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=== Misleading comparison with ivermectin ===
=== Misleading comparison with ivermectin ===
{{further|Ivermectin during the COVID-19 pandemic}}
The combination of nirmatrelvir with ritonavir is sometimes falsely claimed to be a "repackaged" version of the [[antiparasitic]] drug [[ivermectin]], which has been promoted as a COVID-19 therapeutic. Such claims, sometimes using the nickname "Pfizermectin",<ref>{{cite web | vauthors = Bloom J |date=2 December 2021 | url= https://www.acsh.org/news/2021/12/02/how-does-pfizers-pavloxid-compare-ivermectin-15967 | title=How Does Pfizer's Pavloxid Compare With Ivermectin? |publisher=American Council on Science and Health |access-date=12 December 2021 }}</ref> rely on superficial similarities between the [[pharmacokinetics]] of both drugs and the claim that Pfizer is suppressing the benefits of ivermectin.<ref>{{cite web |publisher=[[Science-Based Medicine]] |vauthors=Gorski D |date=15 November 2021 |title=Pfizer's new COVID-19 protease inhibitor drug is not just 'repackaged ivermectin' |url=https://sciencebasedmedicine.org/pfizer-new-covid-19-protease-inhibitor-drug-is-not-just-repackaged-ivermectin/}}</ref>
The combination of nirmatrelvir with ritonavir is sometimes falsely claimed to be a "repackaged" version of the [[antiparasitic]] drug [[ivermectin]], which has been promoted as a COVID-19 therapeutic. Such claims, sometimes using the nickname "Pfizermectin",<ref>{{cite web | vauthors = Bloom J |date=2 December 2021 | url= https://www.acsh.org/news/2021/12/02/how-does-pfizers-pavloxid-compare-ivermectin-15967 | title=How Does Pfizer's Pavloxid Compare With Ivermectin? |publisher=American Council on Science and Health |access-date=12 December 2021 }}</ref> rely on superficial similarities between the [[pharmacokinetics]] of both drugs and the claim that Pfizer is suppressing the benefits of ivermectin.<ref>{{cite web |publisher=[[Science-Based Medicine]] |vauthors=Gorski D |date=15 November 2021 |title=Pfizer's new COVID-19 protease inhibitor drug is not just 'repackaged ivermectin' |url=https://sciencebasedmedicine.org/pfizer-new-covid-19-protease-inhibitor-drug-is-not-just-repackaged-ivermectin/}}</ref>


Revision as of 03:27, 26 December 2021

Nirmatrelvir
Clinical data
Other namesPF-07321332
ATC code
  • None
Legal status
Legal status
Identifiers
  • (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
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEBI
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC23H32F3N5O4
Molar mass499.535 g·mol−1
3D model (JSmol)
Melting point192.9 °C (379.2 °F) [2]
  • CC1([C@@H]2[C@H]1[C@H](N(C2)C(=O)[C@H](C(C)(C)C)NC(=O)C(F)(F)F)C(=O)N[C@@H](C[C@@H]3CCNC3=O)C#N)C
  • 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
  • Key:LIENCHBZNNMNKG-OJFNHCPVSA-N
Xray crystal structure PDB:7si9
Xray crystal structure (PDB:7SI9 and 7VH8) of the SARS-CoV-2 protease inhibitor nirmatrelvir bound to the viral 3CLpro (Mpro) protease enzyme. Ribbon diagram of the protein with the drug shown as sticks. The catalytic residues (His41, Cys145) are shown as yellow sticks.

Nirmatrelvir is an antiviral medication developed by Pfizer which acts as an orally active 3CL protease inhibitor.[3][4][5][6]

In December 2021, the combination of nirmatrelvir co-packaged with ritonavir was granted emergency use authorization by the US Food and Drug Administration (FDA) for the treatment of coronavirus disease COVID-19.[1][7] The co-packaged medications are sold under the brand name Paxlovid.[1][7][8] Paxlovid is not authorized for the pre-exposure or post-exposure prevention of COVID-19 or for initiation of treatment in those requiring hospitalization due to severe or critical COVID-19.[1]

Medical uses

Nirmatrelvir, co-packaged with ritonavir, is indicated for the treatment of mild-to-moderate coronavirus disease (COVID-19) in people aged twelve years of age and older weighing at least 40 kilograms (88 lb) with positive results of direct SARS-CoV-2 testing, and who are at high risk for progression to severe COVID-19, including hospitalization or death.[1] The co-packaged medication is not authorized for the pre-exposure or post-exposure prevention of COVID-19 or for initiation of treatment in those requiring hospitalization due to severe or critical COVID-19.[1]

The efficacy of Paxlovid against hospitalization or death in adult outpatients when administered within 5 days of symptom onset is about 88% (95% CI, 75–94%).[9]

There are no human data on the use of nirmatrelvir during pregnancy related to the risk of birth defects, 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 10 times higher than the authorized human dose of Paxlovid. A temporary reduction in body weight was observed in the offspring of nursing rats.[9]

Contraindications

Paxlovid is contraindicated in patients with hypersensitivity to nirmatrelvir or ritonavir, with severe renal impairment,[9] or co-administered with any of the following drugs:

  • Drugs dependent on CYP3A for clearance for which an elevated concentration results in serious reactions: alfuzosin, pethidine, piroxicam, propoxyphene, ranolazine, amiodarone, dronedarone, flecainide, propafenone, quinidine, colchicine, lurasidone, pimozide, clozapine, dihydroergotamine, ergotamine, methylergonovine, lovastatin, simvastatin, sildenafil (when used for pulmonary arterial hypertension), triazolam, oral midazolam[9]
  • Potent CYP3A inducers for which reduced plasma concentration of nirmatrelvir or ritonavir may result in loss of virologic response and possible resistance: apalutamide, carbamazepine, phenobarbital, phenytoin, rifampin, St. John’s Wort (hypericum perforatum)[9]

Adverse effects

Adverse events of Paxlovid, regardless of causality, observed in the phase II-III EPIC-HR study included dysgeusia (6%), diarrhea (3%), hypertension (1%), and myalgia (1%).[9]

Overdose

There is no specific antidote for overdose with Paxlovid, treatment consists of supportive measures such as monitoring of vital signs and observation of clinical status.[9]

Development

Pharmaceutical

Coronaviral proteases cleave multiple sites in the viral polyprotein, usually after glutamine residues. Early work on related human rhinoviruses showed that the flexible glutamine side chain could be replaced by a rigid pyrrolidone.[10][11] These drugs had been further developed prior to the SARS CoV2 pandemic for other diseases including SARS.[12] The utility of targeting the 3CL protease in a real world setting was first demonstrated in 2018 when GC376 (a prodrug of GC373) was used to treat the previously 100% lethal cat coronavirus disease, feline infectious peritonitis, caused by Feline coronavirus.[13]

Nirmatrelvir is an analog of GC373, where the aldehyde covalent cysteine acceptor has been replaced by a nitrile.[14][15]

Nirmatrelvir was developed by modification of the earlier clinical candidate lufotrelvir,[16][17] which is also a covalent 3CL protease inhibitor but its warhead is a phosphate prodrug of a hydroxyketone. Lufotrelvir needs to be administered intravenously limiting its use to a hospital setting. Stepwise modification of the tripeptide protein mimetic led to nirmatrelvir, which is suitable for oral administration.[2] Key changes include a reduction in the number of hydrogen bond donors, and the number of rotatable bonds by introducing a rigid bicyclic non-canonical amino acid, which mimics the leucine residue found in earlier inhibitors. This residue had previously been used in the synthesis of boceprevir.[18] Tert-leucine used in the P3 position of nirmatrelvir was identified first as optimal non-canonical amino acid in potential drug targeting SARS-CoV-2-Mpro using combinatorial chemistry (Hybrid Combinatorial Substrate Library technology).[19][20]

Clinical

In April 2021, Pfizer began phase I trials.[21] In September 2021, Pfizer began a phase II/III trial.[22] In November 2021, Pfizer announced 89% reduction in hospitalizations of high risk patients studied when given within three days after symptom onset.[23][24]

On 14 December 2021, Pfizer announced that the combination of nirmatrelvir with ritonavir, when given within three days of symptom onset, reduced the risk of hospitalization or death by 89% compared with placebo in 2,246 high-risk participants studied.[5]

Chemistry and pharmacology

Full details of the synthesis of nirmatrelvir were first published by scientists from Pfizer.

In the penultimate step, a synthetic homochiral amino acid is coupled with a homochiral amino amide using the water-soluble carbodiimide EDCI as coupling agent. The resulting intermediate is then treated with Burgess reagent, which dehydrates the amide group to the nitrile of the product.[2]

Nirmatrelvir is a covalent inhibitor, binding directly to the catalytic cysteine (Cys145) residue of the cysteine protease enzyme.[25]

In the co-packaged medication, ritonavir serves to slow down metabolism of nirmatrelvir by cytochrome enzymes to maintain higher circulating concentrations of the main drug.[26]

Society and culture

Economics

The UK placed an order for 250,000 courses in October 2021,[27][28] and Australia pre-ordered 500,000 courses of the drug.[29]

Licensing

In November 2021, Pfizer signed a license agreement with the United Nations–backed Medicines Patent Pool to allow nirmatrelvir to be manufactured and sold in 95 countries.[30] Pfizer stated that the agreement will allow local medicine manufacturers to produce the pill "with the goal of facilitating greater access to the global population". However, the deal excludes several countries with major COVID-19 outbreaks including Brazil, China, Russia, Argentina, and Thailand.[31][32]

Legal status

On 16 November 2021, Pfizer submitted an application to the U.S. Food and Drug Administration (FDA) for emergency use authorization for nirmatrelvir in combination with ritonavir.[33][34][35] The authorization was granted on 22 December 2021.[1][8] The European Medicines Agency (EMA) issued guidance about the use of Paxlovid for the treatment of COVID-19 in the EU on 16 December 2021.[36]

Misleading comparison with ivermectin

The combination of nirmatrelvir with ritonavir is sometimes falsely claimed to be a "repackaged" version of the antiparasitic drug ivermectin, which has been promoted as a COVID-19 therapeutic. Such claims, sometimes using the nickname "Pfizermectin",[37] rely on superficial similarities between the pharmacokinetics of both drugs and the claim that Pfizer is suppressing the benefits of ivermectin.[38]

References

  1. ^ a b c d e f g "FDA Authorizes First Oral Antiviral for Treatment of COVID-19". U.S. Food and Drug Administration (FDA) (Press release). 22 December 2021. Retrieved 22 December 2021. Public Domain This article incorporates text from this source, which is in the public domain.
  2. ^ a b c Owen DR, Allerton CM, Anderson AS, Aschenbrenner L, Avery M, Berritt S, et al. (November 2021). "An oral SARS-CoV-2 Mpro inhibitor clinical candidate for the treatment of COVID-19". Science. 374 (6575): 1586–1593. doi:10.1126/science.abl4784. PMID 34726479. S2CID 240422219.
  3. ^ Şimşek-Yavuz S, Komsuoğlu Çelikyurt FI (August 2021). "Antiviral treatment of COVID-19: An update". Turkish Journal of Medical Sciences. 51 (SI-1): 3372–3390. doi:10.3906/sag-2106-250. PMID 34391321. S2CID 237054672.
  4. ^ Ahmad B, Batool M, Ain QU, Kim MS, Choi S (August 2021). "Exploring the Binding Mechanism of PF-07321332 SARS-CoV-2 Protease Inhibitor through Molecular Dynamics and Binding Free Energy Simulations". International Journal of Molecular Sciences. 22 (17): 9124. doi:10.3390/ijms22179124. PMC 8430524. PMID 34502033.
  5. ^ a b "Pfizer Announces Additional Phase 2/3 Study Results Confirming Robust Efficacy of Novel COVID-19 Oral Antiviral Treatment Candidate in Reducing Risk of Hospitalization or Death" (Press release). 14 December 2021.
  6. ^ Vandyck K, Deval J (August 2021). "Considerations for the discovery and development of 3-chymotrypsin-like cysteine protease inhibitors targeting SARS-CoV-2 infection". Current Opinion in Virology. 49: 36–40. doi:10.1016/j.coviro.2021.04.006. PMC 8075814. PMID 34029993.
  7. ^ a b "Pfizer Receives U.S. FDA Emergency Use Authorization for Novel COVID-19 Oral Antiviral Treatment". Pfizer (Press release). 22 December 2021. Retrieved 22 December 2021.
  8. ^ a b "Frequently Asked Questions on the Emergency Use Authorization for Paxlovid for Treatment of COVID-19" (PDF). U.S. Food and Drug Administration (FDA). 22 December 2021.
  9. ^ a b c d e f g Fact sheet for healthcare providers: Emergency Use Authorization for Paxlovid (PDF) (Technical report). Food and Drug Administration. 22 December 2021. LAB-1492-0.8. Archived from the original on 23 December 2021.
  10. ^ Anand K, Ziebuhr J, Wadhwani P, Mesters JR, Hilgenfeld R (June 2003). "Coronavirus Main Proteinase (3CLpro) Structure: Basis for Design of Anti-SARS Drugs". Science. 300 (5626): 1763–1767. Bibcode:2003Sci...300.1763A. doi:10.1126/science.1085658. PMID 12746549. S2CID 13031405.
  11. ^ Dragovich PS, Prins TJ, Zhou R, Webber SE, Marakovits JT, Fuhrman SA, et al. (April 1999). "Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 4. Incorporation of P1 lactam moieties as L-glutamine replacements". Journal of Medicinal Chemistry. 42 (7): 1213–1224. doi:10.1021/jm9805384. PMID 10197965.
  12. ^ Pillaiyar T, Manickam M, Namasivayam V, Hayashi Y, Jung SH (July 2016). "An Overview of Severe Acute Respiratory Syndrome-Coronavirus (SARS-CoV) 3CL Protease Inhibitors: Peptidomimetics and Small Molecule Chemotherapy". Journal of Medicinal Chemistry. 59 (14): 6595–6628. doi:10.1021/acs.jmedchem.5b01461. PMC 7075650. PMID 26878082.
  13. ^ Pedersen NC, Kim Y, Liu H, Galasiti Kankanamalage AC, Eckstrand C, Groutas WC, et al. (April 2018). "Efficacy of a 3C-like protease inhibitor in treating various forms of acquired feline infectious peritonitis". Journal of Feline Medicine and Surgery. 20 (4): 378–392. doi:10.1177/1098612X17729626. PMC 5871025. PMID 28901812.
  14. ^ Halford B (7 April 2021). "Pfizer unveils its oral SARS-CoV-2 inhibitor". Chemical & Engineering News. 99 (13): 7. doi:10.47287/cen-09913-scicon3. S2CID 234887434.
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  16. ^ Clinical trial number NCT04535167 for "First-In-Human Study To Evaluate Safety, Tolerability, And Pharmacokinetics Following Single Ascending And Multiple Ascending Doses of PF-07304814 In Hospitalized Participants With COVID-19 " at ClinicalTrials.gov
  17. ^ Boras B, Jones RM, Anson BJ, Arenson D, Aschenbrenner L, Bakowski MA, et al. (February 2021). "Discovery of a Novel Inhibitor of Coronavirus 3CL Protease for the Potential Treatment of COVID-19". bioRxiv: 2020.09.12.293498. doi:10.1101/2020.09.12.293498. PMC 7491518. PMID 32935104.
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  23. ^ "Pfizer's Novel COVID-19 Oral Antiviral Treatment Candidate Reduced Risk Of Hospitalization Or Death By 89% In Interim Analysis Of Phase 2/3 EPIC-HR Study" (Press release). Pfizer Inc. 5 November 2021.
  24. ^ Mahase E (November 2021). "Covid-19: Pfizer's paxlovid is 89% effective in patients at risk of serious illness, company reports". BMJ. 375: n2713. doi:10.1136/bmj.n2713. PMID 34750163. S2CID 243834203.
  25. ^ Pavan M, Bolcato G, Bassani D, Sturlese M, Moro S (December 2021). "Supervised Molecular Dynamics (SuMD) Insights into the mechanism of action of SARS-CoV-2 main protease inhibitor PF-07321332". J Enzyme Inhib Med Chem. 36 (1): 1646–1650. doi:10.1080/14756366.2021.1954919. PMC 8300928. PMID 34289752.
  26. ^ Woodley M (19 October 2021). "What is Australia's potential new COVID treatment?". The Royal Australian College of General Practitioners (RACGP). Retrieved 6 November 2021.
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  29. ^ "What are the two new COVID-19 treatments Australia has gained access to?". ABC News (Australia). 17 October 2021. Retrieved 5 November 2021.
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  34. ^ Kimball S (16 November 2021). "Pfizer submits FDA application for emergency approval of Covid treatment pill". CNBC. Retrieved 17 November 2021.
  35. ^ Robbins R (5 November 2021). "Pfizer Says Its Antiviral Pill Is Highly Effective in Treating Covid". The New York Times. ISSN 0362-4331. Archived from the original on 8 November 2021. Retrieved 9 November 2021.
  36. ^ "EMA issues advice on use of Paxlovid (PF-07321332 and ritonavir) for the treatment of COVID-19: rolling review starts in parallel" (Press release). European Medicines Agency (EMA). 16 December 2021.
  37. ^ Bloom J (2 December 2021). "How Does Pfizer's Pavloxid Compare With Ivermectin?". American Council on Science and Health. Retrieved 12 December 2021.
  38. ^ Gorski D (15 November 2021). "Pfizer's new COVID-19 protease inhibitor drug is not just 'repackaged ivermectin'". Science-Based Medicine.

External links

source: https://en.wikipedia.org/w/index.php?title=&diff=prev&oldid=1062076443

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