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
Elimination half-life 3–5 hours
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] [6] This combination treatment is known as highly active antiretroviral therapy (HAART). [6] Ritonavir is a protease inhibitor, though it now mainly serves to boost the potency of other protease inhibitors. [6] [7] It may also be used in combination with other medications to treat hepatitis C and COVID-19. [8] [9] It is taken by mouth. [6] Tablets of ritonavir are not bioequivalent to capsules, as the tablets may result in higher peak plasma concentrations. [6]

Contents

Common side effects of ritonavir include nausea, vomiting, loss of appetite, diarrhea, and numbness of the hands and feet. [6] Serious side effects include liver complications, pancreatitis, allergic reactions, and arrythmias. [6] Serious interactions may occur with a number of other medications including amiodarone and simvastatin. [6] At low doses, it is considered to be acceptable for use during pregnancy. [10] Ritonavir is of the protease inhibitor class. [6] However, it is also commonly used to inhibit the enzyme that metabolizes other protease inhibitors. [11] This inhibition allows lower doses of these latter medications to be used. [11]

Ritonavir was patented in 1989 and came into medical use in 1996. [12] [13] It is on the World Health Organization's List of Essential Medicines. [14] [15] Ritonavir capsules were approved as a generic medication in the United States in 2020. [16]

Medical uses

HIV

Ritonavir is indicated in combination with other antiretroviral agents for the treatment of HIV-1-infected patients. [4] [5] [6] 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. [17] [18] 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. [19]

COVID-19

Two SARS-CoV-2 3CLpro inhibitors are prepackaged with ritonavir to enhance their blood concentration. [20]

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. [21] [22] [23] The co-packaged medications are sold under the brand name Paxlovid. [22] [23] [24] 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. [22] 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". [25] [26]

In January 2023, simnotrelvir/ritonavir was conditionally approved by China's National Medical Products Administration (NMPA) for COVID-19. [20]

Other uses

The use of ritonavir as a CYP3A inhibitor is also seen in the Hepatitis C medication ombitasvir/paritaprevir/ritonavir. [7]

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. [27] 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. [28]

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. [29] [30] The FDA has issued a boxed warning for this type of drug interactions. [7]

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. [7]

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, [31] one of a family of pseudo-C2-symmetric small molecule inhibitors. [32]

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. [33] [34] . 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. [7] [35]

Pharmacokinetics

The capsules of the medication do not have the same bioavailability as the tablets. [6]

Ritonavir was demonstrated to have an in vitro potency of EC50=0.02µM on HIV-1 protease and highly sustained concentration in plasma after oral administration in several species. [36]

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. [36]

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. [31] [37]

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, [39] [40] 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. [38]

In 2014, the FDA approved a combination of ombitasvir/paritaprevir/ritonavir for the treatment of hepatitis C virus (HCV) genotype 4. [8]

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. [41] 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. [42]

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. [43] [44] [45] [46] Ritonavir serves to slow down metabolism of nirmatrelvir by cytochrome enzymes to maintain higher circulating concentrations of the main drug. [47] In November that year, Pfizer announced positive phase 2/3 results, including 89% reduction in hospitalizations when given within three days after symptom onset. [48] [49]

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. [50] 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. [51]

During development—ritonavir was introduced in 1996—only the crystal form now called form I was found; however, in 1998, a lower free energy, [52] 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. [51] 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. [50] 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. [53]

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. [54] Ritonavir tablets produced in a solid dispersion by melt-extrusion was found to remain in form I, and was re-introduced commercially in 2010. [55]

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. [56]

Related Research Articles

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">Atazanavir</span> Chemical compound

Atazanavir, sold under the brand name Reyataz among others, is an antiretroviral medication used to treat HIV/AIDS. 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.

<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">Indinavir</span> Chemical compound

Indinavir is a protease inhibitor used as a component of highly active antiretroviral therapy to treat HIV/AIDS. It is soluble white powder administered orally in combination with other antiviral drugs. The drug prevents protease from functioning normally. Consequently, HIV viruses cannot reproduce, causing a decrease in the viral load. Commercially sold indinavir is indinavir anhydrous, which is indinavir with an additional amine in the hydroxyethylene backbone. This enhances its solubility and oral bioavailability, making it easier for users to intake. It was synthetically produced for the purpose of inhibiting the protease in the HIV virus.

<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).

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

Umifenovir, sold under the brand name Arbidol, is an antiviral medication for the treatment of influenza and COVID infections used 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.

<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">Grazoprevir</span> Drug approved for the treatment of hepatitis C

Grazoprevir is a drug approved for the treatment of hepatitis C. It was developed by Merck and completed Phase III trials, used in combination with the NS5A replication complex inhibitor elbasvir under the trade name Zepatier, either with or without ribavirin.

<span class="mw-page-title-main">COVID-19 drug repurposing research</span> Drug repurposing research related to COVID-19

Drug repositioning is the repurposing of an approved drug for the treatment of a different disease or medical condition than that for which it was originally developed. This is one line of scientific research which is being pursued to develop safe and effective COVID-19 treatments. Other research directions include the development of a COVID-19 vaccine and convalescent plasma transfusion.

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

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The treatment and management of COVID-19 combines both supportive care, which includes treatment to relieve symptoms, fluid therapy, oxygen support as needed, and a growing list of approved medications. Highly effective vaccines have reduced mortality related to SARS-CoV-2; however, for those awaiting vaccination, as well as for the estimated millions of immunocompromised persons who are unlikely to respond robustly to vaccination, treatment remains important. Some people may experience persistent symptoms or disability after recovery from the infection, known as long COVID, but there is still limited information on the best management and rehabilitation for this condition.

<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. Both components are protease inhibitors: nirmatrelvir inhibits SARS-CoV-2 main protease, while ritonavir inhibits HIV-1 protease, and is additionally a strong CYP3A inhibitor. It is taken by mouth.

References

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  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.
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