PAXLOVID™ Oral Antiviral Clinical Trials, Efficacy, Side Effects
Pfizer Inc. Paxlovid™ (nirmatrelvir, Bexovid, ritonavir, PF-07321332) is an Aprroved oral antiviral targeting the SARS-CoV-2 beta coronavirus to prevent COVID-19. Paxlovid is packaged with nirmatrelvir and ritonavir, a strong cytochrome P450 (CYP) 3A4 inhibitor. Nirmatrelvir, a novel main protease (Mpro) inhibitor originating in Pfizer's laboratories, is specifically designed to block the activity of the SARS-CoV-2 Mpro, an enzyme the novel coronavirus needs to replicate. It is an analog of GC373, where the aldehyde covalent cysteine acceptor replaced a nitrile.
Paxlovid works intracellularly, inhibiting viral replication at a stage known as proteolysis, which occurs before viral RNA replication. Protease inhibitors bind to a viral enzyme, preventing the virus from replicating in the cell. A study published on March 29, 2023, concluded multiple single amino acid changes in Mpro confer resistance to nirmatrelvir (the active component of Paxlovid).
Pfizer developed PF-07321332 by modifying PF-07304814 (Lufotrelvir), a covalent inhibitor. PF-07321332 is also a covalent inhibitor, but its warhead is a phosphate prodrug, a hydroxyketone. Paxlovid is co-administration with a low dose of ritonavir, a strong cytochrome P450 (CYP) 3A inhibitor, to slow the metabolism or breakdown of Paxlovid and to remain active in the body for more extended periods at higher concentrations to help combat the virus. In preclinical studies, PF-07321332 did not demonstrate evidence of mutagenic DNA interactions. However, Paxlovid has complex drug-drug interactions, primarily due to the ritonavir component.
Paxlovid became the first orally administered coronavirus-specific investigational protease inhibitor authorized under Emergency Use Authorization (EUA) for certain adults and children by the U.S. Food and Drug Administration (FDA) on December 22, 2021. Then, on January 28, 2022, the European Medicine Agency (EMA) and European Commission granted Pfizer Europe MA EEIG marketing authorization EMEA/H/C/005973 for adults. As a result, effective from Feb. 10, 2022, Paxlovid was added as a first-line treatment option for patients with hospital-onset COVID-19 infection in the United Kingdom (U.K.). The FDA issued its Approval on May 25, 2023. The World Health Organization (WHO) strongly recommended Paxlovid for mild and moderate COVID-19 patients at the highest risk of hospital admission, calling it the best therapeutic choice for high-risk patients as of April 22, 2022. Paxlovid treatment should be initiated within days of disease symptom onset, says the U.S. NIH and the U.S. Centers for Disease Control and Prevention (CDC) on December 5, 2022. On December 20, 2022, Pfizer Inc. announced that the U.S. FDA extended the review period for the New Drug Application (NDA) of PAXLOVID, which remains available to eligible U.S. patients under an EUA. On February 1, 2023, the FDA issued a revised EUA #105.
Please see the EUA Prescribing Information available at fda.gov and COVID19oralRx.com. Chemical Formula: C23H32F3N5O4; DrugBank Accession Number DB16691; CAS Number 2628280-40-8; PubChem CID 155903259; Molecular Weight: 499.5. Contact COVID19Therapeutics@hhs.gov with any questions. To learn more, please visit New York-based Pfizer Inc. at www.Pfizer.com. (NYSE: PFE).
PAXLOVID COVID-19 Efficacy
On May 24, 2024, a non-peer-reviewed preprint phase 3 clinical study (RECOVERY) found that patients hospitalized with COVID-19 were randomized to receive Paxlovid or not. The patients' mortality rates were compared after 28 days. There was no difference.
On April 3, 2024, the New England Journal of Medicine published results from a Pfizer-sponsored phase 2/3 clinical study of younger low-risk patients that concluded that the time to sustained alleviation of all signs and symptoms of COVID-19 did not differ significantly between participants who received nirmatrelvir–ritonavir and those who received placebo. Pfizer's 2021-2022 phase 2/3 clinical trial showed that Paxlovid did not influence symptoms among vaccinated patients with high risks or unvaccinated standard-risk patients.
PAXLOVID Long COVID Efficacy
The JAMA Internal Medicines published results for a study on June 7, 2024, that showed that a 15-day course of NMV/r in a population of patients with PASC was generally safe but did not demonstrate a significant benefit for improving select PASC symptoms in a mostly vaccinated cohort with protracted symptom duration.
On January 4, 2024, a study concluded within a cohort of vaccinated, nonhospitalized individuals, oral nirmatrelvir treatment during acute SARS-CoV-2 infection and rebound after nirmatrelvir treatment was not associated with Long COVID symptoms more than 90 days after infection. Treatment was not associated with fewer Long COVID symptoms or severe symptoms, although these endpoints were limited by the rarity of these outcomes.
PAXLOVID Availability
Paxlovid (Bexovid, nirmatrelvir, ritonavir) was authorized by about 65 countries.
PAXLOVID Price
During the U.S. FDA Emergency Use Authorization, PAXLOVID™, there is no price to the patient; however, there may be related service fees. The original Paxlovid price without insurance was about $530. Additional Paxlovid price and discount information is posted at InstantRx™.
PAXLOVID Rebound
The U.S. FDA acknowledged cases on May 4, 2022, stating it 'was aware of the reports of some patients developing recurrent COVID-19 symptoms after completing a treatment course of Paxlovid.'
PAXLOVID Drug Interactions
In its clinical guidance published on October 4, 2023, the U.S. CDC urges health providers to be aware of Paxlovid's potential for drug interactions. The drug carries a boxed warning about significant drug interactions. NIH treatment guidelines encourage clinicians to review patients’ medications carefully. As of December 30, 2022, Medscape identifies 44 Paxlovid drug interactions. Pfizer confirms PAXLOVID is contraindicated in patients with a history of clinically significant hypersensitivity reactions to its active ingredients (nirmatrelvir or ritonavir) or any other components of the product and with drugs that are highly dependent on CYP3A for clearance and for which elevated concentrations are associated wisevereous and/or life-threatening reactions. Before prescribing ritonavir-boosted nirmatrelvir, clinicians should carefully review the patient's concomitant medications, including over-the-counter medicines, herbal supplements, and recreational drugs, says the U.S. NIH. The FDA provided additional guidance on June 3, 2022, to help prescribers evaluate potential drug interactions when using Paxlovid therapy for COVID-19. On February 24, 2022, the NIH published 'Ritonavir-boosted nirmatrelvir (Paxlovid) has significant and complex drug-drug interaction potential, primarily due to the ritonavir component of the combination. Clinicians who are not experienced in prescribing ritonavir-boosted drugs should refer to resources such as the EUA fact sheet for ritonavir-boosted nirmatrelvir (Paxlovid) and the Liverpool COVID-19 Drug Interactions website for additional guidance.
PAXLOVID Ingredients
The two active substances of the medicine, PF,-07321332, and ritonavir, are available as separate tablets. The EMA confirmed: (1R,2S,5S)-N-((1S)-1-Cyano-2-((3S)-2-oxopyrrolidin-3-yl)ethyl)-3-((2S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido) butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; ritonavir.
PAXLOVID Dosage
Please see Full EUA Prescribing Information at COVID19oralRx.com.
PAXLOVID Indication
PAXLOVID oral antiviral therapy prevents the SARS-CoV-2 virus from replicating in human host cells. CDC treatment guidelines as of April 2024 are here https://www.cdc.gov/coronavirus/2019-ncov/your-health/treatments-for-sev....
PAXLOVID Generic
Under the terms of the head license agreement between Pfizer and MPP, announced on November 16, 2021, qualified generic medicine manufacturers worldwide that are granted sub-licenses will be able to supply PF-07321332 in combination with ritonavir to 95 countries, covering up to approximately 53% of the world's population. This agreement was expanded on March 17, 2022, to include 35 companies. Beximco initially marketed Paxlovid under the brand name in Bangladesh. Manila confirmed on March 10, 2022, that it authorized Bexovid for those aged 12 and above.
Paxlovid Clinical Trials
For PAXLOVID data, visit clinicaltrials.gov.
