Ritonavir

Ritonavir
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)
Routes of
administration		 oral
Legal status
Legal status
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
Molar mass 720.946 g/mol
 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.[1] It may also be used in combination with other medications for hepatitis C.[2] 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.[3] 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.[4]

Ritonavir first came into use in 1996.[5] It is on the World Health Organization's List of Essential Medicines, the most important medications needed in a basic health system.[6] 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.[7] 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.[8]

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. 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.[9] 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).[12] 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.[13] 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[14]

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. [15]

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.[16]

In 2014, FDA approved a combination of ombitasvir/paritaprevir/ritonavir for treatment hepatitis C virus (HCV) genotype 4.[2]

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 2 3 4 5 6 7 8 "Ritonavir". The American Society of Health-System Pharmacists. Retrieved Oct 23, 2015.
  2. 1 2 "FDA approves Viekira Pak to treat hepatitis C". Food and Drug Administration. December 19, 2014.
  3. ↑ "Ritonavir Pregnancy and Breastfeeding Warnings". drugs.com. Retrieved 23 October 2015.
  4. ↑ British National Formulary 69 (69 ed.). Pharmaceutical Pr. March 31, 2015. p. 426. ISBN 9780857111562.
  5. ↑ Hacker, Miles (2009). Pharmacology principles and practice. Amsterdam: Academic Press/Elsevier. p. 550. ISBN 9780080919225.
  6. ↑ "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.
  7. ↑ "Ritonavir". International Drug Price Indicator Guide. Retrieved 23 October 2015.
  8. ↑ Norvir, rxlist.com
  9. ↑ Ritonavir, Merck Manual
  10. ↑ Henry, J. A.; Hill, I. R. (1998). "Fatal interaction between ritonavir and MDMA". Lancet 352 (9142): 1751–1752. doi:10.1016/s0140-6736(05)79824-x. PMID 9848354.
  11. ↑ Papaseit, E.; Vázquez, A.; Pérez-Mañá, C.; Pujadas, M.; De La Torre, R.; Farré, M.; Nolla, J. (2012). "Surviving life-threatening MDMA (3,4-methylenedioxymethamphetamine, ecstasy) toxicity caused by ritonavir (RTV)". Intensive Care Medicine 38 (7): 1239–1240. doi:10.1007/s00134-012-2537-9. PMID 22460853.
  12. ↑ Zeldin RK, Petruschke RA (2004). "Pharmacological and therapeutic properties of ritonavir-boosted protease inhibitor therapy in HIV-infected patients". Journal of Antimicrobial Chemotherapy 53 (1): 4–9. doi:10.1093/jac/dkh029. PMID 14657084.
  13. ↑ Merry, Concepta; Barry, Michael G.; Mulcahy, Fiona; Ryan, Mairin; Heavey, Jane; Tjia, John F.; Gibbons, Sara E.; Breckenridge, Alasdair M.; Back, David J. (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.
  14. ↑ "www.cdc.gov" (PDF).
  15. ↑ "HIV Surveillance --- United States, 1981--2008". Retrieved 8 November 2013.
  16. ↑ Ceci Connolly (2004-08-05). "NIH Declines to Enter AIDS Drug Price Battle". Washington Post. Retrieved 2006-01-16.
  17. 1 2 Bauer J, et al. (2001). "Ritonavir: An Extraordinary Example of Conformational Polymorphism". Pharmaceutical Research 18 (6): 859–866. doi:10.1023/A:1011052932607. PMID 11474792.
  18. 1 2 S. L. Morisette, S. Soukasene, D. Levinson, M. J. Cima and O. Almarsson (2003). "Elucidation of crystal form diversity of the HIV protease inhibitor ritonavir by high-throughput crystallization". Proc. Natl. Acad. Sci. USA 100 (5): 2180–84. doi:10.1073/pnas.0437744100. PMC 151315. PMID 12604798.
  19. ↑ "KALETRA FAQ". AbbVie's Kaletra product information. AbbVie. 2011. Retrieved 5 July 2014.

Further reading

External links

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