By: Kirby An, PharmD Candidate c/o 2023

              Coronavirus Disease (Covid-19) is a virus that took the world by storm with its initial discovery in Wuhan, China in December of 2019. On January 20, 2020, the Centers for Disease Control (CDC) confirmed the first case of Covid-19 in the United States (US) after a 35 year old man presented with cough and fever after returning to Washington from Wuhan, China.¹ By the end of 2020, Covid-19 had infected over 82 million people worldwide, leading to a death toll of over 3 million people.² As of August 2022, there are 94,268,241 total cases of Covid-19 infection in the US, with a death toll reaching 1,040,314.³ Despite the grueling numbers, the US has made great strides in combating the pandemic through prevention. While mask mandates and social distancing played a huge part in diminishing Covid-19 rates in the US, the rapid development of nationwide vaccination initiatives was a key component to slowing down the spread of the virus. Today, thanks to the accessibility of vaccinations, about 224 million people are fully vaccinated and the CDC records that about 84% of people aged 5 and older have received at least the first dose of a vaccine series.³

While vaccines have proved to be efficacious in preventing Covid-19, therapeutic options are still necessary for post-exposure treatment. To date, there are only a few approved and emergency authorized antiviral medications available for use. The drugs currently recommended target either the conserved viral RNA-dependent RNA polymerase (RdRp), the conserved viral main protease (Mpro or 3CL protease), or block SARS-CoV-2 entry.⁴ In the treatment of hospitalized patients with Covid-19 that do not require oxygen supplementation, the drug of choice is a RdRp-specific antiviral medication known as remdesivir.⁵ Remdesivir was the first antiviral medication approved for the treatment of Covid-19 and has been proven to improve clinical outcomes of hospitalized patients and slow disease progression.⁴ Despite the effectiveness of remdesivir, it requires intravenous administration which limits its access to the inpatient setting. In order to continue making strides in combatting the pandemic, oral antiviral medications, like Paxlovid, were developed to provide accessibility in the outpatient setting.

Paxlovid, co-packaged nirmatrelvir and ritonavir, is an oral antiviral medication approved by the Food and Drug Administration (FDA) for emergency use authorization on December 22, 2021.⁶ Nirmatrelvir is a peptidomimetic inhibitor of the SARS-CoV-2 main protease, Mpro (or 3CL protease). Mpro is a cysteine protease that cleaves polyproteins pp1a and pp1ab, which are key components of viral replication for SARS-CoV-2. By irreversibly inhibiting Mpro, viral replication is hindered. Ritonavir is an HIV-1 protease inhibitor that is not directly active against SARS-CoV-2 Mpro. However, ritonavir inhibits CYP3A activity, the enzyme that metabolizes nirmatrelvir, which increases the plasma concentration and half-life of nirmatrelvir.⁷

Clinical Trial Results

Pfizer conducted an international, phase 2-3 double blind, randomized controlled trial to assess the efficacy, viral load, and safety of Paxlovid in preventing disease progression in unvaccinated adults with mild to moderate Covid-19 who were at high risk of progression to severe infection. This study consisted of 2,246 adults aged 18 years or older with confirmed SARS-CoV-2 infection.⁸ Patients who were included in the trial had more than 1 comorbidity associated with increased risk of developing severe Covid-19 illness. These characteristics included age ≥ 60 years, BMI > 25 kg/m², cigarette smoker, immunosuppressive disease or suspected/confirmed active systemic infection, and comorbidity requiring hospitalization and/or surgery or considered life threatening ≤ 7 and ≤ 30 days, respectively, prior to study entry.⁸ 61% of participants had two or more conditions listed in the inclusion criteria.⁹ The study excluded patients who were pregnant or breastfeeding, or who had active liver disease, moderate to severe renal impairment, known HIV, previous confirmed SARS-CoV-2 infection, anticipated need for hospitalization within 48 hours after randomization, and prior receipt of convalescent Covid-19 plasma or SARS-CoV-2 vaccine.⁸

Eligible patients were randomly assigned to the experimental or control group in a 1:1 ratio. Participants were given either nirmatrelvir 300 mg plus ritonavir 100 mg or placebo every 12 hours for 5 days, starting within 5 days of the onset of symptoms. The primary objective was to assess the efficacy of Paxlovid by comparing the percentage of patients with Covid-19 related hospitalizations or death from any cause through day 28. The primary endpoint focused on a modified intention-to-treat population which included 1,379 of the 2,246 patients in the full analysis population. Secondary end points looked to quantify SARS-CoV-2 viral loads, as well as assess adverse events that occurred during or after treatment before day 34.⁸

In the analysis of patients who received treatment within 3 days after symptom onset, 5 of 697 patients (0.72%) in the Paxlovid group and 44 of 682 (6.45%) in the placebo group were hospitalized for Covid-19 or died from any cause through day 28. The study also used the Kaplan-Meier method (statistical analysis of survival probability) and found estimated rates of Covid-19 associated hospitalization or death from any cause at 28 days to be 0.72% in the Paxlovid group and 6.53% in the placebo group, corresponding to a difference of −5.81% (95% CI –7.78 to –3.84; P<0.001) and an 88.9% relative risk reduction in Covid-19–related hospitalization or death from any cause. Looking at mortality rates, nine deaths were reported in the placebo group, and none were reported in the Paxlovid group.⁸ A secondary analysis included patients who received treatment within 5 days after symptom onset to evaluate hospitalization for Covid-19 or death from any cause. In the analysis of this population of study, 8 of 1,039 patients (0.77%) in the Paxlovid group and 66 of 1,046 (6.31%) in the placebo group were hospitalized for Covid-19 or died from any cause through day 28 (P<0.001), corresponding to an 87.8% relative risk reduction.⁸

The incidence of adverse events that occurred during the treatment period was similar in both experimental and control groups. Incidence of any adverse event occurring was 22.6% with Paxlovid vs. 23.9% with placebo. Serious adverse events occurred in 1.6% with Paxlovid vs. 6.6% with placebo. Any adverse events leading to discontinuation of the drugs or placebo were 2.1% in Paxlovid vs. 4.2% in placebo. Dysgeusia (5.6% vs. 0.3%) and diarrhea (3.1% vs. 1.6%) were two adverse reactions that had been found to occur more frequently with Paxlovid than with placebo.⁸

Clinical Use of Paxlovid

Currently, Paxlovid is a preferred therapy in those who do not require hospitalization or supplemental oxygen, and are at higher risk of progression to serious infection. In those aged 12 years and older who weigh ≥ 40 kg, guidelines recommend Paxlovid at a dose of 300 mg of nirmatrelvir and 100 mg of ritonavir by mouth twice daily for 5 days.⁹ Treatment is recommended as soon as possible and within 5 days of the onset of symptoms. The recommended dose reduction in patients with moderate renal impairment and an eGFR between 30-60 mL/min is 150 mg nirmatrelvir and 100 mg of ritonavir twice daily for 5 days.⁵ In patients with severe renal or hepatic impairment, Paxlovid should be avoided. A major concern for Paxlovid is the concomitant use of drugs highly dependent on CYP3A clearance that may otherwise lead to serious adverse reactions; dose adjustments and additional monitoring may be necessary. Paxlovid is currently only authorized in those 12 years and older weighing at least 40 kg. There is currently no human data on nirmatrelvir during pregnancy that evaluated the risk for birth defects, miscarriage, or adverse fetal or maternal outcomes.⁷ The most common side effects correlated with the use of Paxlovid include dysgeusia, diarrhea, hypertension, and myalgia.⁷

Conclusion

While the medical field continues its efforts to keep up with the pandemic, guidelines and new treatments are changing and developing. On July 6, 2022, the FDA recognized the importance of pharmacists in the pandemic and authorized pharmacists to prescribe Paxlovid. Under the revised emergency use authorization, pharmacists can prescribe Paxlovid except for when modification of other medications is necessary due to drug-drug interactions, renal or hepatic function is undefined, or if there is not enough information to assess for the potential of drug interactions.¹⁰ With Paxlovid being an oral antiviral medication that can be dispensed at any community pharmacy and taken from home, we come closer to tackling Covid-19 by providing increased accessibility to treatment.

References

1. Centers for Disease Control. CDC Museum Covid-19 Timeline. CDC. https://www.cdc.gov/museum/timeline/covid19.html. Published 01/05/2022.
2. World Health Organization. The impact of COVID-19 on global health goal. WHO. https://www.who.int/news-room/spotlight/the-impact-of-covid-19-on-global-health-goals. Published 05/20/2021.
3. Centers for Disease Control.CDC Covid Data Tracker. CDC. https://covid.cdc.gov/covid-data-tracker/#datatracker-home.
4. Vangeel, Laura et al. “Remdesivir, Molnupiravir and Nirmatrelvir remain active against SARS-CoV-2 Omicron and other variants of concern.” Antiviral research vol. 198 (2022): 105252. doi:10.1016/j.antiviral.2022.105252
5. National Institute of Health. Therapeutic Management of Non-hospitalized Adults With COVID-19. Covid-19 Treatment Guidelines. https://www.covid19treatmentguidelines.nih.gov/management/clinical-management/nonhospitalized-adults–therapeutic-management/. Published 04/08/2022.
6. Food and Drug Administration. Coronavirus (COVID-19) Update: FDA Authorizes First Oral Antiviral for Treatment of COVID-19. FDA. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-first-oral-antiviral-treatment-covid-19. Published 12/22/2021.
7. Paxlovid (Nirmatrelvir-Ritonavir) [package insert]. New York, NY; Pfizer; Revised 03/18/2022
8. Hammond, Jennifer et al. “Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19.” The New England journal of medicine vol. 386,15 (2022): 1397-1408. doi:10.1056/NEJMoa2118542
9. Lamb, Yvette N. “Nirmatrelvir Plus Ritonavir: First Approval.” Drugs vol. 82,5 (2022): 585-591. doi:10.1007/s40265-022-01692-5
10. Food and Drug Administration. Coronavirus (COVID-19) Update: FDA Authorizes Pharmacists to Prescribe Paxlovid with Certain Limitations. FDA. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-pharmacists-prescribe-paxlovid-certain-limitations

Published by Rho Chi Post