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
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only) [3]
  • CA: ℞-only
  • UK: POM (Prescription only)
  • US: ℞-only
  • EU:Rx-only
  • In general: ℞ (Prescription only)
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]

Developed by pharmaceutical company Tibotec, darunavir is named after Arun K. Ghosh, the chemistry professor who discovered the molecule at the University of Illinois at Chicago. [5] It was approved by the Food and Drug Administration (FDA) in June 2006. [6] It is on the World Health Organization's List of Essential Medicines. [7] It is available as a generic medication. [8]

The fixed-dose combination medication darunavir/cobicistat (Prezcobix, Rezolsta) is available as a single pill. [9]

Medical uses

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. [10] [11] In a study of patients that had never received HIV treatment, darunavir was as effective as lopinavir/ritonavir at 96 weeks with a once-daily dosing. [12] It was approved by the FDA on 21 October 2008 for people not previously treated for HIV. [13] As with other antiretrovirals, darunavir does not cure HIV/AIDS. [14]

It 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] [15]

Adverse effects

Darunavir is generally well tolerated by people. Rash is the most common side effect (7% of patients). [14] Other common side effects are diarrhea (2.3%), headache (3.8%), abdominal pain (2.3%), constipation (2.3%), and vomiting (1.5%). [14] Darunavir can also cause allergic reactions, and people allergic to ritonavir can also have a reaction to darunavir. [14]

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. [14] 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. [14]

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. [14] St. John's wort may reduce the effectiveness of darunavir by increasing the breakdown of darunavir by the metabolic enzyme CYP3A . [14]

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. [16] 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. [17] 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. [18] Furthermore, the backbone of HIV-1 protease maintains its spatial conformation in the presence of mutations. [19] Because darunavir interacts with this stable portion of the protease, the PR-PI interaction is less likely to be disrupted by a mutation. [18]

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. [20] 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. [16]

Cost

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. [21]

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. [22] [23] [24] [25] [15] [ excessive citations ]

The development of first-generation clinical inhibitors was founded on creating more protease-ligand interactions through hydrogen bonding and hydrophobic interactions. [16] The first HIV protease inhibitor approved by the FDA was saquinavir, which was designed to target wild-type HIV-1 protease. [26] 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. [27] Since saquinavir, the FDA has approved several PIs, including darunavir. [24]

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.

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

Atazanavir, sold under the brand name Reyataz among others, is an antiretroviral medication used to treat 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 taken by mouth.

<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">Nevirapine</span> Chemical compound

Nevirapine (NVP), sold under the brand name Viramune among others, is a medication used to treat and prevent HIV/AIDS, specifically HIV-1. It is generally recommended for use with other antiretroviral medications. It may be used to prevent mother to child spread during birth but is not recommended following other exposures. It is taken by mouth.

<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">Tipranavir</span> Chemical compound

Tipranavir (TPV), or tipranavir disodium, is a nonpeptidic protease inhibitor (PI) manufactured by Boehringer Ingelheim under the trade name AptivusAP-tiv-əs. It is administered with ritonavir in combination therapy to treat HIV infection.

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

Indinavir is a protease inhibitor used as a component of highly active antiretroviral therapy to treat HIV/AIDS. It is soluble white powder administered orally in combination with other antiviral drugs. The drug prevents protease from functioning normally. Consequently, HIV viruses cannot reproduce, causing a decrease in the viral load. Commercially sold indinavir is indinavir anhydrous, which is indinavir with an additional amine in the hydroxyethylene backbone. This enhances its solubility and oral bioavailability, making it easier for users to intake. It was synthetically produced for the purpose of inhibiting the protease in the HIV virus.

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

Fosamprenavir (FPV), sold under the brand names Lexiva and Telzir, is a medication used to treat HIV/AIDS. It is a prodrug of the protease inhibitor and antiretroviral drug amprenavir. It is marketed by ViiV Healthcare as the calcium salt.

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

Lopinavir is an antiretroviral of the protease inhibitor class. It is used against HIV infections as a fixed-dose combination with another protease inhibitor, ritonavir (lopinavir/ritonavir).

<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.

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">Lopinavir/ritonavir</span> Combination medication for HIV/AIDS

Lopinavir/ritonavir (LPV/r), sold under the brand name Kaletra among others, is a fixed-dose combination antiretroviral medication for the treatment and prevention of HIV/AIDS. It combines lopinavir with a low dose of ritonavir. 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 taken by mouth as a tablet, capsule, or solution.

<span class="mw-page-title-main">Grazoprevir</span> Drug approved for the treatment of hepatitis C

Grazoprevir is a drug approved for the treatment of hepatitis C. It was developed by Merck and completed Phase III trials, used in combination with the NS5A replication complex inhibitor elbasvir under the trade name Zepatier, either with or without ribavirin.

<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.

Atazanavir/cobicistat, sold under the brand name Evotaz, is a fixed-dose combination antiretroviral medication used to treat and prevent HIV/AIDS. It contains atazanavir and cobicistat. Atazanavir is an HIV protease inhibitor and cobicistat is an inhibitor of cytochrome P450 (CYP) enzymes of the CYP3A family.

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.

<span class="mw-page-title-main">Nirmatrelvir/ritonavir</span> Antiviral combination medication

Nirmatrelvir/ritonavir, sold under the brand name Paxlovid, is a co-packaged medication used as a treatment for COVID‑19. It contains the antiviral medications nirmatrelvir and ritonavir and was developed by Pfizer. Nirmatrelvir inhibits SARS-CoV-2 main protease, while ritonavir is a strong CYP3A inhibitor, slowing down nirmatrelvir metabolism and therefore boosting its effect. It is taken by mouth.

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. Retrieved 21 April 2020.
  3. ↑ "Prescription medicines: registration of new generic medicines and biosimilar medicines, 2017". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 30 March 2024.
  4. 1 2 3 "Prezista- darunavir tablet, film coated Prezista- darunavir suspension". DailyMed. 6 June 2019. Retrieved 21 April 2020.
  5. ↑ "HIV/AIDS Research". Purdue Chemistry: The Ghosh Laboratory. Retrieved 24 June 2021.
  6. ↑ 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.
  7. ↑ 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.
  8. ↑ "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.
  9. ↑ "Darunavir / Cobicistat". AIDSinfo. U.S. Department of Health and Human Services. Archived from the original on 3 March 2020. Retrieved 29 June 2018.
  10. ↑ Panel on Antiretroviral Guidelines for Adults and Adolescents (18 December 2019). "Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV" (PDF). Department of Health and Human Services. Archived from the original (PDF) on 13 August 2020. Retrieved 21 April 2020.
  11. ↑ "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.
  12. ↑ hivandhepatitis.com Archived 13 July 2007 at the Wayback Machine , Efficacy and Safety of Boosted Darunavir (Prezista) Are Superior to Lopinavir/ritonavir (Kaletra) at 96 Weeks: ARTEMIS Trial, 2008-10-28, URL Archived 19 July 2009 at the Wayback Machine .
  13. ↑ hivandhepatitis.com Archived 13 July 2007 at the Wayback Machine , Darunavir (Prezista) Receives Full Traditional Approval, Dose Set for Treatment-naive Patients, Caution Urged for Pregnant Women, 2008-10-24, URL Archived 19 May 2009 at the Wayback Machine .
  14. 1 2 3 4 5 6 7 8 "Drug Monograph, Prezista". Archived from the original on 11 November 2016.
  15. 1 2 "Prezista EPAR". European Medicines Agency (EMA). 17 September 2018. Retrieved 21 April 2020.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  16. 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.
  17. ↑ 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.
  18. 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.
  19. ↑ 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.
  20. ↑ 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.
  21. ↑ 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.
  22. ↑ 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.
  23. ↑ "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.
  24. 1 2 "HIV/AIDS Historical Time Line 2000 - 2010". U.S. Food and Drug Administration . 5 January 2018. Archived from the original on 1 July 2019. Retrieved 21 April 2020.
  25. ↑ "Drug Approval Package: Prezista (Darumavir) NDA #021976". U.S. Food and Drug Administration (FDA). 6 September 2006. Retrieved 21 April 2020.
  26. ↑ 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.
  27. ↑ Eron JJ (June 2000). "HIV-1 protease inhibitors". Clinical Infectious Diseases. 30 (Suppl 2): S160–S170. doi: 10.1086/313853 . PMID   10860901.

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