Considering that other functional proteins, such as RNA polymerase, endoribonuclease and exoribonuclease, are generated by the cleavage of these peptides, non-structural proteins (including proteases) cannot be released to perform their functions, thus inhibiting viral replication. Therefore, it seems obvious that using the 3CLPRO enzyme as a therapeutic target it would make it possible to inhibit viral maturation and improve the host's innate immune response against SARS-CoV-2.
For its part, ritonavir is another agent that inhibits the protease of certain viruses, such as HIV, which was approved in 1996 for the combined treatment of patients with AIDS. But its main function as a member of Paxlovid is its role as a decelerator of the biological destruction of nirmatrelvir, enhancing its permanence in the body for longer at higher concentrations.
Ritonavir is an ideal pharmacological enhancer because it inhibits two key steps in the metabolism of many drugs, including nirmatrelvir. First, it inhibits the so-called first-pass metabolism, which occurs during the absorption process of drugs. The enterocytes lining the intestine contain both CYP3A4, one of the key cytochrome P450 isozymes associated with drug metabolism, and P-glycoprotein, an efflux transporter that can effectively pump drugs out of the intestinal wall and back into the gut. intestinal lumen.
Ritonavir appears to inhibit both proteins and consequently may increase the blood concentration of co-administered drugs that target these enzymes, such as nirmatrelvir. Second, ritonavir also inhibits CYP3A4 in the liver, thus helping to increase the plasma half-life of the drug. It is also possible that ritonavir inhibits the P-glycoprotein found in different types of cells. As a result, less drug is transported out of the cell, thus increasing the intracellular half-life of the drug.
Is Paxlovid effective against virus variants?
Some of the current variants of interest may be resistant to antiviral treatments that inhibit the spike protein found on the surface of the SARS-CoV-2 virus, due to its high mutation rate. However, Paxlovid acts intracellularly, binding to the virus protease to inhibit viral replication.
In fact, nirmatrelvir has shown consistent antiviral activity in vitro against current variants of interest (i.e. alpha, beta, delta, gamma, lambda, and mu). Furthermore, nirmatrelvir potently inhibited MPRO associated with omicron variant in a biochemical assay in vitro, although additional studies with this variant are required.
What is the Paxlovid administration schedule?
Paxlovid is administered as three tablets (two for nirmatrelvir and one for ritonavir) taken together by mouth, twice a day for five days. That is, a total of 30 tablets. It is not authorized for treatments lasting more than five consecutive days.
The efficacy of Paxlovid in clinical trials
Efficacy data supporting Paxlovid authorization come from the EPIC-HR clinical trial (NTC04960202). This is a randomized, double-blind, placebo-controlled clinical trial evaluating the efficacy of Paxlovid in the treatment of symptomatic, non-hospitalized adult patients with a PCR-confirmed diagnosis of SARS-CoV-2 infection.
Study subjects included adult patients with a pre-established risk factor for severe disease or people older than 60 years, regardless of pre-established chronic medical conditions. None of the patients had received the COVID-19 vaccine, nor had they been previously infected. The main objective of the study was to assess the proportion of people who were hospitalized for COVID-19 or who died from any cause during the 28-day follow-up.
The results showed a reduced risk of hospitalization or death 89% after administering Paxlovid to high-risk adults in the first three days after onset of symptoms.
The ratio of hospitalizations and deaths was 0.8% (3 out of a sample of 389 patients), compared to a ratio of 7% (27 out of 385 patients) in the placebo group. The results were similar when treatment was started in the first 5 days after the onset of symptoms. Adverse effects seen in the Paxlovid group included altered sense of taste, diarrhea, increased blood pressure, and muscle aches.
The main problem of the Paxlovid is its security
One of the main security problems that Paxlovid can cause concerns the drug interactions, which can be potentially dangerous, due to the presence of ritonavir. This is a potent inhibitor of biotransformations mediated by CYP3A and CYP2D6 isoenzymes that can cause increased concentrations of drugs that are metabolized by these pathways, which can be serious and life-threatening.
This phenomenon may appear a few days after administering the drug. In fact, treatment with Paxlovid cannot be started immediately after stopping these medicines, as the effects of the medicines remain even after they are stopped. To know the large number of medicines that should not be taken in combination with Paxlovid, consult your data sheet.
On the contrary, taking Paxlovid together with drugs that induce these isoenzymes is also contraindicated, as the antivirals would be metabolized more rapidly, leading to a possible loss of virological response and the development of viral resistance.
Ritonavir can cause liver damage, so caution should be exercised when administered to patients with pre-existing liver diseases, including those with liver enzyme abnormalities. In patients with moderate renal impairment it is necessary to reduce the dose of Paxlovid.
Furthermore, its use in people with uncontrolled or undiagnosed HIV-1 infection may lead to resistance to AIDS drugs.
New therapeutic hope
At a time of great importance in the control of the pandemic due to the increase in the incidence of cases worldwide, the appearance of new variants of the virus, and even infections in patients with a complete and reinforced vaccination schedule, the availability of a second Oral antiviral agent specific for this infection, following the recent authorization of the molnupiravir, represents a significant advance in the fight against COVID-19.
In addition, the company Pfizer has committed to making this antiviral treatment more accessible to patients who need it, through a price policy staggered based on the average income level of each country, in order to promote the equity of access Worldwide.
Following the notification from the European Agency, possibly the national agencies of the different countries will shortly authorize this new drug, as has already been advanced by the german government, although, in any case, we must be expectant, as always, of the benefit / risk balance of this new antiviral cocktail.
Hopefully, in the specific case of the Paxlovid, one plus one adds up to something more than two.
Francisco López-Muñoz is Associate Professor of Pharmacology and Vice-Rector for Research and Science at the Camilo José Cela University. Jose Antonio Guerra Guirao is Professor of Pharmacology and Toxicology at the Faculty of Pharmacy of the Complutense University of Madrid.