Ritonavir

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Ritonavir
Ritonavir structure.svg
Ritonavir ball-and-stick.png
Systematic (IUPAC) 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]carbamate
Clinical data
Trade names Norvir
AHFS/Drugs.com monograph
MedlinePlus a696029
Pregnancy
category
  • AU: B3
  • US: B (No risk in non-human studies)
Legal status
Routes of
administration		 oral
Pharmacokinetic data
Protein binding 98-99%
Metabolism Hepatic
Biological half-life 3-5 hours
Excretion mostly fecal
Identifiers
CAS Number 155213-67-5 YesY
ATC code J05AE03 (WHO)
PubChem CID: 392622
DrugBank DB00503 YesY
ChemSpider 347980 YesY
UNII O3J8G9O825 YesY
KEGG D00427 YesY
ChEBI CHEBI:45409 N
ChEMBL CHEMBL163 YesY
NIAID ChemDB 028478
Chemical data
Formula C37H48N6O5S2
Molecular mass 720.946 g/mol
  • 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 YesY
  • Key:NCDNCNXCDXHOMX-XGKFQTDJSA-N YesY
 NYesY (what is this?)  (verify)

Ritonavir, sold under the trade name Norvir, is an antiretroviral medication used along with other medications to treat HIV/AIDS.[1] This combination treatment is known as highly active antiretroviral therapy (HAART). Often a low dose is used with other protease inhibitors. It is taken by mouth.[1]

Common side effects include nausea, vomiting, loss of appetite, diarrhea, and numbness of the hands and feet. Serious side effects include liver problems, pancreatitis, allergic reactions, and arrythmias. Serious interactions may occur with a number of other medications including amiodarone and simvastatin.[1] At low doses it is considered to be okay during pregnancy.[2] Ritonavir is of the protease inhibitor class.[1] It is often used to inhibit the enzyme that metabolizes other protease inhibitors. This inhibition leads to higher concentrations of these latter medication.[3]

Ritonavir first came into use in 1996.[4] It is on the World Health Organization's List of Essential Medicines, the most important medications needed in a basic health system.[5] The capsules of the medication do not work the same as the tablets.[1] Globally the wholesale cost is between 0.07 and 2.20 USD per day.[6] In the United States it costs about 9.20 to 55 USD per day depending on the dose.[1]

Medical uses

Ritonavir is used along with other medications to treat HIV/AIDS.[1]

Side effects

When administered at doses effective for anti-HIV therapy, the side effects of ritonavir are those shown below. It is currently (2015) much more widely used at lower doses as a pharmacokinetic inhibitor. The adverse effects of these lower doses of ritonavir do not appear to have been extensively characterized.[7]

One of ritonavir's side effects is hyperglycemia. It appears that ritonavir directly inhibits the GLUT4 insulin-regulated transporter, keeping glucose from entering fat and muscle cells.[citation needed] This can lead to insulin resistance and cause problems for people with type Ⅱ diabetes.

Drug interactions

Concomitant therapy of ritonavir with a variety of medications may result in serious and sometimes fatal drug interactions.[8] Ritonavir induces CYP 1A2 and inhibits the major P450 isoforms (3A4 and 2D6).

The list of clinically significant interactions of ritonavir includes but is not limited to following drugs:

Mechanism of action

Ritonavir (center) bound to the active site of HIV protease.

Ritonavir was originally developed as an inhibitor of HIV protease. It is one of the most complex inhibitors. It is now 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 liver enzyme that normally metabolizes protease inhibitors, cytochrome P450-3A4 (CYP3A4).[11] The drug's molecular structure inhibits CYP3A4, so a low dose can be used to enhance other protease inhibitors. This discovery, which has drastically reduced the adverse effects and improved the efficacy of protease inhibitors and HAART, was first communicated in an article published in the journal AIDS in 1997 by researchers at the University of Liverpool.[12] This effect does come with a price: it also affects the efficacy of numerous other medications, making it difficult to know how to administer them concurrently.

History

United States HIV new infections and HIV deaths before and after the FDA approval of ritonavir.
HIV deaths in the United States fell from approximately 50,000 per year to 18,000 in the two years following the FDA approval of ritonavir[13]

Ritonavir is manufactured as Norvir by AbbVie, Inc.. The Food and Drug Administration (FDA) approved ritonavir on March 1, 1996, making it the seventh approved antiretroviral drug and the second approved protease inhibitor in the United States. Within 2 years of the approval of ritonavir (and of saquinavir a few months earlier), the U.S. HIV-associated death rate fell from over 50,000 per year to about 18,000. [14]

In 2003, Abbott (now AbbVie, Inc.) raised the price of a Norvir course from USD $1.71 per day to $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.[15]

In 2014, FDA approved Viekira Pak which ritonavir is one of its components.[16]

Polymorphism and temporary market withdrawal

Ritonavir was originally dispensed as an ordinary capsule, which did not require refrigeration. This was as a crystal of what is now called form I.[17] However, like many drugs, ritonavir exhibits polymorphism, i.e., the same molecule crystallizes into more than one type of crystal. The different crystals, or polymorphs, are made of the same molecules but in different crystalline arrangements. The solubility and hence the bioavailability is very different in the two different arrangements.[18]

During development (it was introduced in 1996), only the polymorph now called form I was found, but in 1998, a lower free energy, more stable polymorph (form II) appeared. This more stable (and so less soluble) crystal form compromised the oral bioavailability of the drug. This caused the removal of the oral capsule formulation from the market.[18]

Even a trace of form II can catalyse the transformation from the more bioavailable form I to form II. Thus form II threatened existing supplies of ritonavir as the lower solubility polymorph caused the therapeutically effective polymorph to convert to form II. Form II, which was not therapeutically effective because of poor solubility and resulting much lower bioavailability, entered production lines and effectively halted production processes.[17]

After this discovery in the late 1990s, Abbott (now AbbVie) withdrew the original capsules from the market, and recommended people switch to Norvir suspension while researchers worked to solve the problem. The capsules have been replaced with refrigerated gelcaps, to solve the crystallization problem of the original capsules.

In 2000 Abbott (now AbbVie) was awarded approval by the FDA for a tablet (called lopinavir/ritonavir) which contains ritonavir that does not require refrigeration.[19]

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 Lua error in package.lua at line 80: module 'strict' not found.
  2. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  3. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  4. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  5. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  6. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  7. ↑ Norvir, rxlist.com
  8. ↑ Ritonavir, Merck Manual
  9. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  10. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  11. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  12. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  13. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  14. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  15. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  16. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  17. ↑ 17.0 17.1 Lua error in package.lua at line 80: module 'strict' not found.
  18. ↑ 18.0 18.1 Lua error in package.lua at line 80: module 'strict' not found.
  19. ↑ Lua error in package.lua at line 80: module 'strict' not found.

Further reading

  • Lua error in package.lua at line 80: module 'strict' not found.

External links

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