Identification

Summary

Nirmatrelvir is an oral protease inhibitor with emergency use authorization for the treatment of mild-to-moderate COVID-19.

Generic Name
Nirmatrelvir
DrugBank Accession Number
DB16691
Background

Nirmatrelvir (PF-07321332) is an orally bioavailable 3C-like protease (3CLPRO) inhibitor that is the subject of clinical trial NCT04756531.4 3CLPRO is responsible for cleaving polyproteins 1a and 1ab of SARS-CoV-2.1 Without the activity of the SARS-CoV-2 3CLPRO, nonstructural proteins (including proteases) cannot be released to perform their functions, inhibiting viral replication.1,2,3

In 2020, Pfizer was investigating another potential treatment for SARS-CoV-2, PF-07304814.5 Both drugs were inhibitors of SARS-CoV-2 3CLPRO, but nirmatrelvir has the advantage of being orally bioavailable.5 Nirmatrelvir is advantageous in that it can be prescribed to patients before they require hospitalization, while PF-07304814 requires intravenous administration in hospital.5

In December 2021, the FDA granted an emergency use authorization to Paxlovid, a co-packaged product containing both nirmatrelvir and ritonavir, for the treatment of certain patients with mild-to-moderate COVID-19.6 Paxlovid was approved for use in Canada in January 2022 for the treatment of adult patients with mild-moderate COVID-19 6 and later granted conditional marketing authorization by the European Commission on January 27, 2022.9

Type
Small Molecule
Groups
Approved, Investigational
Structure
Weight
Average: 499.535
Monoisotopic: 499.240639019
Chemical Formula
C23H32F3N5O4
Synonyms
Not Available
External IDs
  • PF-07321332

Pharmacology

Indication

Nirmatrelvir has received FDA emergency use authorization, in combination with ritonavir, for the treatment of mild-to-moderate coronavirus disease 2019 (COVID-19) in adults and pediatric patients (12 years of age and older weighing at least 40 kg) with positive results of direct severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral testing, and who are at high risk for progression to severe COVID-19, including hospitalization or death.6

In Canada, nirmatrelvir is indicated in combination with ritonavir for the treatment of SARS-CoV-2 positive adult patients with mild-to-moderate COVID-19 who are at high risk of progression to severe disease.7 This therapeutic usage is also valid in Europe under conditional marketing authorization.8

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Associated Conditions
Contraindications & Blackbox Warnings
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Pharmacodynamics

Nirmatrelvir is administered alongside ritonavir, a potent inhibitor of CYP3A enzymes, in order to inhibit its metabolism and increase plasma nirmatrelvir concentrations.6 While therapeutically beneficial, the use of ritonavir poses a significant risk of drug interaction due to its potent inhibition profile - patients and clinicians should consult the prescribing information for Paxlovid (nirmatrelvir and ritonavir) to evaluate any potential for drug interaction with existing medications prior to the initiation of Paxlovid.6

Mechanism of action

Nirmatrelvir is an inhibitor of a cysteine residue in the 3C-like protease (3CLPRO) of SARS-CoV-2.5 This cysteine is responsible to the activity of the 3CLPRO of SARS-CoV-2 and potentially other members of the coronavirus family.1,2 The 3CLPRO, also known as the main protease or non structural protein 5, is responsible for cleaving polyproteins 1a and 1ab.1 These polyproteins contain the 3CLPRO itself, a papain-like (PL) cysteine protease, and 14 other nonstructural proteins.3 Without the activity of the 3CLPRO, nonstructural proteins (including proteases) cannot be released to perform their functions, inhibiting viral replication.1,2,3

TargetActionsOrganism
AReplicase polyprotein 1ab
inhibitor
SARS-CoV-2
Absorption

The median Tmax of nirmatrelvir, when given with ritonavir, is 3 hours.6 After a single oral dose of 300mg nirmatrelvir and 100mg ritonavir in healthy subjects, the Cmax and AUCinf of nirmatrelvir were 2.21 µg/mL and 23.01 µg*hr/mL, respectively.6

Volume of distribution

The mean volume of distribution of nirmatrelvir, when given with ritonavir, is 104.7 liters.6

Protein binding

Nirmatrelvir, when given with ritonavir, is 69% protein-bound in plasma.6

Metabolism

Nirmatrelvir is a substrate of CYP3A4, but undergoes minimal metabolism when administered alongside ritonavir.6

Route of elimination

The major route of nirmaltrevir elimination is via renal elimination, due in part to its coadministration with ritonavir which inhibits its metabolism.6 Following oral administration alongside ritonavir, approximately 49.6% of drug-related material was recovered in the feces and 35.3% was recovered in the urine.6

Half-life

The mean half-life of nirmatrelvir, administered alongside ritonavir, is 6.05 hours.6

Clearance

The mean oral clearance of nirmatrelvir, administered with ritonavir, is 8.99 L/h.6

Adverse Effects
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Toxicity

There are no data regarding overdosage with nirmatrelvir. Treatment of suspected overdose should consist of general supportive measures as clinically indicated.6

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbametapirThe serum concentration of Nirmatrelvir can be increased when it is combined with Abametapir.
Adenovirus type 7 vaccine liveThe therapeutic efficacy of Adenovirus type 7 vaccine live can be decreased when used in combination with Nirmatrelvir.
AmiodaroneThe metabolism of Nirmatrelvir can be decreased when combined with Amiodarone.
AmprenavirThe metabolism of Nirmatrelvir can be decreased when combined with Amprenavir.
Anthrax vaccineThe therapeutic efficacy of Anthrax vaccine can be decreased when used in combination with Nirmatrelvir.
ApalutamideThe serum concentration of Nirmatrelvir can be decreased when it is combined with Apalutamide.
AprepitantThe metabolism of Nirmatrelvir can be decreased when combined with Aprepitant.
AtazanavirThe metabolism of Nirmatrelvir can be decreased when combined with Atazanavir.
Bacillus calmette-guerin substrain connaught live antigenThe therapeutic efficacy of Bacillus calmette-guerin substrain connaught live antigen can be decreased when used in combination with Nirmatrelvir.
Bacillus calmette-guerin substrain russian BCG-I live antigenThe therapeutic efficacy of Bacillus calmette-guerin substrain russian BCG-I live antigen can be decreased when used in combination with Nirmatrelvir.
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Food Interactions
  • Avoid St. John's Wort. Co-administration may reduce serum concentrations of niramtrelvir and interfere with virologic efficacy.
  • Take with or without food. Co-administration of nirmatrelvir with food does not significantly alter its pharmacokinetics.

Products

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Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
PaxlovidNirmatrelvir (150 mg) + Ritonavir (100 mg)TabletOralPfizer Canada Ulc2022-01-18Not applicableCanada flag

Categories

Drug Categories
Classification
Not classified
Affected organisms
  • SARS-CoV-2

Chemical Identifiers

UNII
7R9A5P7H32
CAS number
2628280-40-8
InChI Key
LIENCHBZNNMNKG-OJFNHCPVSA-N
InChI
InChI=1S/C23H32F3N5O4/c1-21(2,3)16(30-20(35)23(24,25)26)19(34)31-10-13-14(22(13,4)5)15(31)18(33)29-12(9-27)8-11-6-7-28-17(11)32/h11-16H,6-8,10H2,1-5H3,(H,28,32)(H,29,33)(H,30,35)/t11-,12-,13-,14-,15-,16+/m0/s1
IUPAC Name
(1R,2S,5S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-3-[(2S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide
SMILES
[H][C@]12CN([C@H](C(=O)N[C@@H](C[C@]3([H])CCNC3=O)C#N)[C@@]1([H])C2(C)C)C(=O)[C@@H](NC(=O)C(F)(F)F)C(C)(C)C

References

Synthesis Reference

Owen DR, Allerton CMN, Anderson AS, Aschenbrenner L, Avery M, Berritt S, Boras B, Cardin RD, Carlo A, Coffman KJ, Dantonio A, Di L, Eng H, Ferre R, Gajiwala KS, Gibson SA, Greasley SE, Hurst BL, Kadar EP, Kalgutkar AS, Lee JC, Lee J, Liu W, Mason SW, Noell S, Novak JJ, Obach RS, Ogilvie K, Patel NC, Pettersson M, Rai DK, Reese MR, Sammons MF, Sathish JG, Singh RSP, Steppan CM, Stewart AE, Tuttle JB, Updyke L, Verhoest PR, Wei L, Yang Q, Zhu Y: An oral SARS-CoV-2 M(pro) inhibitor clinical candidate for the treatment of COVID-19. Science. 2021 Nov 2:eabl4784. doi: 10.1126/science.abl4784.

General References
  1. Ionescu MI: An Overview of the Crystallized Structures of the SARS-CoV-2. Protein J. 2020 Dec;39(6):600-618. doi: 10.1007/s10930-020-09933-w. Epub 2020 Oct 24. [Article]
  2. Muramatsu T, Takemoto C, Kim YT, Wang H, Nishii W, Terada T, Shirouzu M, Yokoyama S: SARS-CoV 3CL protease cleaves its C-terminal autoprocessing site by novel subsite cooperativity. Proc Natl Acad Sci U S A. 2016 Nov 15;113(46):12997-13002. doi: 10.1073/pnas.1601327113. Epub 2016 Oct 31. [Article]
  3. Xiong M, Su H, Zhao W, Xie H, Shao Q, Xu Y: What coronavirus 3C-like protease tells us: From structure, substrate selectivity, to inhibitor design. Med Res Rev. 2021 Jan 18. doi: 10.1002/med.21783. [Article]
  4. Clinical Trials: NCT04756531 [Link]
  5. Pfizer Press Release: PFIZER INITIATES PHASE 1 STUDY OF NOVEL ORAL ANTIVIRAL THERAPEUTIC AGENT AGAINST SARS-COV-2 [Link]
  6. FDA Emergency Use Authorization Fact Sheet: Paxlovid (nirmatrelvir and ritonavir) co-packaged for oral use [Link]
  7. Health Canada Product Monograph: Paxlovid (nirmatrelvir and ritonavir) co-packaged for oral use [Link]
  8. Summary of Product Characteristics: Paxlovid (nirmatrelvir and ritonavir) oral tablets [Link]
  9. EMA News: COVID-19: EMA recommends conditional marketing authorisation for Paxlovid [Link]
ChemSpider
114826566
RxNav
2587892
ChEBI
170007
ChEMBL
CHEMBL4802135
Wikipedia
3C-like_protease

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4RecruitingTreatmentCoronavirus Disease 2019 (COVID‑19) / Safety Issues1
3Active Not RecruitingTreatmentCoronavirus Disease 2019 (COVID‑19)1
3RecruitingPreventionCoronavirus Disease 2019 (COVID‑19)1
3RecruitingTreatmentCoronavirus Disease 2019 (COVID‑19)2
2, 3RecruitingTreatmentCoronavirus Disease 2019 (COVID‑19)2
2, 3RecruitingTreatmentCoronavirus Disease 2019 (COVID‑19) / Severe Acute Respiratory Syndrome (SARS)1
1Active Not RecruitingOtherHealthy Subjects (HS)1
1CompletedBasic ScienceCoronavirus Disease 2019 (COVID‑19) / Healthy Subjects (HS)2
1CompletedBasic ScienceHealthy Subjects (HS)3
1CompletedBasic ScienceHepatic Impairment1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
TabletOral
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0277 mg/mLALOGPS
logP2.12ALOGPS
logP0.44ChemAxon
logS-4.3ALOGPS
pKa (Strongest Acidic)7.1ChemAxon
pKa (Strongest Basic)-1.6ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area131.4 Å2ChemAxon
Rotatable Bond Count8ChemAxon
Refractivity117.52 m3·mol-1ChemAxon
Polarizability47.09 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Targets

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Kind
Protein
Organism
SARS-CoV-2
Pharmacological action
Yes
Actions
Inhibitor
General Function
Replicase polyprotein 1ab Multifunctional protein involved in the transcription and replication of viral RNAs. Contains the proteinases responsible for the cleavages of the polyprotein.
Specific Function
Atp binding
Gene Name
rep
Uniprot ID
P0DTD1
Uniprot Name
Replicase polyprotein 1ab
Molecular Weight
794051.285 Da
References
  1. Ionescu MI: An Overview of the Crystallized Structures of the SARS-CoV-2. Protein J. 2020 Dec;39(6):600-618. doi: 10.1007/s10930-020-09933-w. Epub 2020 Oct 24. [Article]
  2. Pfizer Press Release: PFIZER INITIATES PHASE 1 STUDY OF NOVEL ORAL ANTIVIRAL THERAPEUTIC AGENT AGAINST SARS-COV-2 [Link]
  3. FDA Emergency Use Authorization Fact Sheet: Paxlovid (nirmatrelvir and ritonavir) co-packaged for oral use [Link]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inhibitor
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. FDA Emergency Use Authorization Fact Sheet: Paxlovid (nirmatrelvir and ritonavir) co-packaged for oral use [Link]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inhibitor
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
References
  1. FDA Emergency Use Authorization Fact Sheet: Paxlovid (nirmatrelvir and ritonavir) co-packaged for oral use [Link]

Drug created at April 27, 2021 04:24 / Updated at May 23, 2022 17:31