2.1 Pharmacodynamics
Nirmatrelvir binds directly to the SARS-CoV-2 Mpro (also referred to as 3C-like protease or nsp5 protease) active site, selectively and reversibly inhibiting SARS-CoV-2 Mpro activity [inhibition constant (Ki) value 3.1 nM and half-maximal inhibitory concentration (IC
50) value 19.2 nM in a biochemical assay] [
6,
10,
16]. As a result of this inhibition, the protein is unable to process polyprotein precursors and viral replication is thus prevented [
10,
16]. While ritonavir is a human immunodeficiency virus type 1 (HIV-1) protease inhibitor, it has no activity against SARS-CoV-2 Mpro. Ritonavir increases nirmatrelvir concentrations in the plasma through inhibiting the metabolism of nirmatrelvir (Sect.
2.2) [
10,
16].
Nirmatrelvir demonstrated antiviral activity against SARS-CoV-2 infection of differentiated normal human bronchial epithelial (dNHBE) cells treated with varying doses of nirmatrelvir for 3 days [half-maximal effective concentration (EC
50) and EC
90 values 61.8 nM and 181 nM] [
6,
10,
16]. In accordance with the target protein of nirmatrelvir being highly conserved, the potency of nirmatrelvir against current variants of SARS-CoV-2 is similar to that against wild-type SARS-CoV-2 [
22,
23]. Nirmatrelvir had consistent cell culture antiviral activity (median EC
50 values ≤ 0.28 μM and < 3-fold relative to GHB-03021/2020) against isolates belonging to the Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), and Omicron (B.1.1.529) SARS-CoV-2 variants of concern [
22].
There are currently no data on antiviral resistance to nirmatrelvir with SARS-CoV-2 [
10,
16]. The impact of naturally occurring SARS-CoV-2 Mpro polymorphisms (of unknown clinical significance) on nirmatrelvir activity has been characterized in a biochemical assay using recombinant Mpro [
16]. Certain amino acid substitutions were associated with reduced activity (G15S, H164N, H172Y, and Q189K; 4- to 233-fold reductions). G15S is found in the Lambda variant of SARS-CoV-2, which nirmatrelvir retained potency against in cell culture. Based on limited SARS-CoV-2 sequencing data characterizing resistance to nirmatrelvir in clinical trials, the SARS-CoV-2 Mpro substitutions A260V or A260T (
n = 3 and 1, respectively) emerged in 4% (4/97) of evaluable nirmatrelvir plus ritonavir recipients in the phase II/III EPIC-HR trial (Sect.
2.3). These polymorphisms naturally occur infrequently in publicly available SARS-CoV-2 sequences, as of December 2021. The A260V substitution did not reduce nirmatrelvir activity in a biochemical assay (fold-change < 1). Cross-resistance between nirmatrelvir and remdesivir or anti-SARS-CoV-2 monoclonal antibodies is not expected, as their mechanisms of action differ [
16].
While nirmatrelvir does not appear to affect the QT interval based on the non-clinical and clinical data collected thus far, QT prolongation in humans has not been fully investigated [
16].
2.2 Pharmacokinetics
Ritonavir, a CYP3A inhibitor, acts as a pharmacokinetic enhancer, increasing the systemic exposure of nirmatrelvir and prolonging its half-life when the agents are administered together [
9]. Following repeated twice-daily oral administration of nirmatrelvir plus ritonavir (75 mg + 100 mg, 250 mg + 100 mg, and 500 mg + 100 mg), the increase in systemic exposure of nirmatrelvir plus ritonavir appears to be less than dose proportional at steady state [
9,
10]. Steady state was achieved on day 2 (accumulation ≈ 2-fold). After a single dose of nirmatrelvir 300 mg plus ritonavir 100 mg in healthy subjects, the median times to peak concentrations of nirmatrelvir and ritonavir were 3.00 h and 3.98 h, respectively. Administration of nirmatrelvir plus ritonavir with a high-fat meal modestly increased nirmatrelvir exposure relative to fasting conditions; nirmatrelvir plus ritonavir can be administered with or without food [
9,
10]. In human plasma, nirmatrelvir has a protein binding rate of ≈ 69% and ritonavir has a rate of ≈ 98–99% [
10].
Features and properties of nirmatrelvir plus ritonavir
Alternative names | Nirmatrelvir [PF-07321332] tablets and ritonavir tablets; nirmatrelvir plus ritonavir - Pfizer; nirmatrelvir+ritonavir - Pfizer; PAXLOVID; PF 07321332 plus ritonavir - Pfizer; PF 07321332+ritonavir - Pfizer; PF-07321332/ritonavir |
Class | Amides; amines; antivirals; aza compounds; carbamates; fluorinated hydrocarbons; heterocyclic bicyclo compounds; nitriles; pyrrolidinones; small molecules; thiazoles |
Mechanism of action | Coronavirus-3C-like-proteinase inhibitors (nirmatrelvir); HIV protease inhibitors (ritonavir) |
Route of administration | Oral |
Pharmacodynamics | Nirmatrelvir: Binds directly to SARS-CoV-2 main protease active site; inhibits SARS-CoV-2 main protease, rendering it unable to process polyprotein precursors and consequently preventing viral replication |
Ritonavir: Inhibits CYP3A-mediated metabolism of nirmatrelvir, thus increasing plasma concentrations of nirmatrelvir; not active against SARS-CoV-2 main protease |
Pharmacokinetics | Ritonavir increases systemic concentrations and half-life of nirmatrelvir; half-life of nirmatrelvir ≈ 6 h when administered with ritonavir |
Adverse events | Dysgeusia, diarrhea, hypertension, myalgia |
ATC codes | |
WHO ATC code | J05 (Antivirals for Systemic Use) |
EphMRA ATC code | J5 (Antivirals for Systemic Use) |
Chemical name | (1R,2S,5S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide/1,3-thiazol-5-ylmethyl N-[(2S,3S,5S)-3-hydroxy-5-[[(2S)-3-methyl-2-[[methyl-[(2-propan-2-yl-1,3-thiazol-4-yl)methyl]carbamoyl]amino]butanoyl]amino]-1,6-diphenylhexan-2-yl]carbamate |
Based on in vitro studies, nirmatrelvir is chiefly metabolized by CYP3A4 [
10]. The metabolism of nirmatrelvir is inhibited by the concomitant administration of ritonavir. Ritonavir is in turn primarily metabolized by CYP3A (CYP2D6 is a minor pathway which contributes to the formation of M-2, an oxidation metabolite). Nirmatrelvir is primarily eliminated via renal excretion (with ≈ 50% and 35% of a 300 mg dose recovered in the urine and feces), mainly as unchanged drug. Ritonavir is primarily eliminated via the hepatobiliary system (≈ 86% of a radiolabelled dose was recovered from stool, with some expected to be unabsorbed ritonavir). Both nirmatrelvir and ritonavir had arithmetic mean terminal elimination half-lives of 6.1 h [
10].
The effects of age and sex on nirmatrelvir plus ritonavir pharmacokinetics have not been investigated [
9,
10]. Compared with those in healthy controls, nirmatrelvir maximum plasma concentrations and area under the plasma concentration-time curves were respectively 30% and 24% higher in patients with mild (eGFR ≥ 60 to < 90 mL/min) kidney dysfunction, 38% and 87% higher in patients with moderate (eGFR ≥ 30 to < 60 mL/min) kidney dysfunction, and 48% and 204% higher in patients with severe (eGFR < 30 mL/min) kidney dysfunction. A dose adjustment is required in patients with moderate kidney dysfunction (Sect.
1) and nirmatrelvir plus ritonavir should not be used in patients with severe kidney dysfunction (including those with end-stage renal disease under hemodialysis). The pharmacokinetics of nirmatrelvir did not significantly differ between patients with moderate hepatic impairment and healthy controls. Nirmatrelvir plus ritonavir has not been studied in patients with severe hepatic impairment and is not recommended for use in these patients [
9,
10].
Clinically relevant pharmacokinetic drug-drug interactions are possible when nirmatrelvir plus ritonavir is co-administered with various other agents (e.g. CYP3A substrates, inducers or inhibitors); certain contraindications apply (Sect.
1) [
9,
10]. Local prescribing information should be consulted for further details.
2.3 Therapeutic Trials
Nirmatrelvir plus ritonavir was effective in reducing the risk of progression to severe COVID-19 in non-hospitalized, symptomatic adults (≥ 18 years) at high risk for progression to severe COVID-19 in the randomized, double-blind, placebo-controlled, phase II/III EPIC-HR trial (NCT04960202) [
24]. To be eligible for enrolment in EPIC-HR, patients had laboratory-confirmed SARS-CoV-2 infection, COVID-19 symptom onset ≤ 5 days prior to randomization, and at least one risk factor for progression to severe COVID-19. Risk factors included, but were not limited to, diabetes, chronic lung or kidney disease, cardiovascular disease, immunosuppression, hypertension, cancer, being overweight [body mass index (BMI) > 25 kg/m
2], or being ≥ 60 years of age. Patients with prior COVID-19 infection or vaccination were excluded from EPIC-HR. Eligible patients were randomized (
n = 2246 in a 1:1 ratio) to receive either nirmatrelvir 300 mg plus ritonavir 100 mg or placebo administered orally every 12 h for 5 days. At baseline, patients had a median age of 46 years. The majority of patients were white (71.5%) and 80.5% had a BMI > 25 kg/m
2. Study treatment was initiated within 3 days of symptom onset in 66.3% of participants. At randomization, a minority of patients (6.2%) received or were expected to receive COVID-19 monoclonal antibody (mAb) treatment. The EPIC-HR modified intention-to-treat (mITT) population included all patients treated within 3 days of symptom onset who, at baseline, did not receive nor were expected to receive COVID-19 mAb treatment [
24]. In a planned interim analysis of data from 774 patients in mITT population (primary efficacy analysis), the incidence of COVID-19-related hospitalization or any-cause death through day 28 was significantly lower with nirmatrelvir plus ritonavir than with placebo (0.77% vs 7.01%) [difference −6.32%; 95% CI −9.04% to −3.59%;
p < 0.001], corresponding to a relative risk reduction of 89.1% [
10,
24].
Key clinical trials of nirmatrelvir plus ritonavir (Pfizer)
Drug(s) | Indication | Phase | Status | Location(s) | Identifier |
Nirmatrelvir plus ritonavir; placebo | Treatment of symptomatic COVID-19 (high-risk adults) | II/III | Active, no longer recruiting | Global | EPIC-HR; NCT04960202; EudraCT2021-002895-38; C4671005 |
Nirmatrelvir plus ritonavir; placebo | Treatment of symptomatic COVID-19 (standard-risk adults) | II/III | Active, no longer recruiting | Global | EPIC-SR; NCT05011513; EudraCT2021-002857-28; C4671002 |
Nirmatrelvir plus ritonavir; placebo | Post-exposure prophylaxis of SARS-CoV-2 infection | II/III | Recruiting | Global | EPIC-PEP; NCT05047601; EudraCT2021-002894-24; C4671006 |
Final efficacy results from EPIC-HR were consistent with those from the planned interim analysis [
24]. In the full mITT population (
n = 697 and 682 in the nirmatrelvir plus ritonavir and placebo groups, respectively), Kaplan-Meier estimated event rates for COVID-19-related hospitalization or any-cause death through day 28 were 0.72% with nirmatrelvir plus ritonavir versus 6.53% with placebo (difference − 5.81%; 95% CI − 7.78 to − 3.84%;
p < 0.001), corresponding to a relative risk reduction of 88.9%. In patients treated within 5 days of symptom onset who, at baseline, did not receive nor were expected to receive COVID-19 mAb treatment (mITT1 population;
n = 1039 and 1046 in the nirmatrelvir plus ritonavir and placebo groups, respectively), nirmatrelvir plus ritonavir reduced the risk of COVID-19-related hospitalization or death from any cause through day 28 by 87.8% relative to placebo; estimated event rates were 0.78% versus 6.40% (difference − 5.62%; 95% CI −7.21 to − 4.03%;
p < 0.001) [key secondary endpoint]. When data from all patients treated within 5 days of symptom onset (including those who received or were expected to receive mAb treatment) were analyzed, event rates were similar to those in the mITT and mITT1 populations. In the mITT1 population, the efficacy of nirmatrelvir plus ritonavir was consistent across subgroups based on age (< 65 and ≥ 65 years), sex, diabetes, BMI (< 25 kg/m
2, 25 to < 30 kg/m
2 and ≥ 30 kg/m
2), elapsed time from symptom onset at treatment initiation (≤ 3 and > 3 days), and baseline SARS-CoV-2 serology status (positive and negative). Compared with placebo, nirmatrelvir plus ritonavir was associated with a ≈ 0.9 log
10 copies/mL greater decrease in viral RNA load at day 5 in evaluable mITT patients (
p < 0.001), with a similar result seen in evaluable mITT1 patients [
24].
Nirmatrelvir plus ritonavir did not significantly alleviate symptoms of COVID-19 relative to placebo in an interim analysis from the phase II/III EPIC-SR trial (NCT05011513) in a non-hospitalized, standard-risk population with laboratory-confirmed SARS-CoV-2 infection [
25]. EPIC-SR included both unvaccinated adults at standard risk of progressing to severe illness (and therefore at low risk of hospitalization or death) and vaccinated adults with at least one risk factor for progressing. Patients were randomized to receive either nirmatrelvir plus ritonavir or placebo every 12 h for 5 days. At the time of the interim analysis, enrolment was at 45% of that planned. The primary endpoint of self-reported, sustained alleviation of all symptoms for four consecutive days with nirmatrelvir plus ritonavir versus placebo was not achieved. There was, however, a 70% reduction in hospitalization and a ≈ 10-fold decrease in viral load with nirmatrelvir plus ritonavir relative to placebo. In the nirmatrelvir plus ritonavir group, 0.6% of patients (2/333) were hospitalized following randomization and there were no deaths from any cause. In the placebo group, 2.4% of patients (8/329) were hospitalized with no deaths. A follow-on analysis at 80% of planned enrollment was consistent with the results from the interim analysis: 0.7% of nirmatrelvir plus ritonavir recipients (3/428) were hospitalized following randomization, compared with 2.4% of placebo recipients (10/426;
p = 0.051 for the between-group difference), with no deaths in either group [
25].
2.4 Adverse Events
Based on limited safety data from the EPIC-HR trial, nirmatrelvir plus ritonavir appears to be generally well-tolerated in adult patients with symptomatic SARS-CoV-2 infection (
n = 1109 and 1115 treated with at least one dose of nirmatrelvir 300 mg plus ritonavir 100 mg and placebo, respectively) [
9,
16,
24]. Adverse events (reported while patients were receiving the study treatment and through day 34) occurred in 22.6% of nirmatrelvir plus ritonavir recipients versus 23.9% of placebo recipients, and were mostly of mild to moderate severity [
24]. The most common adverse events of any causality in nirmatrelvir plus ritonavir recipients (≥ 1% incidence and in ≥ 5 patients more than with placebo) were dysgeusia (6% vs < 1% with placebo), diarrhea (3% vs 2%), hypertension (1% vs < 1%), and myalgia (1% vs < 1%) [
9,
16]. Adverse events considered to be related to the study drug occurred in 7.8% of nirmatrelvir plus ritonavir recipients versus 3.8% of placebo recipients and, in nirmatrelvir plus ritonavir recipients, were most commonly dysgeusia (4.5% vs 0.2%) or diarrhea (1.3% vs 0.2%) [
24]. Adverse events of any causality led to treatment discontinuation in 2.1% of nirmatrelvir plus ritonavir recipients compared with 4.2% of placebo recipients [
24]. Serious adverse events were reported in 1.6% of nirmatrelvir plus ritonavir recipients versus 6.6% of placebo recipients, and did not led to death in any nirmatrelvir plus ritonavir recipient. In the EPIC-SR trial, the rates of treatment-emergent adverse events (22% with nirmatrelvir plus ritonavir vs 21% with placebo), serious adverse events (1.4% vs 1.9%) and adverse events leading to treatment discontinuation (2.1% vs 1.2%) were comparable between nirmatrelvir plus ritonavir and placebo recipients [
25].
Given the limited clinical data available for nirmatrelvir plus ritonavir, it is possible that serious and unexpected adverse events that have not been previously reported may emerge with greater clinical experience [
9,
16].