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Identification
Name Fosamprenavir
Accession Number DB01319
Type small molecule
Groups approved
Description

Fosamprenavir is a prodrug of amprenavir, an inhibitor of human immunodeficiency virus (HIV) protease.
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms Not Available
Brand names
  • Lexiva
  • Telzir
Brand name mixtures Not Available
Categories
  • Anti-HIV Agents
  • HIV Protease Inhibitors
  • Prodrugs
CAS number 226700-79-4
Weight Average: 585.607
Monoisotopic: 585.190986967
Chemical Formula C25H36N3O9PS
InChI Key InChIKey=MLBVMOWEQCZNCC-OEMFJLHTSA-N
InChI
InChI=1S/C25H36N3O9PS/c1-18(2)15-28(39(33,34)22-10-8-20(26)9-11-22)16-24(37-38(30,31)32)23(14-19-6-4-3-5-7-19)27-25(29)36-21-12-13-35-17-21/h3-11,18,21,23-24H,12-17,26H2,1-2H3,(H,27,29)(H2,30,31,32)/t21-,23-,24+/m0/s1
Plain Text
IUPAC Name
{[(2R,3S)-1-[N-(2-methylpropyl)(4-aminobenzene)sulfonamido]-3-({[(3S)-oxolan-3-yloxy]carbonyl}amino)-4-phenylbutan-2-yl]oxy}phosphonic acid
SMILES
CC(C)CN(C[C@@H](OP(O)(O)=O)[C@H](CC1=CC=CC=C1)NC(=O)O[C@H]1CCOC1)S(=O)(=O)C1=CC=C(N)C=C1
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Benzenesulfonamides
  • Sulfanilamides
  • Amphetamines
Substructures
  • Hydroxy Compounds
  • Carbamates and Derivatives
  • Phosphonic Acids and Derivatives
  • Organophosphate Esters
  • Sulfonyls
  • Aliphatic and Aryl Amines
  • Ethers
  • Benzene and Derivatives
  • Benzenesulfonamides
  • Phenethylamines
  • Heterocyclic compounds
  • Aromatic compounds
  • Phosphinic Acids and Derivatives
  • Sulfanilamides
  • Sulfonamides
  • Furans
  • Anilines
  • Amphetamines
Pharmacology
Indication Indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus (HIV-1) infection, as well as postexposure prophylaxis of HIV infection in individuals who have had occupational or nonoccupational exposure to potentially infectious body fluids of a person known to be infected with HIV when that exposure represents a substantial risk for HIV transmission. The use of fosamprenavir is pending revision due to a potential association between the drug and myocardial infarction and dyslipidemia in HIV infected adults.
Pharmacodynamics Fosamprenavir is a pro-drug of the protease inhibitor and antiretroviral drug amprenavir. It has little or no antiviral activity until it is hydrolyzed by cellular phosphatases into amprenavir, which is the active ingredient. That metabolization increases the duration that amprenavir is available, making fosamprenavir a slow-release version of amprenavir and thus reducing the number of pills required versus standard amprenavir.
Mechanism of action Fosamprenavir is a prodrug that is rapidly hydrolyzed to amprenavir by cellular phosphatases in the gut epithelium as it is absorbed. Amprenavir is an inhibitor of HIV-1 protease. During HIV replication, HIV protease cleaves viral polypeptide products of the Gag and Gag-Pol genes to form structural proteins of the virion core and essential viral enzymes. Amprenavir interferes with this process by binding to the active site of HIV-1 protease, thereby preventing the processing of viral Gag and Gag-Pol polyprotein precursors, resulting in the formation of immature non-infectious viral particles.
Absorption The absolute oral bioavailability of amprenavir after administration of fosamprenavir in humans has not been established. After administration of a single 1,400 mg dose in the fasted state, fosamprenavir oral suspension (50 mg/mL) and fosamprenavir tablets (700 mg) provided similar amprenavir exposures (AUC), however, the Cmax of amprenavir after administration of the suspension formulation was 14.5 % higher compared with the tablet.
Volume of distribution Not Available
Protein binding Very high (approximately 90%); primarily bound to alpha 1 -acid glycoprotein. Higher amounts of unbound amprenavir present as amprenavir serum concentrations increase.
Metabolism

In the gut epithelium during absorption, fosamprenavir is rapidly and almost completely hydrolyzed to amprenavir and inorganic phosphate prior to reaching the systemic circulation. Amprenavir is metabolized in the liver by the cytochrome P450 3A4 (CYP3A4) enzyme system.
Route of elimination Excretion of unchanged amprenavir in urine and feces is minimal. The renal elimination of unchanged amprenavir represents approximately 1% of the administered dose; therefore, renal impairment is not expected to significantly impact the elimination of amprenavir. Amprenavir, the active metabolite of fosamprenavir, is metabolized in the liver by the cytochrome P450 enzyme system.
Half life The plasma elimination half-life of amprenavir (the active metabolite) is approximately 7.7 hours.
Clearance Not Available
Toxicity Not Available
Affected organisms
  • Human Immunodeficiency Virus
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Viiv healthcare co
Packagers
Dosage forms
Form Route Strength
Suspension Oral
Tablet Oral
Prices
Unit description Cost Unit
Lexiva 700 mg tablet 14.78 USD tablet
Patents
Country Patent Number Approved Expires
United States 6514953 1999-07-15 2019-07-15
United States 6436989 1997-12-24 2017-12-24
Canada 2231700 2005-08-09 2018-03-10
Canada 2224738 2002-08-27 2016-06-28
Properties
State solid
Melting point Not Available
Experimental Properties Not Available
Predicted Properties
Property Value Source
water solubility 6.85e-01 g/l ALOGPS
logP 0.84 ALOGPS
logP 0.94 ChemAxon Molconvert
logS -2.93 ALOGPS
pKa 6.28 ChemAxon Molconvert
hydrogen acceptor count 8 ChemAxon Molconvert
hydrogen donor count 4 ChemAxon Molconvert
polar surface area 177.72 ChemAxon Molconvert
rotatable bond count 13 ChemAxon Molconvert
refractivity 144.95 ChemAxon Molconvert
polarizability 57.77 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference
  1. Smith KY, Weinberg WG, Dejesus E, Fischl MA, Liao Q, Ross LL, Pakes GE, Pappa KA, Lancaster CT: Fosamprenavir or atazanavir once daily boosted with ritonavir 100 mg, plus tenofovir/emtricitabine, for the initial treatment of HIV infection: 48-week results of ALERT. AIDS Res Ther. 2008 Mar 28;5:5. Pubmed
  2. Hoffman RM, Umeh OC, Garris C, Givens N, Currier JS: Evaluation of sex differences of fosamprenavir (with and without ritonavir) in HIV-infected men and women. HIV Clin Trials. 2007 Nov-Dec;8(6):371-80. Pubmed
  3. Chapman TM, Plosker GL, Perry CM: Fosamprenavir: a review of its use in the management of antiretroviral therapy-naive patients with HIV infection. Drugs. 2004;64(18):2101-24. Pubmed
  4. Furfine ES, Baker CT, Hale MR, Reynolds DJ, Salisbury JA, Searle AD, Studenberg SD, Todd D, Tung RD, Spaltenstein A: Preclinical pharmacology and pharmacokinetics of GW433908, a water-soluble prodrug of the human immunodeficiency virus protease inhibitor amprenavir. Antimicrob Agents Chemother. 2004 Mar;48(3):791-8. Pubmed
  5. Sension M: Initial therapy for human immunodeficiency virus: broadening the options. HIV Clin Trials. 2004 Mar-Apr;5(2):99-111. Pubmed
  6. Wood R, Arasteh K, Stellbrink HJ, Teofilo E, Raffi F, Pollard RB, Eron J, Yeo J, Millard J, Wire MB, Naderer OJ: Six-week randomized controlled trial to compare the tolerabilities, pharmacokinetics, and antiviral activities of GW433908 and amprenavir in human immunodeficiency virus type 1-infected patients. Antimicrob Agents Chemother. 2004 Jan;48(1):116-23. Pubmed
  7. Falcoz C, Jenkins JM, Bye C, Hardman TC, Kenney KB, Studenberg S, Fuder H, Prince WT: Pharmacokinetics of GW433908, a prodrug of amprenavir, in healthy male volunteers. J Clin Pharmacol. 2002 Aug;42(8):887-98. Pubmed
  8. Wire MB, Shelton MJ, Studenberg S: Fosamprenavir : clinical pharmacokinetics and drug interactions of the amprenavir prodrug. Clin Pharmacokinet. 2006;45(2):137-68. Pubmed
External Links
Resource Link
PubChem Compound 131536 Link_out
PubChem Substance 46504901 Link_out
ChemSpider 116245 Link_out
Therapeutic Targets Database DAP000707 Link_out
PharmGKB PA10084 Link_out
Drug Product Database 2261545 Link_out
RxList http://www.rxlist.com/cgi/generic/lexiva.htm Link_out
Drugs.com http://www.drugs.com/cdi/fosamprenavir.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Fosamprenavir Link_out
ATC Codes
  • J05AE07
AHFS Codes
  • 08:18.08.08
PDB Entries Not Available
FDA label show (374.4 KB)
MSDS Not Available
Interactions
Drug Interactions Not Available
Food Interactions
  • Avoid alcohol, especially with the oral solution since it contains propylene glycol which competes with alcohol for alcohol dehydrogenase metabolism.
  • Take with or without food, however avoid lipid-rich meals.
  • Vitamin E increases fosamprenavir bioavailability.
Targets

1. HIV-1 protease

Pharmacological action: yes
Actions: inhibitor
Organism class: viral
UniProt ID: O90777 Link_out
Gene: HIV-1 protease
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed
  3. Hoffman RM, Umeh OC, Garris C, Givens N, Currier JS: Evaluation of sex differences of fosamprenavir (with and without ritonavir) in HIV-infected men and women. HIV Clin Trials. 2007 Nov-Dec;8(6):371-80. Pubmed
  4. Furfine ES, Baker CT, Hale MR, Reynolds DJ, Salisbury JA, Searle AD, Studenberg SD, Todd D, Tung RD, Spaltenstein A: Preclinical pharmacology and pharmacokinetics of GW433908, a water-soluble prodrug of the human immunodeficiency virus protease inhibitor amprenavir. Antimicrob Agents Chemother. 2004 Mar;48(3):791-8. Pubmed
  5. Sension M: Initial therapy for human immunodeficiency virus: broadening the options. HIV Clin Trials. 2004 Mar-Apr;5(2):99-111. Pubmed
  6. Wood R, Arasteh K, Stellbrink HJ, Teofilo E, Raffi F, Pollard RB, Eron J, Yeo J, Millard J, Wire MB, Naderer OJ: Six-week randomized controlled trial to compare the tolerabilities, pharmacokinetics, and antiviral activities of GW433908 and amprenavir in human immunodeficiency virus type 1-infected patients. Antimicrob Agents Chemother. 2004 Jan;48(1):116-23. Pubmed
  7. Wire MB, Shelton MJ, Studenberg S: Fosamprenavir : clinical pharmacokinetics and drug interactions of the amprenavir prodrug. Clin Pharmacokinet. 2006;45(2):137-68. Pubmed
  8. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
Enzymes

1. Cytochrome P450 3A4

Actions: substrate, inhibitor

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4- hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. The enzyme also hydroxylates etoposide

UniProt ID: P08684 Link_out
Gene: CYP3A4
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Wire MB, Shelton MJ, Studenberg S: Fosamprenavir : clinical pharmacokinetics and drug interactions of the amprenavir prodrug. Clin Pharmacokinet. 2006;45(2):137-68. Pubmed
  2. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed
Comments
Drug created on June 30, 2007 11:17 / Updated on November 10, 2010 13:47

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.