Darunavir

Darunavir
Systematic (IUPAC) name
[(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
Clinical data
Trade names Prezista
AHFS/Drugs.com monograph
MedlinePlus a607042
Pregnancy
category
  • AU: B2
  • US: C (Risk not ruled out)
Routes of
administration		 oral
Legal status
Legal status
Pharmacokinetic data
Bioavailability 37% (without ritonavir), 82% (with ritonavir)
Protein binding 95%
Metabolism hepatic (CYP3A4)
Biological half-life 15 hours
Excretion Faeces (80%), urine (14%)
Identifiers
CAS Number 206361-99-1 YesY
ATC code J05AE10 (WHO)
PubChem CID 213039
DrugBank DB01264 YesY
ChemSpider 184733 YesY
UNII YO603Y8113 YesY
KEGG D03656 YesY
ChEBI CHEBI:367163 YesY
ChEMBL CHEMBL1323 N
NIAID ChemDB 073035
Chemical data
Formula C27H37N3O7S
Molar mass 547.665 g/mol
 NYesY (what is this?)  (verify)

Darunavir (brand name Prezista, formerly known as TMC114) is a protease inhibitor medication used to treat HIV infection. Darunavir is an OARAC recommended treatment option for treatment-naïve and treatment-experienced adults and adolescents.[1] It was approved by the Food and Drug Administration (FDA) on June 23, 2006.[2]

Darunavir is a second-generation protease inhibitor (PIs), designed specifically to overcome problems with the older agents in this class, such as indinavir. Early PIs often have severe side effects and drug toxicities, require a high therapeutic dose, are costly to manufacture, and show a disturbing susceptibility to drug resistant mutations. Such mutations can develop in as little as a year of use, and effectively render the drugs useless.

Darunavir was designed to form robust interactions with the protease enzyme from many strains of HIV, including strains from treatment-experienced patients with multiple resistance mutations to PIs.[3][4]

It is on the World Health Organization's List of Essential Medicines, the most important medications needed in a basic health system.[5] Darunavir received attention at the time of its release, as it represents an treatment option for people with drug-resistant HIV. Patient advocacy groups pressured developer Tibotec not to follow the previous trend of releasing new drugs at prices higher than existing drugs in the same class. Darunavir was priced to match other common PIs already in use, such as the fixed-dose combination drug lopinavir/ritonavir. The drug costs around $9,000 for a one-year supply.[6][7][8]

Medical uses

Darunavir is an OARAC (DHHS) recommended treatment option for treatment-naïve and treatment-experienced adults and adolescents.[1] It showed comparable efficacy to lopinavir/ritonavir at 96 weeks with a once-daily dosing in treatment-naïve patients.[9] It was approved by the FDA for people not previously treated on October 21, 2008.[10]

Side effects

As with other antiretrovirals, darunavir does not cure HIV infection or AIDS, and does not prevent passing HIV to others.

In studies, darunavir was generally well tolerated. Mild to moderate rash was seen in 7% of patients. Some patients developed severe rash. In clinical studies, 0.3% of patients discontinued due to rash. The most common moderate to severe side effects associated with darunavir include diarrhea (2.3%), headache (3.8%), abdominal pain (2.3%), constipation (2.3%), and vomiting (1.5%). Four percent of patients discontinued treatment due to adverse events. People who are allergic to darunavir or any of its ingredients, or ritonavir (Norvir) should not take darunavir.

Relevant drug-drug interactions with other medications commonly used in HIV patient populations were few, such as other antiretroviral medications, proton pump inhibitors, and H2 receptor antagonists. St. John's wort may reduce its effectiveness by interaction with CYP3A. Patients should talk to their healthcare providers about all the medicines they are taking or plan to take, including prescription and nonprescription medicines, vitamins, and herbal supplements.

Before taking darunavir, patients should tell their healthcare providers if they have any medical conditions, including diabetes, liver problems, hemophilia, or allergy to sulfa medicines, and should tell their doctors if they are pregnant or planning to become pregnant, or are nursing. Darunavir should be used with caution in patients with hepatic impairment.

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. Changes in body fat have been seen in some patients taking anti-HIV medicines, 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 at this time.

Clinical laboratory safety observed in the darunavir group was comparable to the control group.[11]

Mechanism of action

Darunavir is a nonpeptidic inhibitor of PR that lodges itself in the active site of PR through a number of hydrogen bonds.[12] It was developed to increase interactions with HIV-1 protease and to be more resistant against HIV-1 protease mutations. With a Kd value 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.[13] 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.[14] Furthermore, the backbone of HIV-1 protease maintains its spatial conformation in the presence of mutations.[15] Because darunavir interacts with this stable portion of the protease, the PR-PI interaction is less likely to be disrupted by a mutation.[14]

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.[16] 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.[12]

Pharmacoeconomic considerations

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.[17]

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.

The development of first-generation clinical inhibitors was founded on creating more protease-ligand interactions through hydrogen bonding and hydrophobic interactions.[12] The first HIV protease inhibitor approved by the FDA was saquinavir, which was designed to target wild-type HIV-1 protease.[18] 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.[19] Since saquinavir, the FDA has approved several PIs, including darunavir.[20] Darunavir was granted approval by the FDA on June 23, 2006, and is one of the most recently developed protease inhibitors approved for treatment of HIV.[20]

See also

References

  1. 1 2 Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents, November 3, 2008, Developed by the DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents – A Working Group of the Office of AIDS Research Advisory Council (OARAC). full guidelines.
  2. ↑ Rodger D MacArthura, Darunavir: promising initial results, doi:10.1016/S0140-6736(07)60499-1
  3. ↑ Ghosh AK, Dawson ZL, Mitsuya H (2007). "Darunavir, a conceptually new HIV-1 protease inhibitor for the treatment of drug-resistant HIV". Bioorg. Med. Chem. 15 (24): 7576–80. doi:10.1016/j.bmc.2007.09.010. PMC 2112938. PMID 17900913. Retrieved 2007-12-22.
  4. ↑ Darunavir–ritonavir more effective than Lopinavir–ritonavir in HIV infected, treatment-experienced patients, The Lancet, 2007, 370, article URL
  5. ↑ "19th WHO Model List of Essential Medicines (April 2015)" (PDF). WHO. April 2015. Retrieved May 10, 2015.
  6. ↑ Liz Highleyman, Patient Advocates Commend Pricing of New PI Darunavir, HIV and HCV news
  7. ↑ Darunavir - first molecule to treat drug-resistant HIV, Medical news
  8. ↑ Retaining Efficacy Against Evasive HIV, Chemical and engineering news
  9. ↑ hivandhepatitis.com, Efficacy and Safety of Boosted Darunavir (Prezista) Are Superior to Lopinavir/ritonavir (Kaletra) at 96 Weeks: ARTEMIS Trial, 2008-10-28, URL.
  10. ↑ hivandhepatitis.com, Darunavir (Prezista) Receives Full Traditional Approval, Dose Set for Treatment-naive Patients, Caution Urged for Pregnant Women, 2008-10-24, URL.
  11. ↑ (Product Monograph, Darunavir)
  12. 1 2 3 Leonis, G., Czyznikowska, Z. et al. "Computational Studies of Darunavir into HIV-1 Protease and DMPC Bilayer: Necessary Conditions for Effective Binding and the Role of the Flaps" J. Chem. Inf. Model. 2012, 52, 1542-1558.
  13. ↑ King, N. M., Prabu-Jeyabalan, M. et al. "Structural and Thermodynamic Basis for the Binding of TMC114, a Next-Generation Human Immunodeficiency Virus Type 1 Protease Inhibitor" Journal of Virology. 2004, vol. 78 no. 21
  14. 1 2 Lefebvre, E., Schiffer, C. A. "Resilience to Resistance of HIV-1 Protease Inhibitors: Profile of Darunavir" AIDS Rev. 2008; 10(3): 131-142
  15. ↑ Lascar, R. M., Benn, P. "Role of darunavir in the management of HIV infection" HIV AIDS (Auckl). 2009; 1:31-39.
  16. ↑ Li, D., Zhang, Y. et al. "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" J. Molecular Modeling, 2014, 20:2122.
  17. ↑ McKeage K, Perry CM, Keam SJ.. Drugs 2009;69(4):477-503. doi:10.2165/00003495-200969040-00007.
  18. ↑ Liu, F., Kovalevsky, A.Y. "Effect of Flap Mutations on Structure of HIV-1 Protease and Inhibition by Saquinavir and Darunavir" J. Mol. Biol. 2008; 381(1): 102-115.
  19. ↑ Eron, J. "HIV-1 Protease Inhibitors" Oxford Journal of Clinical Infectious Diseases. 2000, vol. 30, Issue Supplement 2, 160-170.
  20. 1 2 "HIV/AIDS Historical Time Line 2000-2010" FDA. 2011.

External links

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