Darunavir: Difference between revisions

{{Use dmy dates|date=NovemberMarch 20222024}}

| class = [[HIV protease inhibitor]]

| legal_US_comment = <ref name="Prezista FDA label" />

| legal_EU_comment = <ref name="Prezista EPAR" />

| metabolism = hepatic[[Liver]] ([[CYP3A4]])

'''Darunavir''' ('''DRV'''), sold under the brand name '''Prezista''' among others, is an [[antiretroviral medication]] used to treat and prevent [[HIV/AIDS]].<ref name=AHFS2016/> It is generally recommended for use with other antiretrovirals.<ref name=AHFS2016/><ref name="Prezista FDA label">{{cite web | title=Prezista- darunavir tablet, film coated Prezista- darunavir suspension | website=DailyMed | date=6 June 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=814301f9-c990-46a5-b481-2879a521a16f | access-date=21 April 2020 | archive-date=6 February 2019 | archive-url=https://web.archive.org/web/20190206184548/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=814301f9-c990-46a5-b481-2879a521a16f | url-status=live }}</ref> It is often used with low doses of [[ritonavir]] or [[cobicistat]] to increase darunavir levels.<ref name=AHFS2016/> It may be used for prevention after a [[needlestick injury]] or other potential exposure.<ref name=AHFS2016/> It is taken [[Oral administration|by mouth]] once to twice a day.<ref name=AHFS2016>{{cite web|title=Darunavir|url=https://www.drugs.com/monograph/darunavir.html|publisher=The American Society of Health-System Pharmacists|access-date=28 November 2016|url-status=live|archive-url=https://web.archive.org/web/20161110112612/https://www.drugs.com/monograph/darunavir.html|archive-date=10 November 2016}}</ref>

Common side effects include [[diarrhea]], [[nausea]], [[abdominal pain]], [[headache]], [[rash]] and [[vomiting]].<ref name=AHFS2016/><ref name="Prezista FDA label" /> Severe side effects include [[allergic reactions]], [[liver problems]], and skin rashes such as [[toxic epidermal necrolysis]].<ref name=AHFS2016/> While poorly studied in [[pregnancy]] it appears to be safe for the baby.<ref name="Drugs.com pregnancy">{{cite web | title=Darunavir (Prezista) Use During Pregnancy | website=Drugs.com | date=23 October 2018 | url=https://www.drugs.com/pregnancy/darunavir.html | access-date=21 April 2020 | archive-date=20 December 2016 | archive-url=https://web.archive.org/web/20161220115210/https://www.drugs.com/pregnancy/darunavir.html | url-status=live }}</ref> It is of the [[Protease inhibitor (pharmacology)|protease inhibitor]] (PI) class and works by blocking [[HIV protease]].<ref name=AHFS2016/>

DevelopedDarunavir was approved by pharmaceuticalthe companyUS [[Tibotec]],Food darunavirand isDrug namedAdministration]] after(FDA) Arunin KJune 2006.<ref Ghosh,name="Drug theApproval chemistryPackage: professorPrezista">{{cite whoweb discovered| thetitle=Drug moleculeApproval atPackage: thePrezista University(Darumavir) ofNDA Illinois#021976 at| Chicagowebsite=U.S.<ref>{{cite web[[Food |title=HIV/AIDSand ResearchDrug Administration]] (FDA) | url=https://www.chemaccessdata.purduefda.edugov/ghoshdrugsatfda_docs/nda/2006/021976s000_SprycelTOC.cfm |website access-date=Purdue26 Chemistry:May The2024 Ghosh| Laboratoryarchive-date=1 July 2016 |access archive-dateurl=24https://web.archive.org/web/20160701210501/http://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021976s000_SprycelTOC.cfm June| url-status=live 2021}}</ref> It was approved by the Food and Drug Administration (FDA) in June 2006.<ref>{{cite journal | vauthors = MacArthur RD | title = Darunavir: promising initial results | journal = Lancet | volume = 369 | issue = 9568 | pages = 1143–1144 | date = April 2007 | pmid = 17416241 | doi = 10.1016/S0140-6736(07)60499-1 | s2cid = 31175809 }}</ref> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO21st">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 21st list 2019 | year = 2019 | hdl = 10665/325771 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO | hdl-access=free }}</ref> It is available as a [[generic medication]].<ref>{{cite web | title=2022 First Generic Drug Approvals | website=U.S. [[Food and Drug Administration]] (FDA) | date=3 March 2023 | url=https://www.fda.gov/drugs/drug-and-biologic-approval-and-ind-activity-reports/2022-first-generic-drug-approvals | archive-url=https://web.archive.org/web/20230630003602/https://www.fda.gov/drugs/drug-and-biologic-approval-and-ind-activity-reports/2022-first-generic-drug-approvals | archive-date=30 June 2023 | url-status=live | access-date=30 June 2023}}</ref>

Darunavir is generally well tolerated by people. Rash is the most common side effect (7% of patients).<ref name=":0Prezista FDA label" /> Other common side effects are diarrhea (2.3%), headache (3.8%), abdominal pain (2.3%), constipation (2.3%), and vomiting (1.5%).<ref name=":0Prezista FDA label" /> Darunavir can also cause allergic reactions, and people allergic to ritonavir can also have a reaction to darunavir.<ref name=":0Prezista FDA label" />

[[Hyperglycemia|High blood sugar]], [[Diabetes mellitus|diabetes]] or worsening of diabetes, [[Myalgia|muscle pain]], tenderness or weakness, and increased bleeding in people with [[Haemophilia|hemophilia]] have been reported in patients taking protease inhibitor medicines like darunavir.<ref name=":0Prezista FDA label" /> 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.<ref name=":0Prezista FDA label" />

Darunavir may interact with medications commonly taken by people with [[HIV/AIDS]] such as other antiretrovirals, and antacids such as [[Proton-pump inhibitor|proton pump inhibitors]] and [[H2 receptor antagonists]].<ref name=":0Prezista FDA label" /> [[St. John's wort]] may reduce the effectiveness of darunavir by increasing the breakdown of darunavir by the metabolic enzyme ''[[CYP3A]]''.<ref name=":0Prezista FDA label" />

Darunavir is a nonpeptidic inhibitor of protease (PR) that lodges itself in the active site of PR through a number of hydrogen bonds.<ref name="Leonis, G. 2012">{{cite journal | vauthors = Leonis G, Czyżnikowska Ż, Megariotis G, Reis H, Papadopoulos MG | title = Computational studies of darunavir into HIV-1 protease and DMPC bilayer: necessary conditions for effective binding and the role of the flaps | journal = Journal of Chemical Information and Modeling | volume = 52 | issue = 6 | pages = 1542–1558 | date = June 2012 | pmid = 22587384 | doi = 10.1021/ci300014z }}</ref> It was developed to increase interactions with HIV-1 protease and to be more resistant against HIV-1 protease mutations. With a K_d ([[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.<ref name="King, N. M. 2004">{{cite journal | vauthors = King NM, Prabu-Jeyabalan M, Nalivaika EA, Wigerinck P, de Béthune MP, Schiffer CA | title = Structural and thermodynamic basis for the binding of TMC114, a next-generation human immunodeficiency virus type 1 protease inhibitor | journal = Journal of Virology | volume = 78 | issue = 21 | pages = 12012–12021 | date = November 2004 | pmid = 15479840 | pmc = 523255 | doi = 10.1128/JVI.78.21.12012-12021.2004 | s2cid = 828919 | doi-access = free }}</ref> 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.<ref name="ReferenceB">{{cite journal | vauthors = Lefebvre E, Schiffer CA | title = Resilience to resistance of HIV-1 protease inhibitors: profile of darunavir | journal = AIDS Reviews | volume = 10 | issue = 3 | pages = 131–142 | year = 2008 | pmid = 18820715 | pmc = 2699666 }}</ref> Furthermore, the backbone of HIV-1 protease maintains its spatial conformation in the presence of mutations.<ref>{{cite journal | vauthors = Lascar RM, Benn P | title = Role of darunavir in the management of HIV infection | journal = HIV/AIDS: Research and Palliative Care| volume = 1 | pages = 31–39 | year = 2009 | pmid = 22096377 | pmc = 3218677 | doi = 10.2147/hiv.s5397 | doi-access = free }}</ref> Because darunavir interacts with this stable portion of the protease, the PR-PI interaction is less likely to be disrupted by a mutation.<ref name="ReferenceB"/>

[[File:Figure 3.a.tiff|thumb|left|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 25’25', are in orange and the other interacting residues in green. Right image is a magnified view of the image on the left (PDB 4qdb).]]

The chemical activity of the HIV-1 protease depends on two residues in the active site, Asp25 and Asp25’Asp25', one from each copy of the homodimer.<ref name="Zhang, Y. 2014">{{cite journal | vauthors = Li D, Zhang Y, Zhao RN, Fan S, Han JG | title = 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 = Journal of Molecular Modeling | volume = 20 | issue = 2 | pages = 2122 | date = February 2014 | pmid = 24526384 | doi = 10.1007/s00894-014-2122-y | s2cid = 23262721 }}</ref> Darunavir interacts with these catalytic aspartates and the backbone of the active site through hydrogen bonds, specifically binding to residues Asp25, Asp25’Asp25', Asp 29, Asp 30, Asp 30’30', 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.<ref name="Leonis, G. 2012"/>

Darunavir was approved for use in the United States in June 2006 and for use in the European Union in February 2007.<ref>{{cite journal | vauthors = MacArthur RD | title = Darunavir: promising initial results | journal = Lancet | volume = 369 | issue = 9568 | pages = 1143–1144 | date = April 2007 | pmid = 17416241 | doi = 10.1016/S0140-6736(07)60499-1 | s2cid = 31175809 }}</ref><ref>{{cite press release|url=https://www.fda.gov/newsEvents/Newsroom/PressAnnouncements/2006/ucm108676.htm|title=FDA Approves New HIV Treatment for Patients Who Do Not Respond to Existing Drugs |website=U.S. [[Food and Drug Administration]] (FDA) |access-date=10 November 2016|url-status=dead|archive-url=https://web.archive.org/web/20161113210634/https://www.fda.gov/newsEvents/Newsroom/PressAnnouncements/2006/ucm108676.htm|archive-date=13 November 2016}}</ref><ref name="FDA 2011"/><ref name="FDA approval">{{cite web | title=Drug Approval Package: Prezista (Darumavir) NDA #021976 | website=U.S. [[Food and Drug Administration]] (FDA) | date=6 September 2006 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021976s000_SprycelTOC.cfm | access-date=21 April 2020 | archive-date=1 July 2016 | archive-url=https://web.archive.org/web/20160701210501/http://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021976s000_SprycelTOC.cfm | url-status=live }}</ref><ref name="Prezista EPAR" />{{citation overkill|date=November 2022}}

The development of first-generation clinical inhibitors was founded on creating more protease-ligand interactions through hydrogen bonding and hydrophobic interactions.<ref name="Leonis, G. 2012"/> The first HIV protease inhibitor approved by the FDA was saquinavir, which was designed to target wild-type HIV-1 protease.<ref>{{cite journal | vauthors = Liu F, Kovalevsky AY, Tie Y, Ghosh AK, Harrison RW, Weber IT | title = Effect of flap mutations on structure of HIV-1 protease and inhibition by saquinavir and darunavir | journal = Journal of Molecular Biology | volume = 381 | issue = 1 | pages = 102–115 | date = August 2008 | pmid = 18597780 | pmc = 2754059 | doi = 10.1016/j.jmb.2008.05.062 }}</ref> 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.<ref>{{cite journal | vauthors = Eron JJ | title = HIV-1 protease inhibitors | journal = Clinical Infectious Diseases | volume = 30 | issue = Suppl 2 | pages = S160–S170 | date = June 2000 | pmid = 10860901 | doi = 10.1086/313853 | doi-access = free }}</ref> Since saquinavir, the FDA has approved several PIs, including darunavir.<ref name="FDA 2011">{{cite web | title=HIV/AIDS Historical Time Line 2000 - 2010 | website=U.S. [[Food and Drug Administration]] (FDA) | date=5 January 2018 | url=https://www.fda.gov/patients/hiv-timeline-and-history-approvals/hivaids-historical-time-line-2000-2010 | archive-url=https://web.archive.org/web/20190701174234/https://www.fda.gov/patients/hiv-timeline-and-history-approvals/hivaids-historical-time-line-2000-2010 | archive-date= 1 July 2019 | url-status=dead | access-date=21 April 2020}}</ref>

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