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Wikipedia

Ritonavir

February 24, 2023

For nirmatrelvir combined with ritonavir (sold under the brand name Paxlovid), see Nirmatrelvir/ritonavir.

Ritonavir, sold under the brand name Norvir, is an antiretroviral medication used along with other medications to treat HIV/AIDS.[3][4][5] This combination treatment is known as highly active antiretroviral therapy (HAART).[5] Ritonavir is a protease inhibitor and is used with other protease inhibitors.[5] It may also be used in combination with other medications to treat hepatitis C and COVID-19.[6][7] It is taken by mouth.[5] Tablets of ritonavir are not bioequivalent to capsules, as the tablets may result in higher peak plasma concentrations.[5]

Ritonavir
Clinical data
Pronunciation/rɪˈtɒnəˌvɪər/
rih-TO-nə-veer
Trade namesNorvir
Other namesRTV
AHFS/Drugs.comMonograph
MedlinePlusa696029
License data
Pregnancy
category
  • AU: B3
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding98–99%
MetabolismLiver
Elimination half-life3–5 hours
ExcretionMostly fecal
Identifiers
  • 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}butanamido]-1,6-diphenylhexan-2-yl]carbamate
CAS Number
  • 155213-67-5
PubChem CID
  • 392622
DrugBank
  • DB00503
ChemSpider
  • 347980
UNII
  • O3J8G9O825
KEGG
  • D00427
ChEBI
  • CHEBI:45409
ChEMBL
  • ChEMBL163
NIAID ChemDB
  • 028478
PDB ligand
  • RIT (PDBe, RCSB PDB)
CompTox Dashboard (EPA)
  • DTXSID1048627
ECHA InfoCard100.125.710
Chemical and physical data
FormulaC37H48N6O5S2
Molar mass720.95 g·mol−1
3D model (JSmol)
  • Interactive image
  • CC(C)c4nc(CN(C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OCc3cncs3)cs4
  • InChI=1S/C37H48N6O5S2/c1-24(2)33(42-36(46)43(5)20-29-22-49-35(40-29)25(3)4)34(45)39-28(16-26-12-8-6-9-13-26)18-32(44)31(17-27-14-10-7-11-15-27)41-37(47)48-21-30-19-38-23-50-30/h6-15,19,22-25,28,31-33,44H,16-18,20-21H2,1-5H3,(H,39,45)(H,41,47)(H,42,46)/t28-,31-,32-,33-/m0/s1 Y
  • Key:NCDNCNXCDXHOMX-XGKFQTDJSA-N Y

Common side effects of ritonavir include nausea, vomiting, loss of appetite, diarrhea, and numbness of the hands and feet.[5] Serious side effects include liver complications, pancreatitis, allergic reactions, and arrythmias.[5] Serious interactions may occur with a number of other medications including amiodarone and simvastatin.[5] At low doses, it is considered to be acceptable for use during pregnancy.[8] Ritonavir is of the protease inhibitor class.[5] However, it is also commonly used to inhibit the enzyme that metabolizes other protease inhibitors.[9] This inhibition allows lower doses of these latter medications to be used.[9]

Ritonavir was patented in 1989 and came into medical use in 1996.[10][11] It is on the World Health Organization's List of Essential Medicines.[12][13] Ritonavir capsules were approved as a generic medication in the United States in 2020.[14]

Medical uses

HIV

Ritonavir is indicated in combination with other antiretroviral agents for the treatment of HIV-1-infected patients.[3][4][5] Though initially developed as an independent antiviral treatment, it is most commonly used as a pharmacokinetic enhancer, in order to increase the plasma concentrations of other antiretrovirals.[15][16] Ritonavir is effective in preventing the replication of HIV-1. Protease inhibitors, including ritonavir, effectively block HIV-1 protease, a crucial enzyme in the reproductive cycle of HIV-1.[17]

COVID-19

In December 2021, the combination of nirmatrelvir and ritonavir was granted emergency use authorization by the US Food and Drug Administration (FDA) for the treatment of coronavirus disease COVID-19.[18][19][20] The co-packaged medications are sold under the brand name Paxlovid.[19][20][21] 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.[19] On 31 December 2021, the UK Medicines and Healthcare products Regulatory Agency (MHRA) approved the same combination "for people with mild to moderate COVID-19 who are at high risk of developing severe COVID-19".[22][23]

Side effects

When administered at the initially tested higher doses effective for anti-HIV therapy, the side effects of ritonavir are those shown below.[3]

Adverse drug reactions

Ritonavir exhibits hepatic activity.[24] It induces CYP1A2[medical citation needed] and inhibits the major P450 isoforms 3A4 and 2D6.[medical citation needed] Concomitant therapy of ritonavir with a variety of medications may result in serious and sometimes fatal drug interactions.[25]

Due to it being a strong inhibitor (that causes at least a five-fold increase in the plasma AUC values, or more than 80% decrease in clearance) of both Cytochrome P450 enzymes CYP2D6 and CYP3A4, ritonavir can severely potentiate and prolong the half-life and/or increase the blood concentration of phenobarbital, primidone, carbamazepine, phenytoin, PDE5 inhibitors like sildenafil, opioids such as hydrocodone, oxycodone, pethidine and fentanyl, antiarrhythmic agents such as amiodarone, propafenone and disopyramide, Immunosuppressants such as tacrolimus, voclosporin and sirolimus, neuroleptics like clozapine, lurasidone and pimozide, as well as some chemotherapeutic agents, benzodiazepines and some ergot derivatives[26] [27]

Pharmacology

 
Ritonavir (center) bound to the active site of HIV protease.[medical citation needed]

Pharmacodynamics

Ritonavir was originally developed as an inhibitor of HIV protease,[28] one of a family of pseudo-C2-symmetric small molecule inhibitors.[29]

Ritonavir is rarely used for its own antiviral activity but remains widely used as a booster of other protease inhibitors. More specifically, ritonavir is used to inhibit a particular enzyme, in intestines, liver, and elsewhere, that normally metabolizes protease inhibitors, cytochrome P450-3A4 (CYP3A4).[30] The drug binds to and inhibits CYP3A4, so a low dose can be used to enhance other protease inhibitors. This discovery drastically reduced the adverse effects and improved the efficacy of protease inhibitors and HAART. However, because of the general role of CYP3A4 in xenobiotic metabolism, dosing with ritonavir also affects the efficacy of numerous other medications, adding to the challenge of prescribing drugs concurrently.[medical citation needed][31][better source needed]

Pharmacokinetics

The capsules of the medication do not have the same bioavailability as the tablets.[5]

Ritonavir was demonstrated to have an in vitro potency of EC50=0.02µM and highly sustained concentration in plasma after oral administration in several species.[32]

Chemistry

Ritonavir was initially derived from a moderately potent and orally bioavailable small molecule, A-80987. The P3 and P2′ heterocyclic groups of A-80987 were redesigned to create an analogue, now known as ritonavir, with improved pharmacokinetic properties to the original.[32]

Full details of the synthesis of ritonavir were first published by scientists from Abbott Laboratories.

 

In the first step shown, an aldehyde derived from phenylalanine is treated with zinc dust in the presence of vanadium(III) chloride. This results in a pinacol coupling reaction which dimerizes the material to provide an intermediate which is converted to its epoxide and then reduced to (2S,3S,5S)-2,5-diamino-1,6-diphenylhexan-3-ol. Importantly, this retains the absolute stereochemistry of the amino acid precursor. The diamine is then treated sequentially with two thiazole derivatives, each linked by an amide bond, to provide ritonavir.[33][34]

History

 
New HIV infections and deaths, before and after the FDA approval of "highly active antiretroviral therapy",[35] of which saquinavir and ritonavir were key as the first two protease inhibitors.[medical citation needed] As a result of the new therapies, HIV deaths in the United States fell dramatically within two years.[35]

Ritonavir is sold as Norvir by AbbVie, Inc..[3][4] The US Food and Drug Administration (FDA) approved ritonavir on March 1, 1996,[36][37] As a result of the introduction of "highly active antiretroviral thearap[ies]" the annual U.S. HIV-associated death rate fell from over 50,000 to about 18,000 over a period of two years.[35]

In 2014, the FDA approved a combination of ombitasvir/paritaprevir/ritonavir for the treatment of hepatitis C virus (HCV) genotype 4.[6]

After the start of the COVID pandemic in 2020, many antivirals, including protease inhibitors in general and ritonavir in particular, were repurposed in an effort to treat the new infection. Lopinavir/ritonavir was found not to work in severe COVID-19.[38] Virtual screening followed by molecular dynamics analysis predicted ritonavir blocks the binding of the SARS-CoV-2 spike (S) protein to the human angiotensin-converting enzyme 2 (hACE2) receptor, which is critical for the virus entry into human cells.[39]

Finally in 2021, a combination of ritonavir with nirmatrelvir, a newly developed orally active 3C-like protease inhibitor, was developed for the treatment of COVID-19.[40][41][42][43] Ritonavir serves to slow down metabolism of nirmatrelvir by cytochrome enzymes to maintain higher circulating concentrations of the main drug.[44] In November that year, Pfizer announced positive phase 2/3 results, including 89% reduction in hospitalizations when given within three days after symptom onset.[45][46]

Polymorphism and temporary market withdrawal

Ritonavir was originally dispensed as a capsule that did not require refrigeration. This contained a crystal form of ritonavir that is now called form I.[47] However, like many drugs, crystalline ritonavir can exhibit polymorphism, i.e., the same molecule can crystallize into more than one crystal type, or polymorph, each of which contains the same repeating molecule but in different crystal packings/arrangements. The solubility and hence the bioavailability can vary in the different arrangements, and this was observed for forms I and II of ritonavir.[48]

During development—ritonavir was introduced in 1996—only the crystal form now called form I was found; however, in 1998, a lower free energy,[49] more stable polymorph, form II, was discovered. This more stable crystal form was less soluble, which resulted in significantly lower bioavailability. The compromised oral bioavailability of the drug led to temporary removal of the oral capsule formulation from the market.[48] As a consequence of the fact that even a trace amount of form II can result in the conversion of the more bioavailable form I into form II, the presence of form II threatened the ruin of existing supplies of the oral capsule formulation of ritonavir; and indeed, form II was found in production lines, effectively halting ritonavir production.[47] Abbott (now AbbVie) withdrew the capsules from the market, and prescribing physicians were encouraged to switch to a Norvir suspension.[citation needed] It has been estimated that Abbott lost more than $250 million USD as a result, and the incident is often cited as a high-profile example of disappearing polymorphs.[50]

The company's research and development teams ultimately solved the problem by replacing the capsule formulation with a refrigerated gelcap.[when?][citation needed] In 2000, Abbott (now AbbVie) received FDA-approval for a tablet formulation of lopinavir/ritonavir (Kaletra) which contained a preparation of ritonavir that did not require refrigeration.[51] Ritonavir produced in a solid dispersion by melt-extrusion was found to remain in form I, and was re-introduced commercially in 2010.[52]

Society and culture

Economics

In 2003, Abbott (AbbVie, Inc.) raised the price of a Norvir course from US$1.71 per day to US$8.57 per day, leading to claims of price gouging by patients' groups and some members of Congress. Consumer group Essential Inventions petitioned the NIH to override the Norvir patent, but the NIH announced on August 4, 2004, that it lacked the legal right to allow generic production of Norvir.[53]

References

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Further reading

  • Chemburkar SR, Bauer J, Deming K, Spiwek H, Patel K, Morris J, et al. (2000). "Dealing with the Impact of Ritonavir Polymorphs on the Late Stages of Bulk Drug Process Development". Organic Process Research & Development. 4 (5): 413–417. doi:10.1021/op000023y.

External links

  • "Ritonavir". Drug Information Portal. U.S. National Library of Medicine.

February 24, 2023
ritonavir, nirmatrelvir, combined, with, ritonavir, sold, under, brand, name, paxlovid, nirmatrelvir, ritonavir, sold, under, brand, name, norvir, antiretroviral, medication, used, along, with, other, medications, treat, aids, this, combination, treatment, kno. For nirmatrelvir combined with ritonavir sold under the brand name Paxlovid see Nirmatrelvir ritonavir Ritonavir sold under the brand name Norvir is an antiretroviral medication used along with other medications to treat HIV AIDS 3 4 5 This combination treatment is known as highly active antiretroviral therapy HAART 5 Ritonavir is a protease inhibitor and is used with other protease inhibitors 5 It may also be used in combination with other medications to treat hepatitis C and COVID 19 6 7 It is taken by mouth 5 Tablets of ritonavir are not bioequivalent to capsules as the tablets may result in higher peak plasma concentrations 5 RitonavirClinical dataPronunciation r ɪ ˈ t ɒ n e ˌ v ɪer rih TO ne veerTrade namesNorvirOther namesRTVAHFS Drugs comMonographMedlinePlusa696029License dataEU EMA by INN US DailyMed RitonavirPregnancycategoryAU B3Routes ofadministrationBy mouthATC codeJ05AE03 WHO Legal statusLegal statusAU S4 Prescription only CA only 1 2 UK POM Prescription only US only 3 EU Rx only 4 Pharmacokinetic dataProtein binding98 99 MetabolismLiverElimination half life3 5 hoursExcretionMostly fecalIdentifiersIUPAC name 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 butanamido 1 6 diphenylhexan 2 yl carbamateCAS Number155213 67 5PubChem CID392622DrugBankDB00503ChemSpider347980UNIIO3J8G9O825KEGGD00427ChEBICHEBI 45409ChEMBLChEMBL163NIAID ChemDB028478PDB ligandRIT PDBe RCSB PDB CompTox Dashboard EPA DTXSID1048627ECHA InfoCard100 125 710Chemical and physical dataFormulaC 37H 48N 6O 5S 2Molar mass720 95 g mol 13D model JSmol Interactive imageSMILES CC C c4nc CN C C O N C H C C C C O N C H Cc1ccccc1 C C H O C H Cc2ccccc2 NC O OCc3cncs3 cs4InChI InChI 1S C37H48N6O5S2 c1 24 2 33 42 36 46 43 5 20 29 22 49 35 40 29 25 3 4 34 45 39 28 16 26 12 8 6 9 13 26 18 32 44 31 17 27 14 10 7 11 15 27 41 37 47 48 21 30 19 38 23 50 30 h6 15 19 22 25 28 31 33 44H 16 18 20 21H2 1 5H3 H 39 45 H 41 47 H 42 46 t28 31 32 33 m0 s1 YKey NCDNCNXCDXHOMX XGKFQTDJSA N YCommon side effects of ritonavir include nausea vomiting loss of appetite diarrhea and numbness of the hands and feet 5 Serious side effects include liver complications pancreatitis allergic reactions and arrythmias 5 Serious interactions may occur with a number of other medications including amiodarone and simvastatin 5 At low doses it is considered to be acceptable for use during pregnancy 8 Ritonavir is of the protease inhibitor class 5 However it is also commonly used to inhibit the enzyme that metabolizes other protease inhibitors 9 This inhibition allows lower doses of these latter medications to be used 9 Ritonavir was patented in 1989 and came into medical use in 1996 10 11 It is on the World Health Organization s List of Essential Medicines 12 13 Ritonavir capsules were approved as a generic medication in the United States in 2020 14 Contents 1 Medical uses 1 1 HIV 1 2 COVID 19 2 Side effects 2 1 Adverse drug reactions 3 Pharmacology 3 1 Pharmacodynamics 3 2 Pharmacokinetics 4 Chemistry 5 History 6 Polymorphism and temporary market withdrawal 7 Society and culture 7 1 Economics 8 References 9 Further reading 10 External linksMedical uses EditThis section needs expansion with a lead sentence that better describes the very important PK PD observationsfor this first in class inhibitor design and its initial application You can help by adding to it February 2020 HIV Edit Ritonavir is indicated in combination with other antiretroviral agents for the treatment of HIV 1 infected patients 3 4 5 Though initially developed as an independent antiviral treatment it is most commonly used as a pharmacokinetic enhancer in order to increase the plasma concentrations of other antiretrovirals 15 16 Ritonavir is effective in preventing the replication of HIV 1 Protease inhibitors including ritonavir effectively block HIV 1 protease a crucial enzyme in the reproductive cycle of HIV 1 17 COVID 19 Edit In December 2021 the combination of nirmatrelvir and ritonavir was granted emergency use authorization by the US Food and Drug Administration FDA for the treatment of coronavirus disease COVID 19 18 19 20 The co packaged medications are sold under the brand name Paxlovid 19 20 21 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 19 On 31 December 2021 the UK Medicines and Healthcare products Regulatory Agency MHRA approved the same combination for people with mild to moderate COVID 19 who are at high risk of developing severe COVID 19 22 23 Side effects EditWhen administered at the initially tested higher doses effective for anti HIV therapy the side effects of ritonavir are those shown below 3 Asthenia malaise Diarrhea Nausea and vomiting Abdominal pain Dizziness Insomnia Kidney failure Sweating Taste abnormality Metabolic effects including Hypercholesterolemia Hypertriglyceridemia Elevated transaminases Elevated creatine kinase Adverse drug reactions Edit Ritonavir exhibits hepatic activity 24 It induces CYP1A2 medical citation needed and inhibits the major P450 isoforms 3A4 and 2D6 medical citation needed Concomitant therapy of ritonavir with a variety of medications may result in serious and sometimes fatal drug interactions 25 Due to it being a strong inhibitor that causes at least a five fold increase in the plasma AUC values or more than 80 decrease in clearance of both Cytochrome P450 enzymes CYP2D6 and CYP3A4 ritonavir can severely potentiate and prolong the half life and or increase the blood concentration of phenobarbital primidone carbamazepine phenytoin PDE5 inhibitors like sildenafil opioids such as hydrocodone oxycodone pethidine and fentanyl antiarrhythmic agents such as amiodarone propafenone and disopyramide Immunosuppressants such as tacrolimus voclosporin and sirolimus neuroleptics like clozapine lurasidone and pimozide as well as some chemotherapeutic agents benzodiazepines and some ergot derivatives 26 27 Pharmacology EditThis section needs expansion with with an accurate description of both its HIV protease and CYP3A4 binding characteristics and structural details You can help by adding to it February 2020 Ritonavir center bound to the active site of HIV protease medical citation needed Pharmacodynamics Edit Ritonavir was originally developed as an inhibitor of HIV protease 28 one of a family of pseudo C2 symmetric small molecule inhibitors 29 Ritonavir is rarely used for its own antiviral activity but remains widely used as a booster of other protease inhibitors More specifically ritonavir is used to inhibit a particular enzyme in intestines liver and elsewhere that normally metabolizes protease inhibitors cytochrome P450 3A4 CYP3A4 30 The drug binds to and inhibits CYP3A4 so a low dose can be used to enhance other protease inhibitors This discovery drastically reduced the adverse effects and improved the efficacy of protease inhibitors and HAART However because of the general role of CYP3A4 in xenobiotic metabolism dosing with ritonavir also affects the efficacy of numerous other medications adding to the challenge of prescribing drugs concurrently medical citation needed 31 better source needed Pharmacokinetics Edit The capsules of the medication do not have the same bioavailability as the tablets 5 Ritonavir was demonstrated to have an in vitro potency of EC50 0 02µM and highly sustained concentration in plasma after oral administration in several species 32 Chemistry EditRitonavir was initially derived from a moderately potent and orally bioavailable small molecule A 80987 The P3 and P2 heterocyclic groups of A 80987 were redesigned to create an analogue now known as ritonavir with improved pharmacokinetic properties to the original 32 Full details of the synthesis of ritonavir were first published by scientists from Abbott Laboratories In the first step shown an aldehyde derived from phenylalanine is treated with zinc dust in the presence of vanadium III chloride This results in a pinacol coupling reaction which dimerizes the material to provide an intermediate which is converted to its epoxide and then reduced to 2S 3S 5S 2 5 diamino 1 6 diphenylhexan 3 ol Importantly this retains the absolute stereochemistry of the amino acid precursor The diamine is then treated sequentially with two thiazole derivatives each linked by an amide bond to provide ritonavir 33 34 History Edit New HIV infections and deaths before and after the FDA approval of highly active antiretroviral therapy 35 of which saquinavir and ritonavir were key as the first two protease inhibitors medical citation needed As a result of the new therapies HIV deaths in the United States fell dramatically within two years 35 Ritonavir is sold as Norvir by AbbVie Inc 3 4 The US Food and Drug Administration FDA approved ritonavir on March 1 1996 36 37 As a result of the introduction of highly active antiretroviral thearap ies the annual U S HIV associated death rate fell from over 50 000 to about 18 000 over a period of two years 35 In 2014 the FDA approved a combination of ombitasvir paritaprevir ritonavir for the treatment of hepatitis C virus HCV genotype 4 6 After the start of the COVID pandemic in 2020 many antivirals including protease inhibitors in general and ritonavir in particular were repurposed in an effort to treat the new infection Lopinavir ritonavir was found not to work in severe COVID 19 38 Virtual screening followed by molecular dynamics analysis predicted ritonavir blocks the binding of the SARS CoV 2 spike S protein to the human angiotensin converting enzyme 2 hACE2 receptor which is critical for the virus entry into human cells 39 Finally in 2021 a combination of ritonavir with nirmatrelvir a newly developed orally active 3C like protease inhibitor was developed for the treatment of COVID 19 40 41 42 43 Ritonavir serves to slow down metabolism of nirmatrelvir by cytochrome enzymes to maintain higher circulating concentrations of the main drug 44 In November that year Pfizer announced positive phase 2 3 results including 89 reduction in hospitalizations when given within three days after symptom onset 45 46 Polymorphism and temporary market withdrawal EditRitonavir was originally dispensed as a capsule that did not require refrigeration This contained a crystal form of ritonavir that is now called form I 47 However like many drugs crystalline ritonavir can exhibit polymorphism i e the same molecule can crystallize into more than one crystal type or polymorph each of which contains the same repeating molecule but in different crystal packings arrangements The solubility and hence the bioavailability can vary in the different arrangements and this was observed for forms I and II of ritonavir 48 During development ritonavir was introduced in 1996 only the crystal form now called form I was found however in 1998 a lower free energy 49 more stable polymorph form II was discovered This more stable crystal form was less soluble which resulted in significantly lower bioavailability The compromised oral bioavailability of the drug led to temporary removal of the oral capsule formulation from the market 48 As a consequence of the fact that even a trace amount of form II can result in the conversion of the more bioavailable form I into form II the presence of form II threatened the ruin of existing supplies of the oral capsule formulation of ritonavir and indeed form II was found in production lines effectively halting ritonavir production 47 Abbott now AbbVie withdrew the capsules from the market and prescribing physicians were encouraged to switch to a Norvir suspension citation needed It has been estimated that Abbott lost more than 250 million USD as a result and the incident is often cited as a high profile example of disappearing polymorphs 50 The company s research and development teams ultimately solved the problem by replacing the capsule formulation with a refrigerated gelcap when citation needed In 2000 Abbott now AbbVie received FDA approval for a tablet formulation of lopinavir ritonavir Kaletra which contained a preparation of ritonavir that did not require refrigeration 51 Ritonavir produced in a solid dispersion by melt extrusion was found to remain in form I and was re introduced commercially in 2010 52 Society and culture EditEconomics Edit In 2003 Abbott AbbVie Inc raised the price of a Norvir course from US 1 71 per day to US 8 57 per day leading to claims of price gouging by patients groups and some members of Congress Consumer group Essential Inventions petitioned the NIH to override the Norvir patent but the NIH announced on August 4 2004 that it lacked the legal right to allow generic production of Norvir 53 References Edit Notice Nirmatrelvir COVID 19 added to Prescription Drug List PDL Health Canada January 17 2022 Archived from the original on May 29 2022 Retrieved June 25 2022 Norvir Product information Health Canada April 25 2012 Retrieved June 25 2022 a b c d e Norvir ritonavir tablet film coated Norvir ritonavir solution Norvir ritonavir powder DailyMed Archived from the original on November 18 2021 Retrieved November 17 2021 a b c d Norvir EPAR European Medicines Agency EMA Archived from the original on October 2 2018 Retrieved August 20 2020 Text was copied from this source which is c European Medicines Agency Reproduction is authorized provided the source is acknowledged a b c d e f g h i j k Ritonavir The American Society of Health System Pharmacists Archived from the original on October 17 2015 Retrieved October 23 2015 a b FDA approves Viekira Pak to treat hepatitis C Press release U S Food and Drug Administration FDA December 19 2014 Archived from the original on October 31 2015 Akinosoglou K Schinas G Gogos C November 2022 Oral Antiviral Treatment for COVID 19 A Comprehensive Review on Nirmatrelvir Ritonavir Viruses 14 11 2540 doi 10 3390 v14112540 PMC 9696049 PMID 36423149 Ritonavir Pregnancy and Breastfeeding Warnings drugs com Archived from the original on September 7 2015 Retrieved October 23 2015 a b British National Formulary 69 69 ed Pharmaceutical Pr March 31 2015 p 426 ISBN 9780857111562 Hacker M 2009 Pharmacology principles and practice Amsterdam Academic Press Elsevier p 550 ISBN 9780080919225 Archived from the original on June 17 2020 Retrieved September 10 2017 Fischer J Ganellin CR 2006 Analogue based Drug Discovery John Wiley amp Sons p 509 ISBN 9783527607495 Archived from the original on June 20 2021 Retrieved August 27 2020 World Health Organization 2019 World Health Organization model list of essential medicines 21st list 2019 Geneva World Health Organization hdl 10665 325771 WHO MVP EMP IAU 2019 06 License CC BY NC SA 3 0 IGO World Health Organization 2021 World Health Organization model list of essential medicines 22nd list 2021 Geneva World Health Organization hdl 10665 345533 WHO MHP HPS EML 2021 02 First Generic Drug Approvals U S Food and Drug Administration FDA Archived from the original on January 26 2021 Retrieved February 13 2021 Ritonavir Patient NIH clinicalinfo hiv gov Retrieved January 11 2023 Ritonavir go drugbank com Retrieved January 11 2023 Protease NIH clinicalinfo hiv gov Retrieved January 11 2023 Paxlovid nirmatrelvir and ritonavir kit DailyMed Archived from the original on December 31 2021 Retrieved December 30 2021 a b c FDA Authorizes First Oral Antiviral for Treatment of COVID 19 U S Food and Drug Administration FDA Press release December 22 2021 Archived from the original on December 27 2021 Retrieved December 22 2021 a b Pfizer Receives U S FDA Emergency Use Authorization for Novel COVID 19 Oral Antiviral Treatment Press release Pfizer December 22 2021 Archived from the original on December 22 2021 Retrieved December 22 2021 via Business Wire Frequently Asked Questions on the Emergency Use Authorization for Paxlovid for Treatment of COVID 19 PDF U S Food and Drug Administration FDA December 22 2021 Archived from the original on January 5 2022 Retrieved January 3 2022 Oral COVID 19 antiviral Paxlovid approved by UK regulator Press release Medicines and Healthcare products Regulatory Agency December 31 2021 Archived from the original on January 11 2022 Retrieved January 3 2022 Reed J December 31 2021 Paxlovid UK medicines regulator approves second Covid antiviral pill BBC News Online Archived from the original on January 1 2022 Retrieved January 3 2022 Yeh RF Gaver VE Patterson KB Rezk NL Baxter Meheux F Blake MJ et al May 2006 Lopinavir ritonavir induces the hepatic activity of cytochrome P450 enzymes CYP2C9 CYP2C19 and CYP1A2 but inhibits the hepatic and intestinal activity of CYP3A as measured by a phenotyping drug cocktail in healthy volunteers Journal of Acquired Immune Deficiency Syndromes 42 1 52 60 doi 10 1097 01 qai 0000219774 20174 64 PMID 16639344 S2CID 39632668 Ritonavir Drug Information Provided by Lexi Comp Merck Manual Professional Merck Manuals Professional Edition April 30 2008 Archived from the original on April 30 2008 Stader F Khoo S Stoeckle M Back D Hirsch HH Battegay M Marzolini C Stopping lopinavir ritonavir in COVID 19 patients duration of the drug interacting effect J Antimicrob Chemother 2020 Oct 1 75 10 3084 3086 doi 10 1093 jac dkaa253 PMID 32556272 PMCID PMC7337877 Carpenter M Berry H amp Pelletier A L 2019 Clinically Relevant Drug Drug Interactions in Primary Care American family physician 99 9 558 564 Espacenet search results worldwide espacenet com Archived from the original on April 5 2022 Retrieved April 5 2022 Kempf DJ Norbeck DW Codacovi L Wang XC Kohlbrenner WE Wideburg NE et al October 1990 Structure based C2 symmetric inhibitors of HIV protease Journal of Medicinal Chemistry 33 10 2687 2689 doi 10 1021 jm00172a002 PMID 2213822 Zeldin RK Petruschke RA January 2004 Pharmacological and therapeutic properties of ritonavir boosted protease inhibitor therapy in HIV infected patients The Journal of Antimicrobial Chemotherapy 53 1 4 9 doi 10 1093 jac dkh029 PMID 14657084 Drug Development and Drug Interactions Table of Substrates Inhibitors and Inducers U S Food and Drug Administration FDA December 3 2019 Archived from the original on March 12 2020 Retrieved February 17 2020 a b Kempf DJ Sham HL Marsh KC Flentge CA Betebenner D Green BE et al February 1998 Discovery of ritonavir a potent inhibitor of HIV protease with high oral bioavailability and clinical efficacy Journal of Medicinal Chemistry 41 4 602 617 doi 10 1021 jm970636 PMID 9484509 WO patent 1994014436 Kempf Dale J Norbeck Daniel W Sham Hing Leung Zhao Chen Sowin Thomas J Reno Daniel S Haight Anthony R and Cooper Arthur J Retroviral protease inhibiting compounds published 1994 07 07 assigned to Abbott Laboratories Vardanyan Ruben Hruby Victor 2016 34 Antiviral Drugs Synthesis of Best Seller Drugs pp 698 701 doi 10 1016 B978 0 12 411492 0 00034 1 ISBN 9780124114920 S2CID 75449475 a b c Centers for Disease Control Prevention CDC June 2011 HIV surveillance United States 1981 2008 PDF MMWR Morbidity and Mortality Weekly Report 60 21 689 93 PMID 21637182 Archived from the original PDF on September 24 2015 Ritonavir FDA approval package PDF March 1 1996 Archived PDF from the original on March 1 2021 Retrieved August 20 2020 FDA Approval of HIV Medicines HIVINFO Retrieved September 29 2022 Cao B Wang Y Wen D Liu W Wang J Fan G et al May 2020 A Trial of Lopinavir Ritonavir in Adults Hospitalized with Severe Covid 19 The New England Journal of Medicine 382 19 1787 1799 doi 10 1056 NEJMoa2001282 PMC 7121492 PMID 32187464 Bagheri M Niavarani A October 2020 Molecular dynamics analysis predicts ritonavir and naloxegol strongly block the SARS CoV 2 spike protein hACE2 binding Journal of Biomolecular Structure amp Dynamics 40 4 1597 1606 doi 10 1080 07391102 2020 1830854 PMID 33030105 S2CID 222217607 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 Schooley RT Carlin AF Beadle JR Valiaeva N Zhang XQ Clark AE et al September 2021 Rethinking Remdesivir Synthesis Antiviral Activity and Pharmacokinetics of Oral Lipid Prodrugs Antimicrobial Agents and Chemotherapy 65 10 e0115521 doi 10 1128 AAC 01155 21 ISSN 0066 4804 PMC 8448143 PMID 34310217 S2CID 236450769 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 Pfizer begins dosing in Phase II III trial of antiviral drug for Covid 19 Clinical Trials Arena September 2 2021 Archived from the original on November 5 2021 Retrieved November 5 2021 Woodley M October 19 2021 What is Australia s potential new COVID treatment The Royal Australian College of General Practitioners RACGP Archived from the original on November 5 2021 Retrieved November 6 2021 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 November 5 2021 Archived from the original on November 16 2021 Retrieved November 17 2021 Weintraub K November 5 2021 Pfizer antiviral drug could nearly end deaths from COVID 19 company study suggests USA Today Archived from the original on November 5 2021 Retrieved November 5 2021 a b Bauer J Spanton S Henry R Quick J Dziki W Porter W Morris J June 2001 Ritonavir an extraordinary example of conformational polymorphism Pharmaceutical Research 18 6 859 866 doi 10 1023 A 1011052932607 PMID 11474792 S2CID 20923508 a b Morissette SL Soukasene S Levinson D Cima MJ Almarsson O March 2003 Elucidation of crystal form diversity of the HIV protease inhibitor ritonavir by high throughput crystallization Proceedings of the National Academy of Sciences of the United States of America 100 5 2180 2184 doi 10 1073 pnas 0437744100 PMC 151315 PMID 12604798 Luttge A February 1 2006 Crystal dissolution kinetics and Gibbs free energy Journal of Electron Spectroscopy and Related Phenomena 150 2 248 259 doi 10 1016 j elspec 2005 06 007 Bucar Dejan Kresimir Lancaster Robert W Bernstein Joel June 8 2015 Disappearing Polymorphs Revisited Angewandte Chemie International Edition 54 24 6972 6993 doi 10 1002 anie 201410356 PMC 4479028 PMID 26031248 Kaletra FAQ AbbVie s Kaletra product information AbbVie 2011 Archived from the original on July 7 2014 Retrieved July 5 2014 Zhang C Matzger AJ February 2017 A Newly Discovered Racemic Compound of Pioglitazone Hydrochloride Is More Stable than the Commercial Conglomerate Crystal Growth amp Design 17 2 414 417 doi 10 1021 acs cgd 6b01638 PMC 6752731 PMID 31537981 Ceci Connolly August 5 2004 NIH Declines to Enter AIDS Drug Price Battle The Washington Post Archived from the original on August 20 2008 Retrieved January 16 2006 Further reading EditChemburkar SR Bauer J Deming K Spiwek H Patel K Morris J et al 2000 Dealing with the Impact of Ritonavir Polymorphs on the Late Stages of Bulk Drug Process Development Organic Process Research amp Development 4 5 413 417 doi 10 1021 op000023y External links Edit Ritonavir Drug Information Portal U S National Library of Medicine Portals Medicine Viruses Retrieved from https en wikipedia org w index php title Ritonavir amp oldid 1135341553, wikipedia, wiki, book, books, library,

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