Ritonavir

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Ritonavir
Ritonavir structure.svg
Ritonavir-from-xtal-Mercury-3D-balls.png
Names
Trade namesNorvir
Clinical data
Pregnancy
category
  • AU: B3
  • US: B (No risk in non-human studies)
Routes of
use
By mouth
Defined daily dose1.2 grams[1]
External links
AHFS/Drugs.comMonograph
MedlinePlusa696029
Legal
License data
Legal status
Pharmacokinetics
Protein binding98-99%
MetabolismHepatic
Elimination half-life3-5 hours
Excretionmostly fecal
Chemical and physical data
FormulaC37H48N6O5S2
Molar mass720.95 g·mol−1
3D model (JSmol)
 ☒N☑Y (what is this?)  (verify)

Ritonavir (RTV), sold under the trade name Norvir, is an antiretroviral medication used along with other medications to treat HIV/AIDS.[2] This combination treatment is known as highly active antiretroviral therapy (HAART).[2] Often a low dose is used with other protease inhibitors.[2] It may also be used in combination with other medications for hepatitis C.[3] It is taken by mouth.[2] The capsules of the medication do not work the same as the tablets.[2]

Common side effects include nausea, vomiting, loss of appetite, diarrhea, and numbness of the hands and feet.[2] Serious side effects include liver problems, pancreatitis, allergic reactions, and arrythmias.[2] Serious interactions may occur with a number of other medications including amiodarone and simvastatin.[2] At low doses it is considered to be acceptable for use during pregnancy.[4] Ritonavir is of the protease inhibitor class.[2] Typically, however, it is used to inhibit the enzyme that metabolizes other protease inhibitors.[5] This inhibition allows lower doses of these latter medication to be used.[5]

Ritonavir was patented in 1989 and came into medical use in 1996.[6][7] It is on the World Health Organization's List of Essential Medicines, the safest and most effective medicines needed in a health system.[8] Globally the wholesale cost in the developing world is between US$0.07 and $2.20 per day.[9] In the United States it costs about $9.20–55 per day depending on the dose.[2]

Medical use

Ritonavir is used along with other medications to treat HIV/AIDS.[2]

Dosage

The defined daily dose is 1.2 grams (by mouth)[1] When used as a booster for a protease inhibitor, the dose in adults is 100 mg once or twice per day by mouth.[10] In those who weight 14 to 25 kg the dose is 50 mg twice per day or 100 mg once per day.[10]

Side effects

As of 2015, ritonavir is much more widely used at a lower doses, based on its activity as a CYP3A4 inhibitor; the adverse effects at these lower doses have not been extensively characterized.[dubious ][citation needed] When administered at the initially tested higher doses effective for anti-HIV therapy, the side effects of ritonavir are those shown below.[11]

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.[citation needed] This can lead to insulin resistance and cause problems for people with type Ⅱ diabetes.[citation needed]

Drug interactions

Ritonavir induces CYP 1A2 and inhibits the major P450 isoforms 3A4 and 2D6.[according to whom?] Concomitant therapy of ritonavir with a variety of medications may result in serious and sometimes fatal drug interactions.[12] The list of clinically significant interactions of ritonavir includes the following drugs:

Mechanism of action

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

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

Ritonavir 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 enzyme, in intestines, liver, and elsewhere, that normally metabolizes protease inhibitors, cytochrome P450-3A4 (CYP3A4).[17] 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.[citation needed][18][better source needed]

Pharmocodymanics and pharmacokinetics

The capsules of the medication do not have the same bioavailability as the tablets.[2]

History

New HIV infections and deaths, before and after the FDA approval of "highly active antiretroviral therapy",[19] of which saquinavir and ritonavir were key as the first two protease inhibitors.[citation needed] As a result of the new therapies, HIV deaths in the United States fell dramatically within two years.[19]

Ritonavir is manufactured as Norvir by AbbVie, Inc..[citation needed] The Food and Drug Administration (FDA) approved ritonavir on March 1, 1996, making it the seventh U.S.-approved antiretroviral drug and the second U.S.-approved protease inhibitor (after saquinavir 4 months earlier).[citation needed] As a result of the introduction of new "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.[20][21]

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.[22]

In 2014, FDA approved a combination of ombitasvir/paritaprevir/ritonavir for treatment hepatitis C virus (HCV) genotype 4,[3] where the presence of ritonavir again capitalizes on its inhibitory interaction with the human drug metabolic enzyme CYP3A4.[citation needed]

Polymorphism and temporary market withdrawal

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.[23] 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.[24]

During development—ritonavir was introduced in 1996—only the crystal form now called form I was found; however, in 1998, a lower free energy,[25] more stable polymorph, form II, was discovered. This more stable crystal form was less soluble form II, and its poor solubility resulted in significantly lower bioavailability. The compromised oral bioavailability of the drug led to temporary removal of the oral capsule formulation from the market.[24] 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.[23] 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.[26]

Research

In 2020 lopinavir/ritonavir was found not to work in severe COVID-19.[27] In the trial the medication was started around 13 days after the start of symptoms.[27]

References

  1. 1.0 1.1 "WHOCC - ATC/DDD Index". www.whocc.no. Retrieved 22 September 2020.
  2. 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 "Ritonavir". The American Society of Health-System Pharmacists. Archived from the original on 2015-10-17. Retrieved Oct 23, 2015.
  3. 3.0 3.1 "FDA approves Viekira Pak to treat hepatitis C". Food and Drug Administration. December 19, 2014. Archived from the original on October 31, 2015.
  4. "Ritonavir Pregnancy and Breastfeeding Warnings". drugs.com. Archived from the original on 7 September 2015. Retrieved 23 October 2015.
  5. 5.0 5.1 British National Formulary 69 (69 ed.). Pharmaceutical Pr. March 31, 2015. p. 426. ISBN 9780857111562.
  6. Hacker, Miles (2009). Pharmacology principles and practice. Amsterdam: Academic Press/Elsevier. p. 550. ISBN 9780080919225.
  7. Fischer, Jnos; Ganellin, C. Robin (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 509. ISBN 9783527607495.
  8. 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.
  9. "Ritonavir". International Drug Price Indicator Guide. Archived from the original on 10 May 2017. Retrieved 23 October 2015.
  10. 10.0 10.1 "RITONAVIR = RTV oral - Essential drugs". medicalguidelines.msf.org. Retrieved 17 August 2020.
  11. "Norvir side effects (Ritonavir) and drug interactions - prescription drugs and medications at RxList". June 27, 2007. Archived from the original on 2007-06-27.
  12. "Ritonavir: Drug Information Provided by Lexi-Comp: Merck Manual Professional". April 30, 2008. Archived from the original on 2008-04-30.
  13. 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.
  14. 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.
  15. Nieminen, Tuija H.; Hagelberg, Nora M.; Saari, Teijo I.; Neuvonen, Mikko; Neuvonen, Pertti J.; Laine, Kari; Olkkola, Klaus T. (2010). "Oxycodone concentrations are greatly increased by the concomitant use of ritonavir or lopinavir/ritonavir". European Journal of Clinical Pharmacology. 66 (10): 977–985. doi:10.1007/s00228-010-0879-1. ISSN 0031-6970. PMID 20697700.
  16. Hsieh, Yi-Ling; Ilevbare, Grace A.; Van Eerdenbrugh, Bernard; Box, Karl J.; Sanchez-Felix, Manuel Vincente; Taylor, Lynne S. (2012-05-12). "pH-Induced Precipitation Behavior of Weakly Basic Compounds: Determination of Extent and Duration of Supersaturation Using Potentiometric Titration and Correlation to Solid State Properties". Pharmaceutical Research. 29 (10): 2738–2753. doi:10.1007/s11095-012-0759-8. ISSN 0724-8741. PMID 22580905.
  17. 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. Archived from the original on 2007-08-21.
  18. Research, Center for Drug Evaluation and (December 3, 2019). "Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers". FDA – via www.fda.gov.
  19. 19.0 19.1 "Wayback Machine" (PDF). Archived from the original (PDF) on 2015-09-24. Retrieved 2020-02-17. Cite uses generic title (help)
  20. "HIV Surveillance—United States, 1981-2008". Archived from the original on 9 November 2013. Retrieved 8 November 2013.
  21. The CDC, in its Morbidity and Mortality Weekly Report, ascribes this to "highly active antiretroviral therapy", without mention of either of these drugs, see the preceding citation. A further citation is needed to make this accurate connection between this drop and the introduction of the protease inhibitors.
  22. Ceci Connolly (2004-08-05). "NIH Declines to Enter AIDS Drug Price Battle". Washington Post. Archived from the original on 2008-08-20. Retrieved 2006-01-16.
  23. 23.0 23.1 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.
  24. 24.0 24.1 S. L. Morissette; S. Soukasene; D. Levinson; M. J. Cima; 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.
  25. Lüttge, Andreas (February 1, 2006). "Crystal dissolution kinetics and Gibbs free energy". Journal of Electron Spectroscopy and Related Phenomena. 150 (2): 248–259. doi:10.1016/j.elspec.2005.06.007.
  26. "KALETRA FAQ". AbbVie's Kaletra product information. AbbVie. 2011. Archived from the original on 7 July 2014. Retrieved 5 July 2014.
  27. 27.0 27.1 Cao, Bin; Wang, Yeming; Wen, Danning; Liu, Wen; Wang, Jingli; Fan, Guohui; Ruan, Lianguo; Song, Bin; Cai, Yanping; Wei, Ming; Li, Xingwang; Xia, Jiaan; Chen, Nanshan; Xiang, Jie; Yu, Ting; Bai, Tao; Xie, Xuelei; Zhang, Li; Li, Caihong; Yuan, Ye; Chen, Hua; Li, Huadong; Huang, Hanping; Tu, Shengjing; Gong, Fengyun; Liu, Ying; Wei, Yuan; Dong, Chongya; Zhou, Fei; Gu, Xiaoying; Xu, Jiuyang; Liu, Zhibo; Zhang, Yi; Li, Hui; Shang, Lianhan; Wang, Ke; Li, Kunxia; Zhou, Xia; Dong, Xuan; Qu, Zhaohui; Lu, Sixia; Hu, Xujuan; Ruan, Shunan; Luo, Shanshan; Wu, Jing; Peng, Lu; Cheng, Fang; Pan, Lihong; Zou, Jun; Jia, Chunmin; Wang, Juan; Liu, Xia; Wang, Shuzhen; Wu, Xudong; Ge, Qin; He, Jing; Zhan, Haiyan; Qiu, Fang; Guo, Li; Huang, Chaolin; Jaki, Thomas; Hayden, Frederick G.; Horby, Peter W.; Zhang, Dingyu; Wang, Chen (18 March 2020). "A Trial of Lopinavir–Ritonavir in Adults Hospitalized with Severe Covid-19". New England Journal of Medicine. doi:10.1056/NEJMoa2001282. PMID 32187464.

Further reading

  • Chemburkar, Sanjay R.; Bauer, John; Deming, Kris; Spiwek, Harry; Patel, Ketan; Morris, John; Henry, Rodger; Spanton, Stephen; 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


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