Materia Medica

Paxlovid: The First Authorized Oral Antiviral for COVID-19 Treatment in Non-Hospitalized Patients

elizABeth posney, phArm.d., pgy-1 phArmACy resident - AmBulAtory CAre, Allegheny heAlth networK, Allegheny generAl hospitAl, pittsBurgh, pA

Pfizer’s anti-COVID medication, Paxlovid (nirmatrelvir/ritonavir), is the newest tool in the healthcare provider’s toolkit to treat COVID-19 in nonhospitalized patients. It was authorized for emergency use by the FDA in December of 2021, and the COVID-19 treatment guidelines have recently been updated to include Paxlovid as the most preferred agent to use for COVID-19 treatment in the outpatient setting.1 Given the expanded access of this medication and still-rising numbers of COVID-19 cases, it is important for practitioners to stay updated on Paxlovid safety and efficacy data.

Figure 1. COVID-19 Treatment Guidelines: therapeutic management of non-hospitalized adults with COVID-191

How it works

Pfizer took a novel approach to fighting the virus—instead of targeting the spike protein of SARS-CoV-2 like other COVID-19 treatments, this medication targets an intra-cellular protease that drives viral replication. Paxlovid is sold as two separate antiviral medications, nirmatrelvir and ritonavir, that are packaged together in a dose card blister pack. Patients take three oral tablets twice daily for 5 days: two tablets of nirmatrelvir 150 mg with one tablet of ritonavir 100 mg.

Nirmatrelvir works by blocking the actions of SARS-CoV-2-3

chymotrypsin-like cysteine protease Mpro (3CL protease), which is an enzyme used for viral replication at the proteolysis stage, before viral RNA replication takes place (Figure 2). This enzyme was targeted because there is a low likelihood of off-target activity, and there are no recognized human analogues.2 Additionally, there is thought to be less mutation in this site compared to spike protein sites on the virus, which means there is a higher likelihood that efficacy can be maintained across variants.

The purpose of the ritonavir component is not to provide additional antiviral activity; instead, it is used to block the elimination of nirmatrelvir so that anti-viral activity is maintained. Ritonavir is a strong CYP3A4 inhibitor and allows for nirmatrelvir concentrations to be maintained at 5-6 times the concentration needed to block viral replication of SARS-CoV-2.2

In terms of pharmacokinetics, the medication is cleared hepatically by CYP3A4 (major) and CYP2D6 (minor) and has an elimination half-life of about 6 hours.3

Figure 2. Nirmatrelvir mechanism of action: inhibition of viral 3CL protease, so that functional, smaller viral proteins cannot be produced.4

Dosing5

This medication should be taken within 5 days of symptom onset. After initiating treatment, if hospitalization is required, completion of a 5-day course can be considered at the provider’s discretion. Patients are to complete a total of 5 days of nirmatrelvir 300 mg with ritonavir 100 mg, taken together twice daily. No dose adjustment is needed for patients with estimated glomerular filtration rate (eGFR) of at least 60 mL/minute, but the dose should be lowered to nirmatrelvir 150 mg and ritonavir 100 mg twice daily in those with eGFR 30 to 59 mL/ minute. Use is contraindicated if eGFR is less than 30 mL/minute. No dose adjustment is necessary in mild to moderate hepatic impairment, but use is not recommended in severe hepatic impairment.

Who can access Paxlovid, and where:

Paxlovid is currently under EUAapproval for use in patients age 12 and up, weighing at least 88 lbs, and meeting at least one of the following high-risk criteria: history of cancer, chronic liver, kidney, lung, or cardiovascular conditions (including hyperlipidemia and hypertension), sickle cell disease, cystic fibrosis, dementia or other neurological conditions, diabetes, disabilities, HIV, mood disorders such as depression or schizophrenia, transplant, substance use disorders, tuberculosis, immunocompromised status, age at least 65 years, or BMI >25 kg/m2.6 Additionally, patients need to be within 5 days of symptom onset and have a positive COVID test in order to qualify for treatment with Paxlovid.

National supplies of Paxlovid began to increase in March 2022 (Figure 3), and President Biden recently announced the national Test-toTreat Initiative to make it easier for higher-risk patients to quickly access oral antiviral treatments.7 There are currently about 2,200 Test to Treat sites in pharmacies and other clinical settings, where patients can get a COVID test, visit with a doctor, and obtain free Paxlovid all in one visit. The Federal government is working to expand access to these sites and include telehealth options.7 Patients can also obtain Paxlovid from any local pharmacy with a prescription from their healthcare provider.

Figure 3. Pfizer report of Paxlovid usage February through April 20228

How well does it work?

Clinical trials testing the efficacy and safety of Paxlovid are called the EPIC trials--Evaluation of Protease Inhibition for COVID-19 in high-risk patients (EPIC-HR) and standard risk patients (EPIC-SR). EPIC-HR was published in the New England Journal of Medicine in April 2022, and EPIC SR has yet to be published, although Pfizer announced interim results of EPIC-SR in December 2021. In the high-risk trial, patients were included if they tested positive to COVID-19, were unvaccinated, and had at least one symptom of COVID-19. Patients also had to meet at least one of the specified high-risk criteria. For the standard-risk study, patients were included if they were unvaccinated with a low risk of hospitalization or death or vaccinated with at least one risk factor for progressing to severe illness.

EPIC-HR showed that Paxlovid was effective in preventing COVID-related hospitalization and death. For patients who started treatment within 3 days of symptom onset, there was a relative risk reduction of 88.9% of COVID-19related hospitalization or death from any cause by day 28 (5 of 697 in the nirmatrelvir group vs. 44 of 682 in the placebo group, p<0.0001, Figure 2).9 Nine deaths were reported in the placebo group vs. no deaths in the treatment group. Among patients who started treatment within 5 days of symptom onset, relative risk reduction was 87.8%. Viral load was also significantly reduced by 10-fold at day 5 (p<0.0001) when treatment was initiated within 5 days of symptom onset.

Figure 4. EPIC-HR primary outcome results9

Pfizer revealed interim results of EPIC-SR with 80% of their target patient population in December of last year. They reported that there was a 70% relative risk reduction of COVID-19 related hospitalizations or death from any cause in the Paxlovid group vs. placebo group. However, the secondary endpoint of self-reported, sustained alleviation of all symptoms for four consecutive days, was not met.10 Interestingly, Pfizer recently stopped enrolling anyone who received a vaccine or booster in the past year, which suggests that those patients may not be benefitting from Paxlovid treatment.

In regard to efficacy against different variants, Pfizer has announced that invitro data showed that the medication was just as effective against Omicron as it was against earlier variants. This is based on data from three laboratory studies.10

Is it safe?

In clinical trials, the most commonly reported side effects of Paxlovid included poor taste (5.6%), diarrhea (3.1%), fibrin d-dimer increase (1.9%), alanine aminotransferase increase (1.5%), headache (1.4%), creatinine clearance decrease (1.4%), nausea (1.4%), and vomiting (1.1%)—all were grade 1-2 in severity and resolved after the treatment course was finished.9 There were fewer grade 3 to 4 events in the treatment group compared to the placebo group. There was a similar overall adverse event incidence in the Paxlovid and placebo groups (22.6% vs. 23.9%, respectively).

After the clinical trial results were released, there have been reports of rebound symptoms several days after patients complete the 5-day treatment regimen. FDA and Pfizer have stated that 1-2% of patients in the original study experienced increased viral levels around 10 days post-treatment, which was about the same among people taking placebo, so the FDA concluded that there is not enough evidence at this time to say that this is related to drug treatment.10 COVID-19 guidelines were updated on May 13, 2022 to acknowledge these reports of viral rebound, but that frequency and clinical implications are unknown.1

Contraindications to Paxlovid in the package labeling include history of hypersensitivity to drug ingredients and co-administration with strong CYP3A4 inhibitors/inducers. Precautions and warnings include hepatotoxicity, HIV drug resistance, and hypersensitivity reactions, which have occurred postclinical trials.3

Drug-drug interactions are one of the biggest barriers to prescribing this medication. Several cardiovascular medications, including digoxin, simvastatin, lovastatin, ranolazine, and amiodarone cannot be used concurrently with Paxlovid, as well as some birth control medications, anti-convulsants, and anticoagulants. Providers should refer to medication labeling for a complete list of drug interactions before prescribing Paxlovid.3 Patients should be counseled on these potential drug interactions and should be aware that they must let their doctor know if they have recently started new medications prior to taking Paxlovid.

Currently, there is no human data regarding safety and efficacy in patients who are pregnant and lactating.

Still to come….

One of the biggest critiques against Paxlovid is that we do not yet know how effective the medication is in patients who are vaccinated. Results from the EPIC-SR trial are expected to be released in the Fall of 2022, which will include a study population that is more representative of the current overall population in the United States. Furthermore, Pfizer has begun phase 2/3 trials of Paxlovid safety and efficacy in children and teens ages 6-17.

Studies directly comparing Paxlovid efficacy with that of alternative antiviral medications such as remdesivir and Merck’s molnupiravir are also underway, as well as studies focusing on efficacy of Paxlovid against new variants.

References:

1. COVID-19 Treatment Guidelines Panel.

Coronavirus Disease 2019 (COVID-19)

Treatment Guidelines. National Institutes of Health. Available at https://www. covid19treatmentguidelines.nih.gov/.

Accessed 5.17.22

2. Hammond J, Leister Tebbe H, Gardner A, et al. Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with COVID-19. N Engl J

Med 2022; 386:1397-1408.

3. Paxlovid Fact Sheet for Healthcare

Providers: EUA for Paxlovid. https://www. fda.gov/media/155050/download.

Accessed 5.18.22.

4. Doyle K. Nimatrelvir’s mechanism of action.

Promega Connections. Posted January 24, 2022. https://www.promegaconnections. com/covid-19-antiviral-therapies-what-arethe-new-drugs-and-how-do-they-work/.

Accessed 5.18.22. 5. Lexicomp. Nirmatrelvir and Ritonavir (Lexi-Drugs). Wolter’s Kluwar. Updated May 25, 2022. Accessed 5.26.22.

6. Medical Conditions. Centers for Disease

Control and Prevention. Updated May 2, 2022. https://www.cdc.gov/coronavirus/2019ncov/need-extra-precautions/people-withmedical-conditions.html. Accessed 5.17.22

7. Fact Sheet: Biden administration increases access to COVID-19 treatments and boosts patient and provider awareness. Whitehouse.gov. https:// www.whitehouse.gov/briefing-room/ statements-releases/2022/04/26/fact-sheetbiden-administration-increases-access-tocovid-19-treatments-and-boosts-patient-andprovider-awareness/. Accessed 5.18.22.

8. Pfizer First Quarter 2022 Earnings

Teleconference. Pfizer. Posted May 3, 2022. https://s28.q4cdn.com/781576035/files/ doc_financials/2022/q1/Q1-2022-Earnings-

Charts-FINAL-(1).pdf. Accessed 5.18.22.

9. Hammond J, Leister Tebbe H, Gardner A, et al. Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with COVID-19. N Engl J

Med 2022; 386:1397-1408.

10. Press release: Pfizer announces additional phase 2/3 study results. Pfizer. Posted

December 14, 2021. https://www.pfizer. com/news/press-release/press-releasedetail/pfizer-announces-additional-phase23-study-results. Accessed 5.18.22.

Dr. Posney is a PGY-1 Ambulatory Care Pharmacy Resident at Allegheny General Hospital.

For any questions concerning this article, please contact Elizabeth Posney, Pharm.D., at the Allegheny Health Network, Allegheny General Hospital, Center for Pharmaceutical Care, Pittsburgh, PA. (412) 359-3192 or email elizabeth.posney@ahn.org