Ritonavir

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

Ritonavir
Ritonavir structure.svg
Ritonavir-from-xtal-Mercury-3D-balls.png
Clinical data
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
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
NIAID ChemDB
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard100.125.710 Edit this at Wikidata
Chemical and physical data
FormulaC37H48N6O5S2
Molar mass720.95 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 checkY
  • Key:NCDNCNXCDXHOMX-XGKFQTDJSA-N checkY

Ritonavir, a protease inhibitor sold under the brand name Norvir, is an antiretroviral medication used along with other medications to treat HIV/AIDS.[1][2][3] This combination treatment is known as highly active antiretroviral therapy (HAART).[3] Often a low dose is used with other protease inhibitors.[3] It may also be used in combination with other medications for hepatitis C.[4] It is taken by mouth.[3] The tablets of ritonavir are not bioequivalent to capsules as tablets may result in higher peak plasma concentrations.[3]

Common side effects include nausea, vomiting, loss of appetite, diarrhea, and numbness of the hands and feet.[3] Serious side effects include liver problems, pancreatitis, allergic reactions, and arrythmias.[3] Serious interactions may occur with a number of other medications including amiodarone and simvastatin.[3] At low doses it is considered to be acceptable for use during pregnancy.[5] Ritonavir is of the protease inhibitor class.[3] Typically, however, it is used to inhibit the enzyme that metabolizes other protease inhibitors.[6] This inhibition allows lower doses of these latter medications to be used.[6]

Ritonavir was patented in 1989 and came into medical use in 1996.[7][8] It is on the World Health Organization's List of Essential Medicines.[9] Ritonavir capsules were approved as a generic medication in the United States in 2020.[10]

Medical uses[edit]

Ritonavir is indicated in combination with other antiretroviral agents for the treatment of HIV-1-infected patients.[1][2][3]

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.[11][12][13] The co-packaged medications are sold under the brand name Paxlovid.[12][13][14] 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.[12] 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".[15][16]

Side effects[edit]

When administered at the initially tested higher doses effective for anti-HIV therapy, the side effects of ritonavir are those shown below.[17]

One of ritonavir's side effects is hyperglycemia, through inhibition of the GLUT4 insulin-regulated transporter, thus keeping glucose from entering fat and muscle cells.[medical citation needed] This can lead to insulin resistance and cause problems for people with type 2 diabetes.[medical citation needed]

Adverse drug reactions[edit]

Ritonavir exhibits hepatic activity.[18] Ritonavir 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.[19]

Due to it being a strong inhibitor (that causes at least a 5-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 serious and life-threatening side-effects of the opioid painkiller Oxycodone.[20]

Combinations of several drug classes with ritonavir may cause risky side effects:[21]

Mechanism of action[edit]

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

Ritonavir was originally developed as an inhibitor of HIV protease,[22] one of a family of pseudo-C2-symmetric small molecule inhibitors.[23]

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).[24] 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][25][better source needed]

Pharmacodynamics and pharmacokinetics[edit]

The capsules of the medication do not have the same bioavailability as the tablets.[3]

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.[26]

Chemistry[edit]

Ritonavir was initially derived by Dale Kempf, et al. 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.[27]

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.[28][29]

History[edit]

New HIV infections and deaths, before and after the FDA approval of "highly active antiretroviral therapy",[30] 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.[30]

Ritonavir is manufactured as Norvir by AbbVie, Inc.[citation needed] The US Food and Drug Administration (FDA) approved ritonavir on March 1, 1996,[31] making it the seventh U.S.-approved antiretroviral drug and the second U.S.-approved protease inhibitor (after saquinavir four months earlier).[citation needed] As a result of the introduction of "highly active antiretroviral thearap[ies]"—of which the protease inhibitors ritonavir and saquinavir were critical[citation needed]—the annual U.S. HIV-associated death rate fell from over 50,000 to about 18,000 over a period of two years.[30][32]

In 2014, the FDA approved a combination of ombitasvir/paritaprevir/ritonavir for the treatment of hepatitis C virus (HCV) genotype 4,[4] where the presence of ritonavir again capitalizes on its inhibitory interaction with the human drug metabolic enzyme CYP3A4.[medical citation needed]

In 2021, a combination of ritonavir with nirmatrelvir, an orally active 3C-like protease inhibitor, was developed for the treatment of COVID-19.[33][34][35][36] Ritonavir serves to slow down metabolism of nirmatrelvir by cytochrome enzymes to maintain higher circulating concentrations of the main drug.[37] In November that year, Pfizer announced positive phase 2/3 results, including 89% reduction in hospitalizations when given within three days after symptom onset.[38][39]

Polymorphism and temporary market withdrawal[edit]

Ritonavir was originally dispensed as an ordinary capsule that did not require refrigeration. This contained a crystal form of ritonavir that is now called form I.[40] 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.[41]

During development—ritonavir was introduced in 1996—only the crystal form now called form I was found; however, in 1998, a lower free energy,[42] 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.[41] 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.[40] Abbott (now AbbVie) withdrew the capsules from the market, and prescribing physicians were encouraged to switch to a Norvir suspension.[citation needed]

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.[43] Ritonavir produced in a solid dispersion by melt-extrusion was found to remain in form I, and was re-introduced commercially in 2010.[44]

Society and culture[edit]

Economics[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.[45]

Research[edit]

In 2020, the fixed-dose combination of lopinavir/ritonavir was found not to work in severe COVID-19.[46] In the trial the medication was started around thirteen days after the start of symptoms.[46] Virtual screening of the 1930 FDA-approved drugs 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.[47]

References[edit]

  1. ^ a b c "Norvir- ritonavir tablet, film coated Norvir- ritonavir solution Norvir- ritonavir powder". DailyMed. Retrieved November 17, 2021.
  2. ^ a b c "Norvir EPAR". European Medicines Agency (EMA). Retrieved August 20, 2020. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  3. ^ 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.
  4. ^ a b "FDA approves Viekira Pak to treat hepatitis C". Food and Drug Administration. December 19, 2014. Archived from the original on October 31, 2015.
  5. ^ "Ritonavir Pregnancy and Breastfeeding Warnings". drugs.com. Archived from the original on September 7, 2015. Retrieved October 23, 2015.
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  11. ^ "Paxlovid- nirmatrelvir and ritonavir kit". DailyMed. Retrieved December 30, 2021.
  12. ^ 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. Retrieved December 22, 2021.
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  21. ^ "Pfizer's Covid pills may be risky with other medications". NBC News.
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  47. ^ 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.

Further reading[edit]

  • 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[edit]

  • "Ritonavir". Drug Information Portal. U.S. National Library of Medicine.
Retrieved from "https://en.wikipedia.org/w/index.php?title=Ritonavir&oldid=1082109713"