Darunavir
Clinical data | |
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Trade names | Prezista, others[1] |
Other names | TMC114, DRV, darunavir ethanolate |
AHFS/Drugs.com | Monograph |
MedlinePlus | a607042 |
License data | |
Pregnancy category |
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Routes of administration | By mouth |
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 | |
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Darunavir (DRV), sold under the brand name Prezista among others, is an
Common side effects include
Developed by pharmaceutical company
The
Medical uses
Darunavir is an
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]
Drug interactions
Darunavir may interact with medications commonly taken by people with
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]
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
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]
References
- ^ a b c d e f g h i "Darunavir". The American Society of Health-System Pharmacists. Archived from the original on 10 November 2016. Retrieved 28 November 2016.
- ^ a b "Darunavir (Prezista) Use During Pregnancy". Drugs.com. 23 October 2018. Retrieved 21 April 2020.
- ^ "Prescription medicines: registration of new generic medicines and biosimilar medicines, 2017". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 30 March 2024.
- ^ a b c "Prezista- darunavir tablet, film coated Prezista- darunavir suspension". DailyMed. 6 June 2019. Retrieved 21 April 2020.
- ^ "HIV/AIDS Research". Purdue Chemistry: The Ghosh Laboratory. Retrieved 24 June 2021.
- S2CID 31175809.
- hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
- ^ "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.
- ^ "Darunavir / Cobicistat". AIDSinfo. U.S. Department of Health and Human Services. Archived from the original on 3 March 2020. Retrieved 29 June 2018.
- ^ 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.
- ^ "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.
- ^ 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.
- ^ 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.
- ^ a b c d e f g h "Drug Monograph, Prezista". Archived from the original on 11 November 2016.
- ^ a b "Prezista EPAR". European Medicines Agency (EMA). 17 September 2018. Retrieved 21 April 2020. This article incorporates text from this source, which is in the public domain.
- ^ PMID 22587384.
- S2CID 828919.
- ^ PMID 18820715.
- PMID 22096377.
- S2CID 23262721.
- S2CID 31175809.
- ^ "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.
- ^ a b "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.
- ^ "Drug Approval Package: Prezista (Darumavir) NDA #021976". U.S. Food and Drug Administration (FDA). 6 September 2006. Retrieved 21 April 2020.
- PMID 18597780.
- PMID 10860901.
Further reading
- 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.