Paxlovid: A promising drug for the challenging treatment of SARS-COV-2 in the pandemic era

Abstract

Coronavirus infection is a pandemic threat and the most dangerous disease of the 21^st century. Despite the rigorous exertion of world-class researchers, there is no perfect cure for it. It has been seen in presently available studies that Paxlovid prevents the progression of diseases and reduces severity in patients tremendously who are at high risk of hospitalization and death. It is a safe oral antiviral drug and has the potential to treat infections from multiple corona variants including omicron which affects humans. Paxlovid is comparatively less expensive than other available effective medicines. Consequently, it reduces hospitalization and death and helps to plummet the economic burden on patients and the health-care system globally. This medicine is still under investigation, and numerous clinical trials are still underway. Its potential side effects are minor and well tolerated by research study participants. Studies show its benefits outweigh the risk, and it is an effective and good alternative for the treatment of coronavirus disease.

Introduction

Coronavirus infection is a pandemic threat and the most dangerous disease in the 20^th century. SARS-COV-2 viruses are continuously mutating, and their nature is unpredictable. Around 400 million people are suffering, and approximately 5.7 million deaths have occurred worldwide, which is increasing in number.[1] Due to this terrible desolation, people are suffering physically, economically, and psychologically. Despite the consummate crusade of world-class research, there is no perfect cure for this lethal disease neither in the form of therapeutic medication nor as ideal vaccines. The structure of the virus is highly complex, and its numerous mutations are progressively dilapidating human existence.

Paxlovid is a therapeutic combination of two drugs, namely, nirmatrelvir and ritonavir. It prevents the progression of the disease and reduces its severity in COVID-19 patients tremendously. However, research on it is still ongoing.[2] It received the Emergency Use Authorization (EUA) from the U. S. Food and Drug Administration (FDA) to combat mild-to-moderate conditions for COVID-19 patients who are 12 years and/or older and carry a high risk of progression to severe disease, hospitalization, or death.[3] Very few studies have been published in this regard, and many clinical trials as mentioned further are ongoing. In the present article, we have discussed the efficacy and safety of Paxlovid from the available published literature and summarized ongoing clinical trials.

Mechanism of Action

Paxlovid is an antiviral preparation containing nirmatrelvir and ritonavir.[4] It works intracellularly and inhibits the main protease (M^pro) of the SARS-CoV-2 virus. It inhibits the replication of viral RNA in the proteolytic stage. Nirmatrelvir is the M^pro inhibitor that blocks the replication of coronavirus (SARS-COV-2 M^pro), whereas ritonavir is a strong inhibitor of cytochrome P 450 (CYP) 3A which inhibits the metabolism and breakdown of nirmatrelvir so that it remains active at higher concentrations in the body for a longer duration.

Safety

Paxlovid is a safe oral antiviral drug. A study done on 1881 patients observed that Paxlovid compared with placebo had 19% and 21% adverse events, respectively. Most of the events were of mild intensity. Nearly 1.7% of serious adverse events were observed in Paxlovid-treated patients, whereas 6.6% were seen in placebo-treated ones. The study was discontinued when 2.1% of serious adverse events occurred in the Paxlovid arm and 4.1% in the placebo arm.[5] A pivotal EPIC-HR study of Paxlovid in transplant patients suggests that it should not be given to those who are highly dependent on CYP3A4 for their clearance.[6] Ritonavir is a strong inhibitor of the cytochrome P450 and p-glycoprotein, and hence, the dose should be monitored and individualized.[6] Furthermore, the FDA has suggested that it is not recommended for those patients who have a history of liver or renal function impairment. However, clinicians must be vigilant and active monitoring of the patient is required during Paxlovid use. It is important to perform risk management when Paxlovid efficacy outweighs the risk to individual transplant recipients.

Efficacy

Paxlovid (nirmatrelvir (PF-07321332) + Ritonavir) is the first oral antiviral therapy administered for coronavirus treatment which is authorized only by the prescription in the United States of America (U. S. A). The data available regarding efficacy of paxlovid in the treatment of COVID-19 are summarized in Table 2. In the clinical trial, scheduled interim analysis proved that this drug reduces dramatically, i.e., by 89%, the risk of hospitalization or death in the patients suffering from COVID-19 in comparison to the placebo. Paxlovid reduces the mortality in patients within 3 days of onset of symptom, with only 0.8% (3/339) admitted to the hospital on the 28^th day after randomization and occurrence of no deaths.[5,6] Hospitalization of 7% (27/385) and deaths of 1.81% of patients were seen in the placebo arm. Furthermore, it had been noticed that, in those patients who were treated with Paxlovid within 5 days of symptom onset, hospitalization was seen in only 1% (6/607) of patients and no deaths were observed.[5,6] However, hospitalization was seen in 6.7% (41/612) of patients and deaths in ten patients (1.6%) in the placebo arm.[5,6] The results of both studies were highly significant (P < 0.0001). Furthermore, in phase 2 and 3 trials, a primary interim analysis of enrolled 1219 adult patients showed that Paxlovid reduced death and hospitalization by 89%.[4]

Table 2.

Efficacy data of paxlovid

Study	Study design/type	Country/Region	Total number of participants/in the paxlovid group (%)/(and or in the control group [if available])	Age group	Patient population and adverse effect outcome due to paxlovid treatment	Findings
Najjar-Debbiny et al., 2022	Retrospective cohort study	Israel	180,351 4737 (2.6%)	≥18 years	Non-hospitalized patients of COVID-19	Paxlovid is highly effective in the Omicron era Paxlovid appears very effective in older, immunosuppressed, and the patient who had underlying diseases such as cardiovascular or neurological
Malden et al., 2022[6]	Retrospective cohort study	California	Paxlovid received 5287 patients	≥12 years	Mild-to-moderate condition or disease progression	Paxlovid reduced hospitalization; it was rare if paxlovid was administered in the early stage
Zheng et al., 2023[7]	Meta-analysis (13 studies included 3 were rebound studies)	-	186,306 patients	Adults	Mild-to-moderate COVID-19	Paxlovid is safe and effective The rebound case of COVID-19 was not unique to paxlovid only
Wen et al., 2022[8]	Meta-analysis Total 8 studies	-	2440 patients (drug group) 2348 patients (control group)	-	Treatment group - 54 (died or hospitalized) Control group - 118 (died or hospitalized)	The finding suggests that three antiviral agents (molnupiravir, fluvoxamine, and paxlovid) are well-safe and very effective which significantly reduced mortality and hospitalization It is also concluded that these three oral antivirals are promising alternatives
Cheema et al., 2023[9]	Systematic review and meta-analysis (12 studies - 2-RCTs and 10-observational studies)	#	#	#	Patients of COVID-19	This study concluded that paxlovid is a safe and effective drug for COVID-19 patients
Amani and Amani, 2022[10]	Review and meta-analysis (23 studies)		314,353 patients	Adults	Patients of COVID-19	The study concluded paxlovid is very efficacious and safe More investigation is required for better precision in rebound cases
Shao et al., 2022[11]	Retrospective, single-lefted study	Shanghai China	226	Median age 52	Vaccinated people rarely get severe disease due to omicron variants	Early administration of paxlovid greatly reduced the severity
Bose-Brill et al., 2022[12]	Retrospective cohort study	Philadelphia USA	1,496,621 total patients 920 paxlovid treated patient	18-23 years	Mild-to-moderated and chronic or complex cases of COVID-19	Patients receiving paxlovid significantly reduce chronic disease burden Implementation of paxlovid in pediatric patients will help to know better precision results
Shah et al., 2022[13]	Retrospective study	USA EHA data	699,848 participants 198,756 (28.4%) Paxlovid treated	≥18 years	Mild-to-moderate cases of COVID-19	Paxlovid-treated adults significantly reduce the risk of hospitalization than the non-treated group
Zhong et al., 2022[14]	A non-randomized, controlled trial	Shanghai, China	142 total patients 106-paxlovid group 36 placebo group	Adults	Mild-to-moderate- confirmed cases of omicron variant	Shorter period of viral infection in the paxlovid group compared to the placebo group
Shi et al., 2022[15]	Retrospective study	Shanghai, China	3 children	12-17 years	Hospitalized children Skin rashes	Paxlovid seems that it was effective and safe for children
Kuehn 2022[16]	Research report (HER data)	USA	700,000 patients (30 sites in the USA)	Adults	Mild-to-moderate cases	Black and other racial groups (including high-risk patients) seem less likely to accept paxlovid treatment than white patients

^#Data not available in public domain. RCTs=Randomized control trails

In another clinical trial, 70% of the 3000 patients were from across the world (North and South America, Africa, Asia, and Europe), and out of these 3000 patients, 45% of patients were from the USA.[2,4,5] The Europe Medicine Agency (EMA) on December 16, 2021, gave an EUA to Paxlovid based on interim results. It was demonstrated that Paxlovid reduced hospitalization and death when treated within 5 days of onset of symptom. Only 1% (6/607) of the Paxlovid-treated patients were hospitalized as against 7% (41/612) of those from the placebo-treated arm within 28 days of starting treatment.[29] None of the deaths occurred in the Paxlovid group, but ten deaths were seen in the placebo group. EMA's human medicines committee (CHMP) has also recommended conditional marketing authorization for Paxlovid. The study of CHMP data evaluated patients of COVID-19 who were treated with Paxlovid significantly reduced hospitalization, and it was 0.8% (8/1039) compared to placebo 6.3% (66/1046).[30] Numerous clinical trials of paxlovid are ongoing and are given in Table 3.

Table 3.

Ongoing clinical trials of paxlovid

Studies	Drug participants	Trial phase	Participants type and/or number of participants	Number of participants	Status
NCT04962022[19]	Drug: PF-07321332/ritonavir Drug: Itraconazole	1	Healthy participants	12	Recruitment completed
NCT04962230[20]	Drug: PF-07321332/ritonavir Drug: Carbamazepine Drug: PF 07321332/ritonavir	1	Healthy participants	12	Recruitment completed
NCT04756531[21]	Drug: PF-07321332 different dose 1, 2 and 3 Drug: PF-07321332 dose 4 Drug: PF-07321332 dose 5 Drug: PF-07321332 dose 4 or placebo (fed)	1	Healthy participants	70	Recruitment completed
NCT05064800[22]	Drug: Dabigatran Drug: PF-07321332/ritonavir + dabigatran Drug: Ritonavir+dabigatran	1	Healthy participants	24	Recruitment completed
NCT05005312[23]	Drug: PF-07321332 Drug: Ritonavir	1	Hepatic impairment	17	Recruitment completed
NCT05032950[24]	Drug: Midazolam Drug: PF-07321332/ritonavir + Midazolam Drug: Ritonavir + midazolam	1	Healthy participants	12	Recruitment completed
NCT05047601[25]	Drug: PF-07321332 Drug: Placebo for PF-07321332 Drug: Placebo for ritonavir Drug: Ritonavir	3	Asymptomatic household contacts of symptomatic COVID-19 patients	2880	Recruitment ongoing
NCT05341609[26]	Drug: JT001 Drug: Paxlovid	Phase 3	Mild-to-moderate COVID-19	864	Recruiting
NCT04381936 (RECOVERY)[27]	Drug: Lopinavir-Ritonavir Drug: Corticosteroid Drug: Hydroxychloroquine Drug: Azithromycin Biological: Convalescent plasma Drug: Tocilizumab Biological: Immunoglobulin Drug: Synthetic neutralizing antibodies Drug: Aspirin Drug: Colchicine Drug: Baricitinib Drug: Anakinra Drug: Dimethyl fumarate Drug: High-dose corticosteroid Drug: Empagliflozin Drug: Sotrovimab Drug: Molnupiravir Drug: Paxlovid	Phase 2 Phase 3	Severe acute respiratory syndrome	50,000	Recruiting
NCT05263908[28]	Nirmatrelvir/ritonavir (paxlovid pack)	Case only, prospective study	The subjects who have been treated with paxlovid pack for the first time	3300	Not recruiting

Dosage recommendation

Paxlovid is now available in two dose packs Table 1:[31]

Table 1.

Available dose packs of Paxlovid

Dose pack	Drug components	Number of tablets per dose	The total dose of components (mg)	Complete regimen
Paxlovid 300 mg;	Nirmatrelvir tablets (pink)	2×150 mg tablets	300	3 tablets twice a day (at the same time) for 5 days
100 mg dose pack	Ritonavir tablets (white to off-white)	1×100 mg tablets	100
Paxlovid 150 mg;	Nirmatrelvir (pink)	1×150 mg tablet	150	Tablets twice a day (at the same time) for 5 days
100 mg dose pack	Ritonavir (white to off-white)	1×100 mg tablet	100

1. Paxlovid 300 mg; 100 mg dose pack: Contains 3 tablets per dose

2. Paxlovid 150 mg; 100 mg dose pack: Contains 2 tablets per dose.

The dosage regimen of the pharmaceutical preparation for the treatment of patients 12 years and older is as follows:

The patient population treatable with paxlovid[3]

Paxlovid is recommended for use in (1) confirmed COVID patients and/or increased risk of severe illness and (2) patients 12 years and older. Its use is not advisable in the following patients: (1) liver/kidney impaired patients; (2) HIV-infected patients; (3) systemic infection other than COVID-19; (4) any patient who has a comorbid condition and requires hospitalization and/or surgery within 7 days before the study or considered life-threatening within 30 days before the study entry; and (5) patients who are pregnant or expected to become pregnant and not using contraception.

Paxlovid: Hopefully an excellent drug for COVID-19 patients

There is a dire need for alternative medicine for corona patients. Paxlovid can be a promising drug because SARS-CoV-2 has single-stranded RNA and a very high transmissibility rate; also it has a higher receptor binding affinity, so more susceptible to protease and can change quickly in alternate host cell receptors. The biochemical nature of the virus shows that it has five types of known variants and its subtypes now alpha, beta, gamma, delta, and omicron (Alpha-B.1.1.7 was first identified in the U.K, Beta B1.351 first identified in South Africa, Gamma P. 1 first identified in Brazil, Delta B.1.617.2 first identified in India, and B.1.1.529-Omicron first distinguished in South Africa and Botswana, are most infected variant among their group).[32,33] Coronavirus has the largest genome among all kinds of known RNA viruses. SARS-CoV-2 genome has nonsegmented positive sense-stranded RNA which is about 30 kb in length and contains a 5'cap and 3'poly-A tail structure.[34] This viral genome has 29 encoded proteins; among these, 25 are nonstructural and accessory and 4 are structural proteins. Nonstructural protein plays a very important role in VIRAL RNA replication and invasion in the human immune system and also accessory structure protein is responsible for multiple functions such as viral infection, transmission, and survival in host cell/human cells, whereas structural protein is responsible for assembling and loading the virus particles.[34,35] Omicron is identified most recent new variant, first reported in South Africa on November 24, 2021, which has 32 mutants.[32] Paxlovid is a broad range spectrum, and the ability to fight against omicron because of its biochemical structure (PF-07321332 and boceprevir) which is a second-generation oral SARS-COV M^pro inhibitor. As the study addressed, Paxlovid is capable of treating infections from multiple coronaviruses which affect the human in vitro such as SARS-COV, SARS-COV-2, HCov-OC43, MERS-COV, HCoV-229E, and HCov-NL63.[32] Owen DR et al, 2021 discovered that PF-07321332 can boost the anti-SARS-CoV-2 activity in animal models (mouse and monkey) without cytotoxic activity and desirable pharmacokinetics and bioavailability properties. Another study suggests that in vitro, M^pro variants (such as G155, T211, L895, K90R, and L205V) are highly susceptible to PF-07321332, and paxlovid is very effective, and the P132H mutant of the omicron variant is not able to perform anti-SARS-CoV 2 activities with Paxlovid.[36] It can destroy the property of Beta and Delta SARS-CoV-2 variants.[32] Hence, we can expect that Paxlovid is a promising effective and safe alternative in the era of the omicron variant. Along with paxlovid, remdesivir, and molnupiravir are also effective, and all these three drugs have different mechanisms of action and proven efficacy in clinical trials in different markers in disease progression.

It is anticipated when Paxlovid is used alone or in combination with molnupiravir (also an antiviral agent) or remdesivir could change the pandemic turbulence worldwide.[2]

Because of this pathogen, the economic burden on the world/hospital/healthcare system is increasing continuously and it will be not sustainable if the progression will continue. Therefore, there is an unmet need for an aggressive approach to control SARS-CoV-2 with early treatment at home at the community level. Paxlovid is cheaper and can be given at home also. Consequently, it reduces the economic burden globally.

Discussion and Summary

Paxlovid is an emerging antiviral treatment that is anticipated to be highly beneficial in SARS-CoV-2 infection. It seems very effective in all kinds of corona variants, including new variants such as omicron as it can counter the several S protein mutations in the new variant that are not neutralized by vaccines or other existing drugs.[32] It is comparatively cheaper than other antiviral drugs, available monoclonal antibodies, immunomodulatory agents, or other adjunctive treatments such as remdesivir, tocilizumab, or interleukin-6 inhibitor, respectively.[37] It is to be used cautiously in liver and kidney patients. Moreover, Paxlovid is contraindicated to be used with drugs that are metabolized by CYP3A such as statins, silodosin, antiarrhythmics such as amiodarone and quinine; antipsychotics like clozapine and pimozide; oral midazolam, etc., as it can lead to serious reactions.[33] An example of this is a robust drug–drug interaction between Paxlovid and tacrolimus (metabolized by CYP P450 3A4) when Paxlovid was given to a kidney transplant patient receiving tacrolimus.[38] Furthermore, inducers of CYP3A4 when coadministered with Paxlovid can significantly reduce the plasma concentrations of nirmatrelvir or Paxlovid and may result in reduced antiviral response.[33]

In a recently conducted preclinical study, Paxlovid was shown to accelerate degeneration of cartilage by the activation of endoplasmic reticulum stress and interfering with redox homeostasis. Therefore, a long-term follow-up is recommended to look out for the development of osteoarthritis.[39] Paxlovid has demonstrated favorable outcomes in preclinical studies with minimum genetic toxicity and negative effect. A preclinical study done on male and female rats reported that nirmatrelvir given in very high doses (up to 1000 mg/kg/day, leading to more than 4 times systemic exposure of a human dose) did not affect their fertility, reproductive potential, or early embryonic potential.[8,18] Moreover, ritonavir too, does not adversely affect fertility as observed in rats, when the exposure was twice that of humans (in males) and 4 times (in females).[8] Moreover, oral antiviral drugs are likely to be safer and quicker in action than existing vaccines or hydroxychloroquine.[40] Another positive aspect is that oral antiviral drugs can be produced on large scale in a shorter period as well with no requirement of refrigeration, shipping, or treatment in the hospital and are less costly than other existing regimens such as monoclonal antibodies, vaccines, or adjuvant drugs.[8,37]

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.