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Encyclopedia > 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
Identifiers
CAS number 206361-99-1
ATC code  ?
PubChem 213039
Chemical data
Formula C27H37N3O7S 
Mol. mass 547.665 g/mol
Pharmacokinetic data
Bioavailability  ?
Protein binding 95%
Metabolism hepatic (CYP)
Half life 15 hours
Excretion  ?
Therapeutic considerations
Pregnancy cat.

B Image File history File links Darunavir. ... IUPAC nomenclature is a system of naming chemical compounds and of describing the science of chemistry in general. ... CAS registry numbers are unique numerical identifiers for chemical compounds, polymers, biological sequences, mixtures and alloys. ... The Anatomical Therapeutic Chemical Classification System is used for the classification of drugs. ... PubChem is a database of chemical molecules. ... This article or section does not cite any references or sources. ... General Name, Symbol, Number carbon, C, 6 Chemical series nonmetals Group, Period, Block 14, 2, p Appearance black (graphite) colorless (diamond) Standard atomic weight 12. ... General Name, Symbol, Number hydrogen, H, 1 Chemical series nonmetals Group, Period, Block 1, 1, s Appearance colorless Atomic mass 1. ... General Name, Symbol, Number nitrogen, N, 7 Chemical series nonmetals Group, Period, Block 15, 2, p Appearance colorless gas Standard atomic weight 14. ... General Name, Symbol, Number oxygen, O, 8 Chemical series nonmetals, chalcogens Group, Period, Block 16, 2, p Appearance colorless (gas) very pale blue (liquid) Standard atomic weight 15. ... General Name, Symbol, Number sulfur, S, 16 Chemical series nonmetals Group, Period, Block 16, 3, p Appearance lemon yellow Standard atomic weight 32. ... The molecular mass (abbreviated Mr) of a substance, formerly also called molecular weight and abbreviated as MW, is the mass of one molecule of that substance, relative to the unified atomic mass unit u (equal to 1/12 the mass of one atom of carbon-12). ... In pharmacology, bioavailability is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. ... A drugs efficacy may be affected by the degree to which it binds to the proteins within blood plasma. ... Drug metabolism is the metabolism of drugs, their biochemical modification or degradation, usually through specialized enzymatic systems. ... Cytochrome P450 Oxidase (CYP2E1) Cytochrome P450 oxidase (commonly abbreviated CYP) is a generic term for a large number of related, but distinct, oxidative enzymes (EC 1. ... It has been suggested that Effective half-life be merged into this article or section. ... Excretion is the process of eliminating waste products of metabolism and other materials that are of no use. ... The pregnancy category of a pharmaceutical agent is an assessment of the risk of fetal injury due to the pharmaceutical, if it is used as directed by the mother during pregnancy. ...

Legal status
Routes oral

Darunavir, sold as Prezista®, is a protease inhibitor used to treat HIV. It was developed at Tibotec and is named after Arun K. Ghosh, the inventor chemist, who discovered it while working at the University of Illinois, Chicago. It was approved by the Food and Drug Administration (FDA) on June 23, 2006.[1] The regulation of therapeutic goods, that is drugs and therapeutic devices, varies by jurisdiction. ... In pharmacology and toxicology, a route of administration is the path by which a drug, fluid, poison or other substance is brought into contact with the body 1. ... A trademark (Commonwealth English: trade mark)[1] is a distinctive sign of some kind which is used by a business to identify itself and its products or services to consumers, and to set the business and its products or services apart from those of other businesses. ... Protease inhibitors are a class of medication used to treat or prevent viral infections. ... Species Human immunodeficiency virus 1 Human immunodeficiency virus 2 Human immunodeficiency virus (HIV) is a retrovirus that causes acquired immunodeficiency syndrome (AIDS, a condition in humans in which the immune system begins to fail, leading to life-threatening opportunistic infections). ... Tibotec is a pharmaceutical company with focus on research and development for drugs, e. ... This article does not cite any references or sources. ... FDA logo The Food and Drug Administration (FDA) is an agency of the United States Department of Health and Human Services and is responsible for regulating food, dietary supplements, drugs, biological medical products, blood products, medical devices, radiation-emitting devices, veterinary products, and cosmetics in the United States. ... is the 174th day of the year (175th in leap years) in the Gregorian calendar. ... For the Manfred Mann album, see 2006 (album). ...


Several ongoing phase III trials are showing a high efficiency for the PREZISTA/rtv combination being superior to the lopinavir/rtv combination for first-line therapy[2]. In health care, including medicine, a clinical trial (synonyms: clinical studies, research protocols, medical research) is the application of the scientific method to human health. ... Ritonavir is a drug from the protease inhibitor class used to treat AIDS. It is manufactured as Norvir® by Abbott Laboratories. ... Lopinavir (ABT-378) is an antiretroviral of the protease inhibitor class. ... Ritonavir is a drug from the protease inhibitor class used to treat AIDS. It is manufactured as Norvir® by Abbott Laboratories. ...


Darunavir is the first drug in a long time that didn't come with a price increase. It leapfrogged two other approved drugs of its type, and is matching the price of a third [3][4][5]. Leapfrogging is a theory of development in which developing countries skip inferior, less efficient, more expensive or more polluting technologies and industries and move directly to more advanced ones. ...

Contents

Efficacy

Darunavir showed superiority to lopinavir and other protease inhibitors in the POWER trials. The POWER 1 and POWER 2 are designed for treatment-experienced patients, together with supportive data from the POWER 3 analysis [6]. The patients eligible for these studies had experience with at least one protease inhibitor, one non-nucleoside reverse transcriptase inhibitor (NNRTI) and two nucleoside reverse transcriptase inhibitors (NRTI), and had one or more primary protease inhibitor mutations. Lopinavir (ABT-378) is an antiretroviral of the protease inhibitor class. ... Protease inhibitors are a class of medication used to treat or prevent viral infections. ... Reverse transcriptase inhibitors (RTIs) are a class of antiretroviral drug used to treat HIV infection. ... Reverse transcriptase inhibitors (RTIs) are a class of antiretroviral drug used to treat HIV infection. ...


Darunavir showed also superior results to lopinavir in the TITAN trials (pre-planned, secondary endpoint, week 48), which was designed for patients with less advanced HIV disease compared to the POWER trials[7]. Lopinavir (ABT-378) is an antiretroviral of the protease inhibitor class. ... Species Human immunodeficiency virus 1 Human immunodeficiency virus 2 Human immunodeficiency virus (HIV) is a retrovirus that causes acquired immunodeficiency syndrome (AIDS, a condition in humans in which the immune system begins to fail, leading to life-threatening opportunistic infections). ...


TITAN trial

Analysis of 595 treatment-experienced patients being lopinavir/r-naïve, HIV-1 infected adults with a viral load of >1000 HIV-1 RNA copies/mL. Pre-planned secondary endpoint findings include: Lopinavir (ABT-378) is an antiretroviral of the protease inhibitor class. ... Ritonavir is a drug from the protease inhibitor class used to treat AIDS. It is manufactured as Norvir® by Abbott Laboratories. ... Ribonucleic acid or RNA is a nucleic acid polymer consisting of nucleotide monomers that plays several important roles in the processes that translate genetic information from deoxyribonucleic acid (DNA) into protein products; RNA acts as a messenger between DNA and the protein synthesis complexes known as ribosomes, forms vital portions...

  • 71 percent of patients in the darunavir/r arm reached an undetectable viral load (<50 copies/mL) vs. 60 percent of patients in the lopinavir/r arm, a statistically significant difference (p=0.005)
  • 77 percent of patients in the darunavir/r arm achieved at least a 1 log10 reduction in HIV RNA vs. 69 percent in the lopinavir/r arm, a statistically significant difference (p=0.028)
  • The median increase from baseline in CD4 cell count was similar between the darunavir/r and lopinavir/r arms (88 cells per cubic millimeter vs. 81 cells per cubic millimeter)

Development of resistance also was studied. Findings include: In statistical hypothesis testing, the p-value of a random variable T used as a test statistic is the probability that T will assume a value at least as extreme as the observed value tobserved, given that a null hypothesis being considered is true. ... In statistical hypothesis testing, the p-value of a random variable T used as a test statistic is the probability that T will assume a value at least as extreme as the observed value tobserved, given that a null hypothesis being considered is true. ...

  • 10 percent of patients in the darunavir/r arm experienced virological failure vs. 22 percent of patients in the lopinavir/r arm
  • Among patients experiencing virologic failure who had baseline and endpoint genotype data, 21 percent of patients in the darunavir/r arm developed primary PI resistance mutations vs. 36 percent of patients in the lopinavir/r arm, and 14 percent of patients in the darunavir/r arm developed primary NRTI resistance mutations vs. 27 percent of patients in the lopinavir/r arm

POWER 1 and POWER 2 trials

A pooled analysis of results from POWER 1 and POWER 2 demonstrated that after 24 weeks:

  • Significantly more treatment-experienced patients achieved a reduction in viral load at the 24-week primary endpoint with PREZISTA, compared with the investigator-selected PI (70% vs 21%, respectively).
  • Almost four times as many treatment-experienced patients (45%) have achieved an undetectable viral load with the PREZISTA containing regimen, compared with the investigator-selected PI arm (12%).
  • In treatment-experienced patients, the PREZISTA containing regimen increases CD4 cell counts five times more than the investigator-selected PI arm (92 cells/mm3 vs 17 cells/mm3, respectively) (Johnson & Johnson Press Release, 2006; Lazzarin, 2005)

The efficacy results of POWER 1 and POWER 2 are confirmed by data from a large, non-randomized, open-label analysis known as POWER 3. After 24 weeks:

  • 65 percent of patients achieved a reduction in viral load of 1 log10 or more, versus baseline.
  • 40 percent of patients reached undetectable virus levels (<50 HIV RNA copies/mL). (Molina, 2005)

Safety

As other antivirals does PREZISTA not cure HIV infection or AIDS, and does not prevent passing HIV to others. Antiviral drugs are a class of medication used specifically for treating viral infections. ... Acquired Immune Deficiency Syndrome or acquired immunodeficiency syndrome (AIDS or Aids) is a collection of symptoms and infections resulting from the specific damage to the immune system caused by the human immunodeficiency virus (HIV). ...


In studies, PREZISTA ™ 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 PREZISTA ™ 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 PREZISTA ™ or any of its ingredients, or ritonavir (NORVIR) should not take PREZISTA ™ .


There were few relevant drug-drug interactions with other medications commonly used in HIV patient populations, such as other antiretroviral medications, proton pump inhibitors, and H2 receptor antagonists. Patients should talk to their healthcare provider about all the medicines they are taking or plan to take, including prescription and nonprescription medicines, vitamins, and herbal supplements.


Before taking PREZISTA ™ , patients should tell their healthcare provider if they have any medical conditions, including diabetes, liver problems, hemophilia, or allergy to sulfa medicines and should tell their doctor if they are pregnant or planning to become pregnant, or are nursing. PREZISTA ™ 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 PREZISTA ™ . 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 PREZISTA ™ group was comparable to the control group. (Product Monograph, Prezista)


Dosing and Administration

The recommended oral dose of PREZISTA ™ tablets is 600 mg (two 300 mg tablets) twice daily (BID) taken with ritonavir 100mg BID and with food. The drug can be taken with any type of food.


Additional Studies Involving PREZISTA ™

  • TMC114-C211: Investigating a dose of 800 mg of the drug boosted with 100 mg of ritonavir once daily in treatment-naïve patients.
  • TMC114-C214: Investigating a dose of 600 mg of the drug boosted with 100 mg of ritonavir twice daily in moderately treatment-experienced patients.
  • DUET trial: The drug is being studied with TMC125, an investigational non-nucleoside reverse transcriptase inhibitor, in one of the few HIV clinical trials to involve two investigational HIV treatments in treatment-experienced patients. (Tibotec 2006)

References

  1. ^ Rodger D MacArthura, Darunavir: promising initial results, doi:10.1016/S0140-6736(07)60499-1
  2. ^ Darunavir-ritonavir more effective than Lopinavir-ritonavir in HIV infected, treatment-experienced patients,The Lancet, Volume 370, Number 9581, 07 July 2007, http://www.thelancet.com/journals/lancet/issue?volume=370&issue=9581
  3. ^ Liz Highleyman, Patient Advocates Commend Pricing of New PI Darunavir, http://www.hivandhepatitis.com/recent/2006/ad1/063006_a.html
  4. ^ [Darunavir - first molecule to treat drug-resistant HIV, http://www.news-medical.net/?id=19211]
  5. ^ [Retaining Efficacy Against Evasive HIV, http://pubs.acs.org/cen/news/84/i34/8434drugdesign.html]
  6. ^ Bonaventura Clotet, Nicholas Bellos, Jean-Michel Molina, David Cooper, Jean-Christophe Goffard, Adriano Lazzarin, Andrej Wöhrmann, Christine Katlama, Timothy Wilkin, Richard Haubrich, et al., Efficacy and safety of darunavir-ritonavir at week 48 in treatment-experienced patients with HIV-1 infection in POWER 1 and 2: a pooled subgroup analysis of data from two randomised trials, The Lancet, Volume 369, Issue 9568, 7 April 2007-13 April 2007, Pages 1169-1178.
  7. ^ José Valdez Madruga, Daniel Berger, Marilyn McMurchie, Fredy Suter, Denes Banhegyi, Kiat Ruxrungtham, Dorece Norris, Eric Lefebvre, Marie-Pierre de Béthune, Frank Tomaka, et al., Efficacy and safety of darunavir-ritonavir compared with that of lopinavir-ritonavir at 48 weeks in treatment-experienced, HIV-infected patients in TITAN: a randomised controlled phase III trial, Pages 49-58. DOI 10.1016/S0140-6736(07)61049-6
  • Lazzarin A, Queiroz-Telles F, Frank I, Rockstroh J, Walmsley S, De Paepe E, Vangeneugden T, Spinosa-Guzman S and Lefebvre E Lazzarin A, et al. XVI IAC 2006.
  • Johnson & Johnson FDA Approval Press Release, June 23 2006, http://www.jnj.com/news/jnj_news/20060623_191250.htm;jsessionid=NT1BC4RC4RHKYCQPCAOWU3YKB2IIWTT
  • Molina JM, Cohen C, Katlama C et al. TMC114/r in treatment-experienced HIV patients in power 3: 24-week efficacy and safety analysis. Poster abstract TUPE0060.
  • Janssen-Ortho, Prezista Mongraph information. Updated 2006. http://www.janssen-ortho.com/JOI/pdf_files/Prezista_E.pdf
  • TMC114, Tibotec, http://www.tibotec.com/bgdisplay.jhtml?itemname=HIV_tmc114
  • Ghosh, A. K., et. al. Bioorg. Med. Chem. Lett. 1998, 8, 687-90;
  • Mitsuya, H. Ghosh, A. K., et. al. J. Virology 2002, 76, 1349;
  • Ghosh, A. K. Duzguiness, N., et. al. Antiviral Res. 2002, 54, 29;
  • Koh,Y., Ghosh,A. K., Mitsuya, H., et. al. Antimicrobial Agents and Chemotherapy, 2003, 47, 3123
  • Ghosh, A. K., Mitsuya, H., et al. ChemMedChem 2006, 1, 937

See also

Tibotec is a pharmaceutical company with focus on research and development for drugs, e. ...

External links

  • Prezista FAQ at AIDSmeds.com
  • Drug information in PDF
  • Arun Ghosh group
  • Tibotec

 
 

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