Darunavir

Last updated

Darunavir
Darunavir structure.svg
Darunavir-from-xtal-3D-bs-17.png
Clinical data
Trade names Prezista, others [1]
Other namesTMC114, DRV, darunavir ethanolate
AHFS/Drugs.com Monograph
MedlinePlus a607042
License data
Pregnancy
category
Routes of
administration 		By mouth
Drug class HIV protease inhibitor
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 37% (without ritonavir), 82% (with ritonavir)
Protein binding 95%
Metabolism Liver (CYP3A4)
Elimination half-life 15 hours (with ritonavir)
Excretion Feces (80%), urine (14%)
Identifiers
  • [(1R,5S,6R)-2,8-dioxabicyclo[3.3.0]oct-6-yl] N-[(2S,3R)-4- [(4-aminophenyl)sulfonyl- (2-methylpropyl)amino]-3-hydroxy-1-phenyl- butan-2-yl] carbamate
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
NIAID ChemDB
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard 100.111.730 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C27H37N3O7S
Molar mass 547.67 g·mol−1
3D model (JSmol)
  • O=S(=O)(c1ccc(N)cc1)N(CC(C)C)C[C@@H](O)[C@@H](NC(=O)O[C@H]2CO[C@H]3OCC[C@@H]23)Cc4ccccc4
  • InChI=1S/C27H37N3O7S/c1-18(2)15-30(38(33,34)21-10-8-20(28)9-11-21)16-24(31)23(14-19-6-4-3-5-7-19)29-27(32)37-25-17-36-26-22(25)12-13-35-26/h3-11,18,22-26,31H,12-17,28H2,1-2H3,(H,29,32)/t22-,23-,24+,25-,26+/m0/s1 Yes check.svgY
  • Key:CJBJHOAVZSMMDJ-HEXNFIEUSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Darunavir (DRV), sold under the brand name Prezista among others, is an antiretroviral medication used to treat and prevent HIV/AIDS. [1] It is generally recommended for use with other antiretrovirals. [1] [4] It is often used with low doses of ritonavir or cobicistat to increase darunavir levels. [1] It may be used for prevention after a needlestick injury or other potential exposure. [1] It is taken by mouth once to twice a day. [1]

Contents

Common side effects include diarrhea, nausea, abdominal pain, headache, rash and vomiting. [1] [4] Severe side effects include allergic reactions, liver problems, and skin rashes such as toxic epidermal necrolysis. [1] While poorly studied in pregnancy it appears to be safe for the baby. [2] It is of the protease inhibitor (PI) class and works by blocking HIV protease. [1]

Darunavir was approved by the US Food and Drug Administration (FDA) in June 2006. [6] [7] It is on the World Health Organization's List of Essential Medicines. [8] It is available as a generic medication. [9]

It is available in the fixed-dose combination medication darunavir/cobicistat (Prezcobix, Rezolsta), [10] [11] and in the fixed-dose combination medication darunavir/cobicistat/emtricitabine/tenofovir alafenamide (Symtuza). [12] [13]

Medical uses

Darunavir is indicated for the treatment of human immunodeficiency virus (HIV-1) infection in adults and children three years of age and older when co-administered with ritonavir, in combination with other antiretroviral agents. [4] [5]

Darunavir is an Office of AIDS Research Advisory Council (DHHS) recommended treatment option for adults and adolescents, regardless of whether they have received HIV treatment in the past. [14] [15] In a study of people that had never received HIV treatment, darunavir was as effective as lopinavir/ritonavir at 96 weeks with a once-daily dosing. [16] It was approved by the FDA in October 2008, for people not previously treated for HIV. [17] Darunavir does not cure HIV/AIDS. [4]

Adverse effects

Darunavir is generally well tolerated by people. Rash is the most common side effect (7% of patients). [4] Other common side effects are diarrhea (2.3%), headache (3.8%), abdominal pain (2.3%), constipation (2.3%), and vomiting (1.5%). [4] Darunavir can also cause allergic reactions, and people allergic to ritonavir can also have a reaction to darunavir. [4]

High blood sugar, diabetes or worsening of diabetes, muscle pain, tenderness or weakness, and increased bleeding in people with hemophilia have been reported in patients taking protease inhibitor medicines like darunavir. [4] Changes in body fat have been seen in some patients taking medicines for HIV, including loss of fat from legs, arms and face, increased fat in the abdomen and other internal organs, breast enlargement, and fatty lumps on the back of the neck. The cause and long-term health effects of these conditions are not known. [4]

Drug interactions

Darunavir may interact with medications commonly taken by people with HIV/AIDS such as other antiretrovirals, and antacids such as proton pump inhibitors and H2 receptor antagonists. [4] St. John's wort may reduce the effectiveness of darunavir by increasing the breakdown of darunavir by the metabolic enzyme CYP3A . [4]

Mechanism of action

Darunavir is a nonpeptidic inhibitor of protease (PR) that lodges itself in the active site of PR through a number of hydrogen bonds. [18] It was developed to increase interactions with HIV-1 protease and to be more resistant against HIV-1 protease mutations. With a Kd (dissociation constant) of 4.5 x 10−12 M, darunavir has a much stronger interaction with PR and its dissociation constant is 1/100 to 1/1000 of other protease inhibitors. [19] This strong interaction comes from increased hydrogen bonds between darunavir and the backbone of the PR active site (Figure 2). Darunavir's structure allows it to create more hydrogen bonds with the PR active site than most PIs that have been developed and approved by the FDA. [20] Furthermore, the backbone of HIV-1 protease maintains its spatial conformation in the presence of mutations. [21] Because darunavir interacts with this stable portion of the protease, the PR-PI interaction is less likely to be disrupted by a mutation. [20]

Figure 3. Ribbon structure of PR with darunavir in active site: Structures colored as in Fig. 1. with certain residues partaking in hydrogen bonding further highlighted. The catalytic aspartates, 25 and 25', are in orange and the other interacting residues in green. Right image is a magnified view of the image on the left (PDB 4qdb). Figure 3.a.tiff
Figure 3. Ribbon structure of PR with darunavir in active site: Structures colored as in Fig. 1. with certain residues partaking in hydrogen bonding further highlighted. The catalytic aspartates, 25 and 25', are in orange and the other interacting residues in green. Right image is a magnified view of the image on the left (PDB 4qdb).

Catalytic site

The chemical activity of the HIV-1 protease depends on two residues in the active site, Asp25 and Asp25', one from each copy of the homodimer. [22] Darunavir interacts with these catalytic aspartates and the backbone of the active site through hydrogen bonds, specifically binding to residues Asp25, Asp25', Asp 29, Asp 30, Asp 30', and Gly 27 (Figure 3). This interaction prevents viral replication, as it competitively inhibits the viral polypeptides from gaining access to the active site and strongly binds to the enzymatic portions of this protein. [18]

History

Figure 2. Hydrogen bonds between darunavir and HIV-1 protease: The bonds with the red residues indicate hydrogen bonds that are also present between the PI saquinavir and HIV-1 protease. The hydrogen bonds with the blue residue are unique to darunavir. Darunavir-protease bonds.svg
Figure 2. Hydrogen bonds between darunavir and HIV-1 protease: The bonds with the red residues indicate hydrogen bonds that are also present between the PI saquinavir and HIV-1 protease. The hydrogen bonds with the blue residue are unique to darunavir.

Darunavir was approved for use in the United States in June 2006 and for use in the European Union in February 2007. [23] [24] [25] [26] [5] [ excessive citations ]

The development of first-generation clinical inhibitors was founded on creating more protease-ligand interactions through hydrogen bonding and hydrophobic interactions. [18] The first HIV protease inhibitor approved by the FDA was saquinavir, which was designed to target wild-type HIV-1 protease. [27] However, this inhibitor is no longer effective due to resistance-causing mutations on the HIV-1 protease structure. The HIV genome has high plasticity, so has been able to become resistant to multiple HIV-1 protease inhibitors. [28] Since saquinavir, the FDA has approved several PIs, including darunavir. [25]

Society and culture

Economics

In the US and UK, healthcare costs were estimated to be lower with boosted darunavir than with investigator-selected control protease inhibitors in treatment-experienced patients. [29]

Related Research Articles

The management of HIV/AIDS normally includes the use of multiple antiretroviral drugs as a strategy to control HIV infection. There are several classes of antiretroviral agents that act on different stages of the HIV life-cycle. The use of multiple drugs that act on different viral targets is known as highly active antiretroviral therapy (HAART). HAART decreases the patient's total burden of HIV, maintains function of the immune system, and prevents opportunistic infections that often lead to death. HAART also prevents the transmission of HIV between serodiscordant same-sex and opposite-sex partners so long as the HIV-positive partner maintains an undetectable viral load.

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.

Reverse-transcriptase inhibitors (RTIs) are a class of antiretroviral drugs used to treat HIV infection or AIDS, and in some cases hepatitis B. RTIs inhibit activity of reverse transcriptase, a viral DNA polymerase that is required for replication of HIV and other retroviruses.

ATC code J05Antivirals for systemic use is a therapeutic subgroup of the Anatomical Therapeutic Chemical Classification System, a system of alphanumeric codes developed by the World Health Organization (WHO) for the classification of drugs and other medical products. Subgroup J05 is part of the anatomical group J Antiinfectives for systemic use.

<span class="mw-page-title-main">Ritonavir</span> Antiretroviral medication

Ritonavir, sold under the brand name Norvir, is an antiretroviral medication used along with other medications to treat HIV/AIDS. This combination treatment is known as highly active antiretroviral therapy (HAART). Ritonavir is a protease inhibitor, though it now mainly serves to boost the potency of other protease inhibitors. It may also be used in combination with other medications to treat hepatitis C and COVID-19. It is taken by mouth. Tablets of ritonavir are not bioequivalent to capsules, as the tablets may result in higher peak plasma concentrations.

<span class="mw-page-title-main">Tenofovir disoproxil</span> Antiviral drug used to treat or prevent HIV and hepatitis infections

Tenofovir disoproxil, sold under the brand name Viread among others, is a medication used to treat chronic hepatitis B and to prevent and treat HIV/AIDS. It is generally recommended for use with other antiretrovirals. It may be used for prevention of HIV/AIDS among those at high risk before exposure, and after a needlestick injury or other potential exposure. It is sold both by itself and together in combinations such as emtricitabine/tenofovir, efavirenz/emtricitabine/tenofovir, and elvitegravir/cobicistat/emtricitabine/tenofovir. It does not cure HIV/AIDS or hepatitis B. It is available by mouth as a tablet or powder.

<span class="mw-page-title-main">Efavirenz</span> Antiretroviral medication

Efavirenz (EFV), sold under the brand names Sustiva among others, is an antiretroviral medication used to treat and prevent 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 sold both by itself and in combination as efavirenz/emtricitabine/tenofovir. 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">Emtricitabine/tenofovir</span> Drug combination for HIV/AIDS prophylaxis and treatment

Emtricitabine/tenofovir, sold under the brand name Truvada among others, is a fixed-dose combination antiretroviral medication used to treat and prevent HIV/AIDS. It contains the antiretroviral medications emtricitabine and tenofovir disoproxil. For treatment, it must be used in combination with other antiretroviral medications. For prevention before exposure, in those who are at high risk, it is recommended along with safer sex practices. It does not cure HIV/AIDS. Emtricitabine/tenofovir is taken by mouth.

<span class="mw-page-title-main">Efavirenz/emtricitabine/tenofovir</span> Combination drug for HIV

Efavirenz/emtricitabine/tenofovir, sold under the brand name Atripla among others, is a fixed-dose combination antiretroviral medication used to treat HIV/AIDS. It contains efavirenz, emtricitabine, and tenofovir disoproxil. It can be used by itself or together with other antiretroviral medications. It is taken by mouth.

Integrase inhibitors (INIs) are a class of antiretroviral drug designed to block the action of integrase, a viral enzyme that inserts the viral genome into the DNA of the host cell. Since integration is a vital step in retroviral replication, blocking it can halt further spread of the virus. Integrase inhibitors were initially developed for the treatment of HIV infection, but have been applied to other retroviruses. The class of integrase inhibitors called integrase strand transfer inhibitors (INSTIs) are in established medical use. Other classes, such as allosteric integrase inhibitors (ALLINIs) or integrase binding inhibitors (INBIs), are still experimental.

<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">Rilpivirine</span> HIV treatment

Rilpivirine, sold under the brand names Edurant and Rekambys, is a medication, developed by Tibotec, used for the treatment of HIV/AIDS. It is a second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) with higher potency, longer half-life and reduced side-effect profile compared with older NNRTIs such as efavirenz.

Many major physiological processes depend on regulation of proteolytic enzyme activity and there can be dramatic consequences when equilibrium between an enzyme and its substrates is disturbed. In this prospective, the discovery of small-molecule ligands, like protease inhibitors, that can modulate catalytic activities has an enormous therapeutic effect. Hence, inhibition of the HIV protease is one of the most important approaches for the therapeutic intervention in HIV infection and their development is regarded as major success of structure-based drug design. They are highly effective against HIV and have, since the 1990s, been a key component of anti-retroviral therapies for HIV/AIDS.

<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">Tenofovir alafenamide</span> Chemical compound

Tenofovir alafenamide, sold under the brand name Vemlidy, is an antiviral medication used against hepatitis B and HIV. It is used for the treatment of chronic hepatitis B virus (HBV) infection in adults with compensated liver disease and is given in combination with other medications for the prevention and treatment of HIV. It is taken by mouth.

Elvitegravir/cobicistat/emtricitabine/tenofovir, sold under the brand name Stribild, also known as the Quadpill, is a fixed-dose combination antiretroviral medication for the treatment of HIV/AIDS. Elvitegravir, emtricitabine and tenofovir disoproxil directly suppress viral reproduction. Cobicistat increases the effectiveness of the combination by inhibiting the liver and gut wall enzymes that metabolize elvitegravir. It is taken by mouth.

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

Bictegravir is a second-generation integrase inhibitor (INSTI) class that was structurally derived from an earlier compound dolutegravir by scientists at Gilead Sciences. In vitro and clinical results were presented by Gilead in the summer of 2016. In 2016, bictegravir was in a Phase 3 trial as part of a single tablet regimen in combination with tenofovir alafenamide (TAF) and emtricitabine (FTC) for the treatment of HIV-1 infection.

<span class="mw-page-title-main">Bictegravir/emtricitabine/tenofovir alafenamide</span> Fixed dose combination HIV drug

Bictegravir/emtricitabine/tenofovir alafenamide, sold under the brand name Biktarvy, is a fixed-dose combination antiretroviral medication for the treatment of HIV/AIDS. One tablet, taken orally once daily, contains 50 mg bictegravir, 200 mg emtricitabine, and 25 mg tenofovir alafenamide.

Darunavir/cobicistat, sold under the brand names Prezcobix (US) and Rezolsta (EU), is a fixed-dose combination antiretroviral medication used to treat and prevent HIV/AIDS. It contains darunavir and cobicistat. Darunavir is an HIV protease inhibitor and cobicistat increases the effectiveness of darunavir by blocking its metabolism by the enzyme CYP3A.

References

  1. 1 2 3 4 5 6 7 8 9 "Darunavir". The American Society of Health-System Pharmacists. Archived from the original on 10 November 2016. Retrieved 28 November 2016.
  2. 1 2 "Darunavir (Prezista) Use During Pregnancy". Drugs.com. 23 October 2018. Archived from the original on 20 December 2016. Retrieved 21 April 2020.
  3. ↑ "Prescription medicines: registration of new generic medicines and biosimilar medicines, 2017". Therapeutic Goods Administration (TGA). 21 June 2022. Archived from the original on 6 July 2023. Retrieved 30 March 2024.
  4. 1 2 3 4 5 6 7 8 9 10 11 12 "Prezista- darunavir tablet, film coated Prezista- darunavir suspension". DailyMed. 6 June 2019. Archived from the original on 6 February 2019. Retrieved 21 April 2020.
  5. 1 2 3 "Prezista EPAR". European Medicines Agency (EMA). Archived from the original on 25 June 2019. Retrieved 21 April 2020. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  6. ↑ "Drug Approval Package: Prezista (Darumavir) NDA #021976". U.S. Food and Drug Administration (FDA). Archived from the original on 1 July 2016. Retrieved 26 May 2024.
  7. ↑ MacArthur RD (April 2007). "Darunavir: promising initial results". Lancet. 369 (9568): 1143–1144. doi:10.1016/S0140-6736(07)60499-1. PMID   17416241. S2CID   31175809.
  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. ↑ "2022 First Generic Drug Approvals". U.S. Food and Drug Administration (FDA). 3 March 2023. Archived from the original on 30 June 2023. Retrieved 30 June 2023.
  10. ↑ "Prezcobix - darunavir ethanolate and cobicistat tablet, film coated". DailyMed. 2 January 2024. Archived from the original on 28 November 2023. Retrieved 26 May 2024.
  11. ↑ "Darunavir / Cobicistat". Clinicalinfo. 27 November 2023. Archived from the original on 25 February 2024. Retrieved 26 May 2024.
  12. ↑ "Symtuza - darunavir, cobicistat, emtricitabine, and tenofovir alafenamide tablet, film coated". DailyMed. 18 August 2023. Archived from the original on 9 July 2021. Retrieved 26 May 2024.
  13. ↑ "Darunavir / Cobicistat / Emtricitabine / Tenofovir Alafenamide". Clinicalinfo. 20 June 2023. Archived from the original on 23 January 2024. Retrieved 26 May 2024.
  14. ↑ "What's New: Adult and Adolescent ARV Guidelines". Clinicalinfo. 27 February 2024. Archived from the original on 26 November 2023. Retrieved 26 May 2024.
  15. ↑ "What's New in the Guidelines? Adult and Adolescent ARV". AIDSinfo. 26 June 2018. Archived from the original on 14 September 2020. Retrieved 22 April 2023.
  16. ↑ Antinori A, Lazzarin A, Uglietti A, Palma M, Mancusi D, Termini R (March 2018). "Efficacy and safety of boosted darunavir-based antiretroviral therapy in HIV-1-positive patients: results from a meta-analysis of clinical trials". Scientific Reports. 8 (1): 5288. doi:10.1038/s41598-018-23375-6. PMC   5869729 . PMID   29588457.
  17. ↑ "U.S. Food and Drug Administration (FDA) Approves Prezista Once-Daily as Part of Combination Therapy for Treatment-Naive Adults with HIV-1". Drugs.com. 22 October 2008. Archived from the original on 23 September 2013. Retrieved 26 May 2024.
  18. 1 2 3 Leonis G, Czyżnikowska Ż, Megariotis G, Reis H, Papadopoulos MG (June 2012). "Computational studies of darunavir into HIV-1 protease and DMPC bilayer: necessary conditions for effective binding and the role of the flaps". Journal of Chemical Information and Modeling. 52 (6): 1542–1558. doi:10.1021/ci300014z. PMID   22587384.
  19. ↑ King NM, Prabu-Jeyabalan M, Nalivaika EA, Wigerinck P, de Béthune MP, Schiffer CA (November 2004). "Structural and thermodynamic basis for the binding of TMC114, a next-generation human immunodeficiency virus type 1 protease inhibitor". Journal of Virology. 78 (21): 12012–12021. doi: 10.1128/JVI.78.21.12012-12021.2004 . PMC   523255 . PMID   15479840. S2CID   828919.
  20. 1 2 Lefebvre E, Schiffer CA (2008). "Resilience to resistance of HIV-1 protease inhibitors: profile of darunavir". AIDS Reviews. 10 (3): 131–142. PMC   2699666 . PMID   18820715.
  21. ↑ Lascar RM, Benn P (2009). "Role of darunavir in the management of HIV infection". HIV/AIDS: Research and Palliative Care. 1: 31–39. doi: 10.2147/hiv.s5397 . PMC   3218677 . PMID   22096377.
  22. ↑ Li D, Zhang Y, Zhao RN, Fan S, Han JG (February 2014). "Investigation on the mechanism for the binding and drug resistance of wild type and mutations of G86 residue in HIV-1 protease complexed with Darunavir by molecular dynamic simulation and free energy calculation". Journal of Molecular Modeling. 20 (2): 2122. doi:10.1007/s00894-014-2122-y. PMID   24526384. S2CID   23262721.
  23. ↑ MacArthur RD (April 2007). "Darunavir: promising initial results". Lancet. 369 (9568): 1143–1144. doi:10.1016/S0140-6736(07)60499-1. PMID   17416241. S2CID   31175809.
  24. ↑ "FDA Approves New HIV Treatment for Patients Who Do Not Respond to Existing Drugs". U.S. Food and Drug Administration (FDA) (Press release). Archived from the original on 13 November 2016. Retrieved 10 November 2016.
  25. 1 2 "HIV/AIDS Historical Time Line 2000 - 2010". U.S. Food and Drug Administration (FDA). 5 January 2018. Archived from the original on 1 July 2019. Retrieved 21 April 2020.
  26. ↑ "Drug Approval Package: Prezista (Darumavir) NDA #021976". U.S. Food and Drug Administration (FDA). 6 September 2006. Archived from the original on 1 July 2016. Retrieved 21 April 2020.
  27. ↑ Liu F, Kovalevsky AY, Tie Y, Ghosh AK, Harrison RW, Weber IT (August 2008). "Effect of flap mutations on structure of HIV-1 protease and inhibition by saquinavir and darunavir". Journal of Molecular Biology. 381 (1): 102–115. doi:10.1016/j.jmb.2008.05.062. PMC   2754059 . PMID   18597780.
  28. ↑ Eron JJ (June 2000). "HIV-1 protease inhibitors". Clinical Infectious Diseases. 30 (Suppl 2): S160–S170. doi: 10.1086/313853 . PMID   10860901.
  29. ↑ McKeage K, Perry CM, Keam SJ (2009). "Darunavir: a review of its use in the management of HIV infection in adults". Drugs. 69 (4): 477–503. doi:10.2165/00003495-200969040-00007. PMID   19323590. S2CID   195690027.

,

This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.