Paxlovid (nirmatrelvir and ritonavir)
SARS-CoV-2-3CL protease inhibitor
Mild to moderate Covid-19
US FDA emergency use authorisation (EUA)
Paxlovid is a ritonavir-boosted nirmatrelvir drug indicated for the treatment of mild to moderate COVID-19 patients aged 12 years and older who are at high risk of progressing to severe COVID-19, including hospitalisation or death.
Developed by US-based pharmaceutical firm Pfizer, Paxlovid is available as nirmatrelvir tablets co-packaged with ritonavir tablets for oral co-administration. Nirmatrelvir is available as pink-coloured, oval, immediate-release, film-coated tablets, while ritonavir is supplied as white film-coated ovaloid tablets.
Nirmatrelvir is a novel main protease (Mpro) inhibitor developed by Pfizer to block the SARS-CoV-2 Mpro enzyme activity, while ritonavir is an antiretroviral protease inhibitor and a strong cytochrome P450 (CYP) 3A inhibitor that improves the exposure of nirmatrelvir to an effective level against SARS-CoV-2.
Pfizer plans to deliver 20 million treatment courses of Paxlovid to the US Government to combat COVID-19 in 2022.
Regulatory approvals for Paxlovid
In December 2021, the US Food and Drug Administration (FDA) authorised Paxlovid for emergency use in high-risk adult and paediatric patients with mild to moderate COVID-19.
In the same month, the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) also recommended the use of Paxlovid for the treatment of COVID-19 patients who do not require supplemental oxygen and are at greater risk of progressing to severe illness.
Pfizer plans to submit a new drug application (NDA) to the FDA for full regulatory approval in 2022.
COVID-19 causes and symptoms
COVID-19 is a viral infection caused by the SARS-CoV-2 virus. It can affect an individual’s upper respiratory tract (sinuses, nose and throat) or lower respiratory tract (windpipe and lungs).
The virus can spread from an infected individual’s mouth or nose in the form of microscopic droplets when the person coughs, sneezes, speaks, sings or breathes.
Symptoms of COVID-19 include fever, cough, body ache, shortness of breath, chills, runny nose, nausea, loss of smell or taste, sore throat, and diarrhoea.
Paxlovid’s mechanism of action
Paxlovid is a specially designed SARS-CoV-2-3CL protease inhibitor containing nirmatrelvir and ritonavir. Nirmatrelvir is a peptidomimetic inhibitor of the SARS-CoV-2 Mpro, also known as 3CLpro or nsp5 protease, while ritonavir is an HIV-1 protease inhibitor that is inactive against SARS-CoV-2 Mpro.
Nirmatrelvir binds directly to the SARS-CoV-2 Mpro active site and inhibits the coronavirus’ viral replication process, while ritonavir increases nirmatrelvir’s plasma concentrations by inhibiting its CYP3A-mediated metabolism. Ritonavir helps to slow down the breakdown of nirmatrelvir, allowing it to remain active in the body for a longer time at higher concentrations to help fight the virus.
Clinical trials on Paxlovid
The FDA’s emergency use authorisation (EUA) for Pfizer’s Paxlovid was based on the results of EPIC-HR, a Phase II/III, randomised, double-blind, placebo-controlled clinical study.
In the study, 2,246 non-hospitalised symptomatic adult patients with confirmed SARS-CoV-2 infection were randomly assigned to receive either Paxlovid (300mg/100mg) or placebo orally every 12 hours for five days. The patients enrolled in the study had not received a COVID-19 vaccination and had not been previously infected with COVID-19.
The trial’s primary endpoint was the proportion of patients who had been hospitalised due to COVID-19 or died for any reason during the 28-day follow-up period.
Paxlovid reduced the risk of COVID-19-related hospitalisation or death from any cause by 89% in patients within three days of symptom onset and 88% within five days of symptom onset compared with placebo. No patient treated with Paxlovid died by day 28, compared with nine deaths in the placebo group. The drug’s safety and efficacy profile in treating Covid-19 is still being investigated.
Possible side effects of Paxlovid treatment include loss of taste, diarrhoea, high blood pressure and muscular pains.