The unprecedented increase in coronavirus disease 2019 (COVID-19)-associated morbidity and mortality has led to the development of several vaccines and therapeutic drugs globally for mitigating the effects of the disease. The World Health Organisation (WHO) on April 22, 2022, has given a strong recommendation for Pfizer’s orally delivered directly-acting antiviral drug, Paxlovid over other drugs such as Gilead’s Remdesivir and Merck’s Molnupiravir for mild and moderate COVID-19 patients.
Composition, mechanism, and pharmacological properties
The treatment regimen of Paxlovid comprises three film-coated tablets- two pink-colored tablets of Nirmatrelvir (150 mg each), and one white-colored tablet of Ritonavir (100 mg). The three tablets have to be taken simultaneously by the oral route twice daily for five consecutive days. Therefore, in total, the patients would be administered 30 tablets over five days.
Nirmatrelvir is a peptidomimetic inhibitor of the coronavirus 3C-like (3CL) protease, including the SARS-CoV-2 3CL protease. Inhibiting 3CL protease renders the protein incapable of processing polyprotein precursors which prevents viral replication. Ritonavir inhibits the CYP3A-mediated metabolism of nirmatrelvir, thereby providing increased plasma concentrations of nirmatrelvir. Since Paxlovid works by inhibiting SARS-CoV-2 replication in the host cells, it must be administered in the initial stage of COVID-19 within five days of onset of symptoms.
Indications, contraindications, and clinical efficacy
The patients must be 18 years and above, and have a high risk of progression to severe COVID-19 but not require oxygen supplementation. However, this drug is contraindicated for children, pregnant or breastfeeding women, and patients with severe hepatic or renal impairments.
The recommended Paxlovid use are based on the results of two randomized controlled trials conducted on over 3,000 patients that demonstrated an 85% reduction in risk of hospitalization on Paxlovid use.
Quoting Mikael Dolsten, M.D., Ph.D., Chief Scientific Officer and President, Worldwide Research, Development and Medical of Pfizer, ‘Following the clinical findings – showing Paxlovid reduced risk of hospitalization or death by nearly 90% compared to placebo for high-risk patients when treated within five days of symptom onset – we are encouraged by these initial laboratory findings.’
Of note, based on an official statement from Pfizer dated January 18, 2022, Paxlovid is effective against the recently emerged Omicron variant along with other variants containing mutations in their spike (S) protein.
Safety profile, special concerns, and drug interactions
Based on reports, the common side effects of Paxlovid use include diarrhea, dysgeusia, nausea, hypertension, and muscle aches. However, Paxlovid has a better safety profile compared to molnupiravir and is more convenient to administer compared to the intravenously administered remdesivir and monoclonal antibodies. Therefore, it is a superior choice, especially for the unvaccinated, immunocompromised, and elderly COVID-19 patients. Janet Diaz, WHO lead on clinical management has also stated that Paxlovid is not a substitute for COVID-19 vaccines, but an effective adjunct for reducing the COVID-19 burden.
Paxlovid must be used with caution in patients with hepatic diseases. The patients must be regularly monitored for clinical signs and symptoms of jaundice, clinical hepatitis and the serum levels of hepatic transaminase must be routinely checked. In addition, there is a potential risk of developing resistance to HIV protease inhibitors on Paxlovid use among individuals with uncontrolled or undiagnosed HIV-1 infection. Moreover, since Paxlovid is a CYP3A inhibitor, it may increase the plasma concentrations of drugs that are metabolized by the cytochrome P450 enzyme.
At present, the full course of Paxlovid costs $530 in the United States. In early 2022, Pfizer officials declared that they expected $22 billion in sales in 2022. The high cost and indication for use in early COVID-19 impedes its use in low- and middle-income nations.
The US-based company has agreed to sell up to four million treatment courses of Paxlovid to UNICEF for use in 95 low-income nations (including India) which encompass just over half of the global population. This deal accounts for just over 3% of Pfizer’s projected production of 120 million courses this year. In addition, more than 30 generic drugmakers have been granted permission to manufacture more economic versions of Paxlovid for developing nations. However, based on WHO’S statements, these economic versions are unlikely to be available in the near future, highlighting that the lack of pricing transparency could mean that the low- and middle-income nations would be pushed to the end of the queue, as happened with COVID-19 vaccines.
Paxlovid has received accelerated approval from the Drugs Controller General of India (DCGI) for emergency use in COVID-19, amid rising infections in the country. Hyderabad-based Hetero labs will manufacture the generic version of Pfizer’s Paxlovid in India and the drug is stated to be available in India by the end of the coming week.
Dr. Pooja Toshniwal Paharia is a Consultant Oral and Maxillofacial Physician and Radiologist, M.DS (Oral Medicine and Radiology) from Mumbai. She strongly believes in evidence-based radiodiagnosis and therapeutic regimens for benign, potentially malignant, or malignant lesions and conditions either arising from the oral and maxillofacial structures or manifesting in the associated regions.