Ritonavir

Last updated

Ritonavir
Ritonavir structure.svg
Ritonavir-from-xtal-Mercury-3D-balls.png
Clinical data
Pronunciation /rɪˈtɒnəˌvɪər/
rih-TO-nə-veer
Trade names Norvir
Other namesRTV
AHFS/Drugs.com Monograph
MedlinePlus a696029
License data
Pregnancy
category
  • AU:B3
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding 98–99%
Metabolism Liver, CYP3A4
Elimination half-life 3–4 hours [6] [7]
Excretion Mostly 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
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
NIAID ChemDB
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard 100.125.710 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C37H48N6O5S2
Molar mass 720.95 g·mol−1
3D model (JSmol)
  • 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 Yes check.svgY
  • Key:NCDNCNXCDXHOMX-XGKFQTDJSA-N Yes check.svgY

Ritonavir, sold under the brand name Norvir, is an antiretroviral medication used along with other medications to treat HIV/AIDS. [4] [5] [8] This combination treatment is known as highly active antiretroviral therapy (HAART). [8] Ritonavir is a protease inhibitor, though it now mainly serves to boost the potency of other protease inhibitors. [8] [9] It may also be used in combination with other medications to treat hepatitis C and COVID-19. [10] [11] It is taken by mouth. [8]

Contents

Common side effects of ritonavir include nausea, vomiting, loss of appetite, diarrhea, and numbness of the hands and feet. [8] Serious side effects include liver complications, pancreatitis, allergic reactions, and arrhythmias. [8] Serious interactions may occur with a number of other medications including amiodarone and simvastatin. [8] At low doses, it is considered to be acceptable for use during pregnancy. [12] Ritonavir is of the protease inhibitor class. [8] However, it is also commonly used to inhibit the enzyme that metabolizes other protease inhibitors. [13] This inhibition allows lower doses of these latter medications to be used. [13]

Ritonavir was patented in 1989 and came into medical use in 1996. [14] [15] It is on the World Health Organization's List of Essential Medicines. [16] [17] Ritonavir capsules were approved as a generic medication in the United States in 2020. [18]

Medical uses

HIV

Ritonavir is indicated in combination with other antiretroviral agents for the treatment of HIV-1-infected patients. [4] [5] [8] 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. [19] [20] 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. [21]

COVID-19

Two SARS-CoV-2 3CLpro inhibitors are prepackaged with ritonavir to enhance their blood concentration. [22]

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. [23] [24] [25] The co-packaged medications are sold under the brand name Paxlovid. [24] [25] [26] 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. [24] On December 31, 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". [27] [28]

In January 2023, simnotrelvir/ritonavir was conditionally approved by China's National Medical Products Administration (NMPA) for COVID-19. [22]

Other uses

The use of ritonavir as a CYP3A inhibitor is also seen in the Hepatitis C medication ombitasvir/paritaprevir/ritonavir. [9]

Side effects

When administered at the initially tested higher doses effective for anti-HIV therapy, the side effects of ritonavir are those shown below. [4]

Adverse drug reactions

Ritonavir exhibits hepatic activity. [29] It induces CYP1A2 and inhibits CYP3A4 and CYP2D6. Concomitant therapy of ritonavir with a variety of medications may result in serious and sometimes fatal drug interactions. [30]

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. [31] [32] The FDA has issued a boxed warning for this type of drug interactions. [9]

CYP3A4 inducers can counteract the inhibiting effects of ritonavir and lead to drastically reduced levels of "boosted" drugs, increasing the risk of developing drug resistance. Other CYP3A4 inhibitors may have an additive effect with ritonavir, causing increased drug levels. [9]

Pharmacology

Ritonavir (center) bound to the active site of HIV protease. HIV protesase with ritonavir.png
Ritonavir (center) bound to the active site of HIV protease.

Pharmacodynamics

Ritonavir was originally developed as an inhibitor of HIV protease, [33] one of a family of pseudo-C2-symmetric small molecule inhibitors. [34]

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). 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. [35] [36] . 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. See § Adverse drug reactions above. [9] [37]

Pharmacokinetics

Ritonavir at a 200 mg dose reaches maximum plasma concentration in about 3 hours and has a half life of 3–4 hours. [6] [7] Importantly, the pharmacokinetics of Ritonavir are not linear—the half life increases at higher doses or under repeated dosing. [6] For instance, the half life of a 500 mg tablet is 4–6 hours rather than 3–4 hours for a 200 mg tablet. [6] The drug has high bioavailability but about 20% is lost due to first-pass metabolism. [6] Rivonavir capsules are not absorbed as quickly as Ritonavir tablets and may exhibit different bioavailability. [8]

Ritonavir was demonstrated to have an in vitro potency of EC50=0.02 μM on HIV-1 protease and highly sustained concentration in plasma after oral administration in several species. [38]

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. [38]

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

Ritonavir synthesis.svg

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] [39]

History

New HIV infections and deaths, before and after the FDA approval of "highly active antiretroviral therapy", of which saquinavir and ritonavir were key as the first two protease inhibitors. As a result of the new therapies, HIV deaths in the United States fell dramatically within two years. HIV new infections and deaths 1981-2008.jpg
New HIV infections and deaths, before and after the FDA approval of "highly active antiretroviral therapy", of which saquinavir and ritonavir were key as the first two protease inhibitors. As a result of the new therapies, HIV deaths in the United States fell dramatically within two years.

Ritonavir is sold as Norvir by AbbVie, Inc. [4] [5] The US Food and Drug Administration (FDA) approved ritonavir on March 1, 1996, [41] [42] 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. [40]

In 2014, the FDA approved a combination of ombitasvir/paritaprevir/ritonavir for the treatment of hepatitis C virus (HCV) genotype 4. [10]

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. [43] 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. [44]

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. [45] [46] [47] [48] Ritonavir serves to slow down metabolism of nirmatrelvir by cytochrome enzymes to maintain higher circulating concentrations of the main drug. [49] In November that year, Pfizer announced positive phase 2/3 results, including 89% reduction in hospitalizations when given within three days after symptom onset. [50] [51]

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. [52] 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. [53]

During development—ritonavir was introduced in 1996—only the crystal form now called form I was found; however, in 1998, a lower free energy, [54] 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. [53] 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. [52] 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 US$250 million as a result, and the incident is often cited as a high-profile example of disappearing polymorphs. [55]

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. [56] Ritonavir tablets produced in a solid dispersion by melt-extrusion was found to remain in form I, and was re-introduced commercially in 2010. [57]

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. [58]

Related Research Articles

<span class="mw-page-title-main">Pravastatin</span> Cholesterol lowering medication in the statin class

Pravastatin, sold under the brand name Pravachol among others, is a statin medication, used for preventing cardiovascular disease in those at high risk and treating abnormal lipids. It is suggested to be used together with diet changes, exercise, and weight loss. It is taken by mouth.

Protease inhibitors (PIs) are medications that act by interfering with enzymes that cleave proteins. Some of the most well known are antiviral drugs widely used to treat HIV/AIDS, hepatitis C and COVID-19. These protease inhibitors prevent viral replication by selectively binding to viral proteases and blocking proteolytic cleavage of protein precursors that are necessary for the production of infectious viral particles.

<span class="mw-page-title-main">Saquinavir</span> Chemical compound

Saquinavir, sold under the brand name Invirase among others, is an antiretroviral medication used together with other medications to treat or prevent HIV/AIDS. Typically it is used with ritonavir or lopinavir/ritonavir to increase its effect. It is taken by mouth.

<span class="mw-page-title-main">Tipranavir</span> Chemical compound

Tipranavir (TPV), or tipranavir disodium, is a nonpeptidic protease inhibitor (PI) manufactured by Boehringer Ingelheim under the trade name AptivusAP-tiv-əs. It is administered with ritonavir in combination therapy to treat HIV infection.

<span class="mw-page-title-main">Fosamprenavir</span> Chemical compound

Fosamprenavir (FPV), sold under the brand names Lexiva and Telzir, is a medication used to treat HIV/AIDS. It is a prodrug of the protease inhibitor and antiretroviral drug amprenavir. It is marketed by ViiV Healthcare as the calcium salt.

<span class="mw-page-title-main">Lopinavir</span> Chemical compound

Lopinavir is an antiretroviral of the protease inhibitor class. It is used against HIV infections as a fixed-dose combination with another protease inhibitor, ritonavir (lopinavir/ritonavir).

Synergistic enhancers of antiretrovirals usually do not possess any antiretroviral properties alone, but when they are taken concurrently with antiretroviral drugs they enhance the effect of that drug.

<span class="mw-page-title-main">Umifenovir</span> Chemical compound

Umifenovir, sold under the brand name Arbidol, is sold and used as an antiviral medication for influenza in Russia and China. The drug is manufactured by Pharmstandard. It is not approved by the U.S. Food and Drug Administration (FDA) for the treatment or prevention of influenza.

<span class="mw-page-title-main">Darunavir</span> Antiretroviral medication

Darunavir (DRV), sold under the brand name Prezista among others, is an antiretroviral medication used to treat and prevent HIV/AIDS. It is generally recommended for use with other antiretrovirals. It is often used with low doses of ritonavir or cobicistat to increase darunavir levels. It may be used for prevention after a needlestick injury or other potential exposure. It is taken by mouth once to twice a day.

<span class="mw-page-title-main">Elvitegravir</span> Chemical compound

Elvitegravir (EVG) is an integrase inhibitor used to treat HIV infection. It was developed by the pharmaceutical company Gilead Sciences, which licensed EVG from Japan Tobacco in March 2008. The drug gained approval by the U.S. Food and Drug Administration on August 27, 2012, for use in adult patients starting HIV treatment for the first time as part of the fixed dose combination known as Stribild. On September 24, 2014, the FDA approved Elvitegravir as a single pill formulation under the trade name Vitekta. On November 5, 2015, the FDA approved the drug for use in patients affected with HIV-1 as a part of a second fixed dose combination pill known as Genvoya.

Many major physiological processes depend on regulation of proteolytic enzyme activity and there can be dramatic consequences when equilibrium between an enzyme and its substrates is disturbed. In this prospective, the discovery of small-molecule ligands, like protease inhibitors, that can modulate catalytic activities has an enormous therapeutic effect. Hence, inhibition of the HIV protease is one of the most important approaches for the therapeutic intervention in HIV infection and their development is regarded as major success of structure-based drug design. They are highly effective against HIV and have, since the 1990s, been a key component of anti-retroviral therapies for HIV/AIDS.

<span class="mw-page-title-main">Cobicistat</span> Chemical compound

Cobicistat, sold under the brand name Tybost, is a medication for use in the treatment of human immunodeficiency virus infection (HIV/AIDS). Its major mechanism of action is through the inhibition of human CYP3A proteins.

<span class="mw-page-title-main">Lopinavir/ritonavir</span> Combination medication for HIV/AIDS

Lopinavir/ritonavir (LPV/r), sold under the brand name Kaletra among others, is a fixed-dose combination antiretroviral medication for the treatment and prevention of HIV/AIDS. It combines lopinavir with a low dose of ritonavir. It is generally recommended for use with other antiretrovirals. It may be used for prevention after a needlestick injury or other potential exposure. It is taken by mouth as a tablet, capsule, or solution.

<span class="mw-page-title-main">Simeprevir</span> Chemical compound

Simeprevir, sold under the brand name Olysio among others, is a medication used in combination with other medications for the treatment of hepatitis C. It is specifically used for hepatitis C genotype 1 and 4. Medications it is used with include sofosbuvir or ribavirin and peginterferon-alfa. Cure rates are in 80s to 90s percent. It may be used in those who also have HIV/AIDS. It is taken by mouth once daily for typically 12 weeks.

<span class="mw-page-title-main">3C-like protease</span> Class of enzymes

The 3C-like protease (3CLpro) or main protease (Mpro), formally known as C30 endopeptidase or 3-chymotrypsin-like protease, is the main protease found in coronaviruses. It cleaves the coronavirus polyprotein at eleven conserved sites. It is a cysteine protease and a member of the PA clan of proteases. It has a cysteine-histidine catalytic dyad at its active site and cleaves a Gln–(Ser/Ala/Gly) peptide bond.

<span class="mw-page-title-main">COVID-19 drug development</span> Preventative and therapeutic medications for COVID-19 infection

COVID-19 drug development is the research process to develop preventative therapeutic prescription drugs that would alleviate the severity of coronavirus disease 2019 (COVID-19). From early 2020 through 2021, several hundred drug companies, biotechnology firms, university research groups, and health organizations were developing therapeutic candidates for COVID-19 disease in various stages of preclinical or clinical research, with 419 potential COVID-19 drugs in clinical trials, as of April 2021.

<span class="mw-page-title-main">Nirmatrelvir</span> COVID-19 antiviral medication

Nirmatrelvir is an antiviral medication developed by Pfizer which acts as an orally active 3C-like protease inhibitor. It is part of a nirmatrelvir/ritonavir combination used to treat COVID-19 and sold under the brand name Paxlovid.

<span class="mw-page-title-main">Nirmatrelvir/ritonavir</span> Antiviral combination medication

Nirmatrelvir/ritonavir, sold under the brand name Paxlovid, is a co-packaged medication used as a treatment for COVID‑19. It contains the antiviral medications nirmatrelvir and ritonavir and was developed by Pfizer. Nirmatrelvir inhibits SARS-CoV-2 main protease, while ritonavir is a strong CYP3A inhibitor, slowing down nirmatrelvir metabolism and therefore boosting its effect. It is taken by mouth.

<span class="mw-page-title-main">Jun12682</span> Antiviral drug

Jun12682 is an experimental antiviral medication being studied as a potential treatment for COVID-19. It is believed to work by inhibiting SARS-CoV-2 papain-like protease (PLpro), a crucial enzyme for viral replication.

<span class="mw-page-title-main">Ibuzatrelvir</span> Antiviral drug

Ibuzatrelvir is an experimental antiviral drug being developed by Pfizer for the treatment of COVID-19. It is a second-generation improvement over nirmatrelvir which has a similar chemical structure. One of the disadvantages of nirmatrelvir is that it has low metabolic stability and must be given in combination with ritonavir to limit its metabolic degradation in the body. Ibuzatrelvir incorporates modifications to the chemical structure of nirmatrelvir that give it enhanced oral bioavailability, so it does not require coadministration with ritonavir.

References

  1. ↑ "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.
  2. ↑ "Norvir Product information". Health Canada. April 25, 2012. Retrieved June 25, 2022.
  3. ↑ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA . Retrieved October 22, 2023.
  4. 1 2 3 4 5 "Norvir- ritonavir tablet, film coated Norvir- ritonavir solution Norvir- ritonavir powder". DailyMed. Archived from the original on November 18, 2021. Retrieved November 17, 2021.
  5. 1 2 3 4 "Norvir EPAR". European Medicines Agency (EMA). September 17, 2018. Archived from the original on October 2, 2018. Retrieved August 20, 2020. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  6. 1 2 3 4 5 Hsu A, Granneman GR, Witt G, Locke C, Denissen J, Molla A, et al. (May 1997). "Multiple-dose pharmacokinetics of ritonavir in human immunodeficiency virus-infected subjects". Antimicrobial Agents and Chemotherapy. 41 (5): 898–905. doi:10.1128/aac.41.5.898. PMC   163822 . PMID   9145841.
  7. 1 2 Danner SA, Carr A, Leonard JM, Lehman LM, Gudiol F, Gonzales J, Raventos A, Rubio R, Bouza E, Pintado V, Aguado AG, Garcia de Lomas J, Delgado R, Borleffs JC, Hsu A, Valdes JM, Boucher CA, Cooper DA (December 1995). "A short-term study of the safety, pharmacokinetics, and efficacy of ritonavir, an inhibitor of HIV-1 protease. European-Australian Collaborative Ritonavir Study Group". The New England Journal of Medicine. 333 (23): 1528–1533. doi:10.1056/NEJM199512073332303. hdl: 2445/121979 . PMID   7477167.
  8. 1 2 3 4 5 6 7 8 9 10 "Ritonavir". The American Society of Health-System Pharmacists. Archived from the original on October 17, 2015. Retrieved October 23, 2015.
  9. 1 2 3 4 5 Talha B, Dhamoon AS (August 8, 2023). "Ritonavir". StatPearls. StatPearls Publishing. PMID   31335032 . Retrieved January 6, 2024.
  10. 1 2 "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.
  11. ↑ 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.
  12. ↑ "Ritonavir Pregnancy and Breastfeeding Warnings". drugs.com. Archived from the original on September 7, 2015. Retrieved October 23, 2015.
  13. 1 2 British National Formulary 69 (69 ed.). Pharmaceutical Pr. March 31, 2015. p. 426. ISBN   9780857111562.
  14. ↑ 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.
  15. ↑ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 509. ISBN   9783527607495. Archived from the original on June 20, 2021. Retrieved August 27, 2020.
  16. ↑ 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.
  17. ↑ 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.
  18. ↑ "First Generic Drug Approvals". U.S. Food and Drug Administration (FDA). Archived from the original on January 26, 2021. Retrieved February 13, 2021.
  19. ↑ "Ritonavir - Patient". clinicalinfo.hiv.gov. Retrieved January 11, 2023.
  20. ↑ "Ritonavir". go.drugbank.com. Retrieved January 11, 2023.
  21. ↑ "Protease". clinicalinfo.hiv.gov. Retrieved January 11, 2023.
  22. 1 2 Zhu KW (September 2023). "Deuremidevir and Simnotrelvir-Ritonavir for the Treatment of COVID-19". ACS Pharmacology & Translational Science. 6 (9): 1306–1309. doi:10.1021/acsptsci.3c00134. PMC   10496140 . PMID   37705591.
  23. ↑ "Paxlovid- nirmatrelvir and ritonavir kit". DailyMed. Archived from the original on December 31, 2021. Retrieved December 30, 2021.
  24. 1 2 3 "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.
  25. 1 2 "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.
  26. ↑ "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.
  27. ↑ "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.
  28. ↑ 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.
  29. ↑ 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.
  30. ↑ "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.
  31. ↑ Stader F, Khoo S, Stoeckle M, Back D, Hirsch HH, Battegay M, Marzolini C (October 2020). "Stopping lopinavir/ritonavir in COVID-19 patients: duration of the drug interacting effect". The Journal of Antimicrobial Chemotherapy. 75 (10): 3084–3086. doi:10.1093/jac/dkaa253. PMC   7337877 . PMID   32556272.
  32. ↑ Carpenter M, Berry H, Pelletier AL (May 2019). "Clinically Relevant Drug-Drug Interactions in Primary Care". American Family Physician. 99 (9): 558–564. PMID   31038898.
  33. 1 2 WO 1994014436,Kempf DJ, Norbeck DW, Sham HL, Zhao C, Sowin TJ, Reno DS, Haight AR, Cooper AJ,"Retroviral protease inhibiting compounds",published July 7, 1994, assigned to Abbott Laboratories.
  34. ↑ 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.
  35. ↑ 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.
  36. ↑ Merry C, Barry MG, Mulcahy F, Ryan M, Heavey J, Tjia JF, et al. (March 1997). "Saquinavir pharmacokinetics alone and in combination with ritonavir in HIV-infected patients". AIDS. 11 (4): F29–F33. doi:10.1097/00002030-199704000-00001. PMID   9084785.
  37. ↑ "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.
  38. 1 2 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.
  39. ↑ Vardanyan R, Hruby V (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.
  40. 1 2 3 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.
  41. ↑ "Ritonavir FDA approval package" (PDF). March 1, 1996. Archived (PDF) from the original on March 1, 2021. Retrieved August 20, 2020.
  42. ↑ "FDA Approval of HIV Medicines". HIVINFO. Retrieved September 29, 2022.
  43. ↑ 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.
  44. ↑ 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 & Dynamics. 40 (4): 1597–1606. doi:10.1080/07391102.2020.1830854. PMID   33030105. S2CID   222217607.
  45. ↑ 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.
  46. ↑ 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.
  47. ↑ 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.
  48. ↑ "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.
  49. ↑ Woodley M (October 19, 2021). "What is Australia's potential new COVID treatment?". Newsgp. Archived from the original on November 5, 2021. Retrieved November 6, 2021.
  50. ↑ "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.
  51. ↑ 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.
  52. 1 2 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.
  53. 1 2 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.
  54. ↑ Lüttge A (February 1, 2006). "Crystal dissolution kinetics and Gibbs free energy". Journal of Electron Spectroscopy and Related Phenomena. 150 (2): 248–259. Bibcode:2006JESRP.150..248L. doi:10.1016/j.elspec.2005.06.007.
  55. ↑ Bučar DK, Lancaster RW, Bernstein J (June 2015). "Disappearing polymorphs revisited". Angewandte Chemie. 54 (24): 6972–6993. doi:10.1002/anie.201410356. PMC   4479028 . PMID   26031248.
  56. ↑ "Kaletra FAQ". AbbVie's Kaletra product information. AbbVie. 2011. Archived from the original on July 7, 2014. Retrieved July 5, 2014.
  57. ↑ Zhang C, Matzger AJ (February 2017). "A Newly Discovered Racemic Compound of Pioglitazone Hydrochloride Is More Stable than the Commercial Conglomerate". Crystal Growth & Design. 17 (2): 414–417. doi:10.1021/acs.cgd.6b01638. PMC   6752731 . PMID   31537981.
  58. ↑ Connolly C (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

This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.