Nirmatrelvir/ritonavir

Nirmatrelvir/ritonavir, sold under the brand name Paxlovid, is a co-packaged medication used as a treatment for COVID‑19.[7][9][15] It contains the antiviral medications nirmatrelvir and ritonavir and was developed by Pfizer.[7][9] Both are protease inhibitors: nirmatrelvir inhibits SARS-CoV-2 main protease, while ritonavir inhibits HIV-1 protease, and is additionally a strong CYP3A inhibitor.[9][16]

Nirmatrelvir/ritonavir
Nirmatrelvir
Ritonavir
Combination of
NirmatrelvirAntiviral drug
RitonavirCYP3A inhibitor; Antiviral drug
Clinical data
Trade namesPaxlovid
AHFS/Drugs.comMonograph
MedlinePlusa622005
License data
Pregnancy
category
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Identifiers
KEGG
ChEBI

Side effects of nirmatrelvir/ritonavir include changes in sense of taste (dysgeusia), diarrhea, high blood pressure (hypertension), and muscle pain (myalgia).[9]

In December 2021, nirmatrelvir/ritonavir was granted emergency use authorization by the United States Food and Drug Administration (FDA) for the treatment of COVID‑19.[11][17] It was approved in the United Kingdom later that month,[18] and in the European Union and Canada in January 2022.[13][19][20] In May 2023, it got full FDA approval for high-risk adults, while children 12-18 were still covered under the EUA.[12]

Medical uses

In the United States, nirmatrelvir/ritonavir is indicated for the treatment of mild-to-moderate COVID‑19 in adults who are at high risk for progression to severe COVID‑19, including hospitalization or death.[9][12] It is not authorized for the pre-exposure or post-exposure prevention of COVID‑19.[10][12]

In the European Union, the co-packaged medication is indicated for the treatment of COVID‑19 in adults who do not require supplemental oxygen and who are at increased risk for progressing to severe COVID‑19.[13]

If administered within five days of symptom onset, the efficacy of the co-packaged medication against hospitalization or death in unvaccinated high-risk adults is about 88% (95% CI, 75–94%).[11][21]

Contraindications

The medication is contraindicated in those with hypersensitivity to either of the two main components, and in those with severely reduced kidney or liver function.[11] Co-administration with certain drugs may have serious, sometimes fatal, effects.[22]

Pregnancy

The co-packaged medication is not recommended during pregnancy, in women who can become pregnant and who are not using contraception, and for women who are breastfeeding.[23] These recommendations are because laboratory studies in animals suggest that high doses of the co-packaged medication may affect the growth of the fetus.[23]

There are no human data on the use of nirmatrelvir during pregnancy related to the risk of birth defects, spontaneous abortions (miscarriage), or adverse outcomes. There are also no human data on the presence of nirmatrelvir in human milk, its effects on milk production or the infant. In pregnant rabbits, a reduction in fetal body weight was observed with systemic exposure ten times higher than the authorized human dose of the co-packaged medication. A temporary reduction in body weight was observed in the offspring of nursing rats.[11]

Side effects

Nirmatrelvir/ritonavir has a high potential for potentially serious drug interactions due to strong CYP3A inhibition by ritonavir.[9][16]

Adverse events of the co-packaged medication, regardless of causality, observed in the phase II-III EPIC-HR study included: dysgeusia (6% vs. < 1% for placebo), diarrhea (3% vs. 2% for placebo), hypertension (1% vs. < 1% for placebo), and myalgia (1% vs. < 1% for placebo).[9][11][23] In clinical trials, 2% of people discontinued treatment due to side effects with nirmatrelvir/ritonavir while 4% in the placebo group did so.[9] Nirmatrelvir/ritonavir is still under investigation, so its side effects have yet to be fully evaluated and may not be completely known.[16]

Other side effects of nirmatrelvir/ritonavir may include hypersensitivity reactions, liver toxicity, and development of HIV drug resistance in people with uncontrolled or undiagnosed HIV infection.[9][16] Hypersensitivity reactions (allergic reactions) may manifest as skin rash, hives, difficulty swallowing, difficulty breathing, angioedema, and/or anaphylaxis.[9][16] Liver toxicity may manifest as elevated transaminases and clinical hepatitis, including symptoms like appetite loss, jaundice (yellowing of the skin and whites of eyes), dark-colored urine, pale-colored stools, itchy skin, and abdominal pain.[9][16]

Interactions

Co-administration of Paxlovid with certain drugs is contra-indicated, including drugs dependent on CYP3A for removal, for which a raised concentration results in serious reactions, or those with potent CYP3A inducers, for which reduced blood concentration of the two main components may result in loss of effect against the virus and possible resistance, among others. Co-administration also affects the concentration of several drugs, sometimes requiring changing the dose or careful monitoring.[11][23] Many of these drugs are widely prescribed to people at high risk from COVID‑19.[24] With the extension of the emergency authorization in August 2022, the FDA updated a checklist to help evaluate potential drug interactions and other patient factors before prescribing Paxlovid, including more than 120 drugs which are either contraindicated, should be avoided or held from use, or require dose adjustments or special monitoring.[25][11]

Nirmatrelvir/ritonavir is said to be safe in combination with over-the-counter pain- and fever-reducing medications such as acetaminophen (paracetamol; Tylenol) and ibuprofen (Motrin).[26]

Pharmacology

Nirmatrelvir is responsible for the antiviral activity of the medication against SARS-CoV-2, while ritonavir works by inhibiting the metabolism of nirmatrelvir, strengthening its activity.[9][16]

Pharmacodynamics

Nirmatrelvir is a SARS-CoV-2 main protease (Mpro, 3CLpro, nsp5 protease) inhibitor while ritonavir is an HIV-1 protease inhibitor and strong CYP3A inhibitor.[9][16] Nirmatrelvir is the main active agent in the formulation, while ritonavir inhibits the metabolism of nirmatrelvir and thereby strengthens its activity.[9][16] Ritonavir is not active against or thought to directly contribute to the antiviral activity of the medication against SARS-CoV-2.[16][9] Nirmatrelvir/ritonavir works against COVID‑19 by preventing the replication of SARS-CoV-2, which the SARS-CoV-2 main protease is essential for.[9][16]

Absorption

The time to peak concentrations of nirmatrelvir combined with ritonavir is 3.00 hours (range 1.02–6.00 hours) while that of ritonavir is 3.98 hours.[9] Peak concentrations of nirmatrelvir combined with ritonavir following a single dose (300 mg nirmatrelvir and 100 mg ritonavir) in healthy individuals are 2.21 μg/mL while total exposure is 23.01 μg•h/mL.[9] Taking nirmatrelvir/ritonavir with a high-fat meal modestly increases exposure to nirmatrelvir (peak concentrations increased by 15% and total exposure increased by 1.6%) relative to taking them under fasting conditions.[9]

Distribution

The volume of distribution (Vz/F) of nirmatrelvir combined with ritonavir is 104.7 L while that of ritonavir is 112.4 L.[9] The blood-to-plasma ratio of nirmatrelvir combined with ritonavir is 0.60 while the red-blood-cell-to-plasma ratio of ritonavir is 0.14.[9] The plasma protein binding of nirmatrelvir combined with ritonavir is 69% while that of ritonavir is 98 to 99%.[9]

Metabolism

Nirmatrelvir is mainly a substrate of CYP3A in terms of its metabolism.[9] When combined with ritonavir however, which is a strong CYP3A4 inhibitor, the metabolism of nirmatrelvir is minimal and its elimination instead is mainly via renal excretion.[9] Ritonavir is eliminated mainly by hepatic metabolism, with CYP3A4 being the major enzyme involved, and CYP2D6 the minor enzyme.[9]

Elimination

Nirmatrelvir combined with ritonavir is excreted 35.3% in feces and 49.6% in urine, while ritonavir is excreted 86.4% in feces and 11.3% in urine.[9]

The oral clearance (CL/F) of nirmatrelvir combined with ritonavir is 8.99 while that of ritonavir is 13.92.[9] The elimination half-life of nirmatrelvir combined with ritonavir is (mean ± SD) 6.05 ± 1.79 hours while that of ritonavir is 6.15 hours.[9] The half-life of nirmatrelvir combined with ritonavir makes the formulation suitable for administration every 12 hours.[9][16]

Specific populations

The pharmacokinetics of nirmatrelvir/ritonavir based on age or gender have not been assessed.[9] Exposure to nirmatrelvir/ritonavir was numerically lower in Japanese than in Western people, but not to a clinically meaningful extent.[9] Peak concentrations, total exposure, time to peak concentrations, and elimination half-life of nirmatrelvir combined with ritonavir are severity-dependently increased in people with renal impairment,[9] but not increased in people with moderate hepatic impairment.[9] The combination has not been studied in people with severe hepatic impairment.[9]

History

Nirmatrelvir belongs to a family of 3C-like protease inhibitors developed in the late 2010s against feline coronavirus, while ritonavir is an antiretroviral drug developed in the 1980s and used since the 1990s to inhibit the enzyme that metabolizes other protease inhibitors.

The primary data supporting the US Food and Drug Administration (FDA) emergency use authorization for nirmatrelvir/ritonavir were from the EPIC-HR trial, a randomized, double-blind, placebo-controlled clinical trial studying nirmatrelvir/ritonavir for the treatment of non-hospitalized symptomatic adults with a laboratory-confirmed diagnosis of SARS-CoV-2 infection.[9][10][27] Participants were 18 years of age and older with a pre-specified risk factor for progression to severe disease, or were 60 years and older regardless of pre-specified chronic medical conditions.[10] No participants had received a COVID‑19 vaccine or been previously infected with COVID‑19.[10] The main outcome measured in the trial was the proportion of people who were hospitalized due to COVID‑19 or died due to any cause during 28 days of follow-up.[10] EPIC-HR started in July 2021, and completed in December 2021.[28] Nirmatrelvir/ritonavir significantly reduced the proportion of people with COVID‑19-related hospitalization or death from any cause by 88% compared to placebo among participants treated within five days of symptom onset and who did not receive COVID‑19 therapeutic monoclonal antibody treatment.[10] On 14 December 2021, Pfizer also announced that a Phase II/III study of nirmatrelvir/ritonavir showed a reduced risk of hospitalization or death.[29]

In August 2021, Pfizer began a phase II/III trial of nirmatrelvir/ritonavir for COVID‑19 in standard-risk individuals with COVID‑19 known as EPIC-SR.[30][31] Interim results of this trial were announced in December 2021, and final results were released in June 2022.[30] The study did not find a statistically significant reduction in the risk of hospitalization, death, or sustained alleviation of symptoms, although there was a significant decrease in COVID‑19-related medical visits. Pfizer discontinued enrollment in the study, with the reason given being the very low rate of hospitalization and death in this population.[32]

In December 2021, nirmatrelvir/ritonavir was granted emergency use authorization by the United States Food and Drug Administration (FDA) for the treatment of COVID‑19.[11] On 31 December, the United Kingdom's Medicines and Healthcare products Regulatory Agency (MHRA) approved the use of nirmatrelvir combined with ritonavir for adults with mild to moderate infection and at high risk of their illness worsening.[33][18]

In April 2022, it was announced that the PANORAMIC trial would start testing the effectiveness of nirmatrelvir/ritonavir for treating COVID‑19 infections.[34]

Nirmatrelvir/ritonavir has been evaluated in the treatment of COVID‑19 in standard-risk individuals in the EPIC-SR trial.[30][32] This study did not achieve its primary goal of reducing time to sustained alleviation of COVID‑19 symptoms (treatment: 13 days (95% CI 12–15 days); placebo: 13 days (95% CI 11–14 days)).[30][32] It also did not find a statistically significant reduction in the risk of hospitalization or death (treatment: 5/576 [0.9%]; placebo: 10/569 [1.8%]; p > 0.05).[30][32] Likewise, findings were not statistically significant for reducing hospitalization rates in a subgroup of vaccinated adults with at least one risk factor for severe COVID‑19 (treatment: 3/361 [0.8%]; placebo: 7/360 [1.9%]; 57% reduction – RR 0.43, 95% CI 0.11–1.64).[30][32] However, the trial did find a statistically significant 62% decrease in COVID‑19-related medical visits, similar to the 67% reduction from the EPIC-HR study of high-risk individuals.[30][32] Enrollment in EPIC-SR was discontinued due to the low rate of hospitalization and death in this population.[30][32]

In May 2023, nirmatrelvir/ritonavir received full FDA approval for the treatment of mild-to-moderate COVID‑19 in adults at high risk for progression to severe COVID‑19, including hospitalization or death. Children 12-18 were still covered under the 2021 EUA.[12]

Society and culture

Canada

Health Canada approved the use of the co-packaged medication in January 2022.[19][6][35][36]

China

In February 2022, China approved the medication for the treatment of adults who have mild to moderate COVID‑19 and are at a high risk of progressing to a severe condition.[37]

European Union

The European Medicines Agency (EMA) issued guidance about the use of the co-packaged medication for the treatment of COVID‑19 in the EU on 16 December 2021.[23]

Israel

The Israeli Ministry of Health approved the use of the co-packaged medication on 26 December 2021.[38]

Singapore

The Singapore Health Sciences Authority approved the use of the co-packaged medication for treating adults in February 2022.[39]

South Korea

South Korea approved the use of the co-packaged medication on 27 December 2021.[40]

United Kingdom

Paxlovid is available on prescription via the National Health Service (NHS), only to people considered to be in the highest risk group.[41]

United States

On 16 November 2021, Pfizer submitted an application to the US Food and Drug Administration (FDA) for emergency use authorization for the co-packaged medication.[42][43][44] The authorization was granted on 22 December 2021, for people aged 12 or older who are infected with Covid and at risk.[10][15][45]

Manufacturing

Pfizer selected its largest oral tablet factory in Freiburg as the launch facility for the manufacturing of the co-packaged medication.[46] Nirmatrelvir, the novel portion of the co-packaged medication, was first developed in the United States and was initially manufactured in small amounts in Groton, Connecticut, to support clinical trials,[47] but the Freiburg facility in Germany was responsible for figuring out how to mass-produce the co-packaged medication on an industrial scale.[46] Pfizer selected another factory in Ascoli Piceno, Italy, to assist the Freiburg factory with packaging tablets into blister packs.[48]

Economics

In December 2021, the German government ordered 1 million doses of, but by August 2022, only around 43,000 had been delivered by wholesalers to pharmacies. In Germany, Paxlovid is by prescription through physicians only and German physicians have been reluctant to prescribe it. Hence, health minister Karl Lauterbach decided that general practitioners can stock 5 Paxlovid courses in their practice and dispense it directly to patients, that a prescription would be remunerated with 15 Euros and that every nursing home should appoint a vaccination officer as well as a Paxlovid officer. As of August 2022 the treatment guidelines, which German family doctors follow, have not been updated since February 2022 and recommend Paxlovid only in unvaccinated risk patients, i.e. in only a few people.[49]

As of April 2022, the United States ordered a total of 20 million Paxlovid courses.[50] As of July 2022, the United States Department of Health and Human Services set up at least 2,200 sites where people could receive Paxlovid as soon as they test positive for the virus, including pharmacies, community health centers and long-term care facilities.[45] In July 2022, the US FDA allowed state-licensed pharmacists to prescribe it to people with COVID‑19 at high risk of progressing to severe disease.[51]

In December 2022, after China abandoned its Zero Covid policy, while Paxlovid was in short supply, the powerful and elite in China scrambled to purchase Paxlovid and give it as a valuable gift.[52]

Brand names

Primovir, produced by Astrica, and Paxista which is produced by Azista, are generic versions manufactured and distributed in India.[53][54]

Comparison to ivermectin
Further information: Ivermectin during the COVID-19 pandemic

It is sometimes falsely claimed that Paxlovid is a repackaged version of the antiparasitic drug ivermectin, or that Paxlovid is just like ivermectin as both are protease inhibitors.[55][56] Ivermectin has been falsely[57] promoted as a COVID‑19 therapeutic. Such claims, sometimes using the nickname "Pfizermectin",[58] arise from superficial similarities between the mechanism of action of the drugs[55] and the claim that Pfizer is suppressing information about the benefits of ivermectin.[56]

Research

Rebound

An additional analysis of the original EPIC-HR clinical trial data (Delta variant) showed that about 2% of both the treatment and placebo groups experienced a symptomatic rebound after the 5 day treatment, meaning they felt ill again and tested positive again (antigen test and PCR test) after testing negative.[59] This is important, because people with rebound cannot go back to work or school. The exact cause is not known, but there is speculation that it is due to reservoirs in tissues that are not reached by the medication, or reinfection. In May 2022, Pfizer suggested repeating the treatment, but the FDA said there had been no evidence of benefit.[60][61]

In 2022 a US case report of ten people with rebound COVID‑19 found viral load during relapse was comparable to levels during an initial infection, and high enough to cause secondary transmission.[62] President Joe Biden, First Lady Jill Biden, Anthony Fauci,[60] Peter Hotez and Rochelle Walensky[63] are known to have experienced rebound. As of June 2022, Pfizer was studying the phenomenon in a new trial it calls EPIC-SR (standard risk) while the omicron variant is circulating.[62]

As of July 2022, no Paxlovid drug resistant SARS-CoV-2 had been observed in clinical context.[64] The engineering of a nirmatrelvir-resistant chimera of Vesicular Stomatitis Virus (VSV) under laboratory conditions was published without formal peer review in July 2022.[65] As of November 2022, multiple pathways that could lead to Paxlovid resistance had been demonstrated in vitro.[66]

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