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
Synonyms
  • Fosamprenavir
External IDs
GW-433908 / GW433908
Product Ingredients
IngredientUNIICASInChI Key
Fosamprenavir calciumID1GU2627N226700-81-8PMDQGYMGQKTCSX-HQROKSDRSA-L
Fosamprenavir sodiumXSG28FSA0W226700-80-7FZMGUXZZROZJIT-KMIZVRHLSA-L
Active Moieties
NameKindUNIICASInChI Key
Amprenavirprodrug5S0W860XNR161814-49-9YMARZQAQMVYCKC-OEMFJLHTSA-N
Product Images
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
LexivaTablet, film coated700 mg/1OralViiV Healthcare ULC2010-10-04Not applicableUs
LexivaTablet, film coated700 mg/1OralState of Florida DOH Central Pharmacy2014-11-01Not applicableUs53808 101020180907 15195 1ykc60z
LexivaTablet, film coated700 mg/1OralGlaxosmithkline Inc2003-11-062012-11-19Us
LexivaTablet, film coated700 mg/1OralRemedy Repack2011-11-11Not applicableUs49702 0207 18 nlmimage10 6e193749
LexivaTablet, film coated700 mg/1OralPhysicians Total Care, Inc.2003-11-062011-09-30Us
LexivaTablet, film coated700 mg/1OralState of Florida DOH Central Pharmacy2009-07-01Not applicableUs
LexivaSuspension50 mg/1mLOralViiV Healthcare ULC2010-10-04Not applicableUs
LexivaTablet, film coated700 mg/1OralAvera McKennan Hospital2015-03-302018-07-05Us
LexivaSuspension50 mg/1mLOralGlaxosmithkline Inc2007-08-012013-06-30Us
TelzirSuspension50 mg/mlOralViiV Healthcare ULC2004-07-12Not applicableEu
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Fosamprenavir CalciumTablet, film coated700 mg/1OralMylan Pharmaceuticals Inc.2017-09-18Not applicableUs
Categories
UNII
WOU1621EEG
CAS number
226700-79-4
Weight
Average: 585.607
Monoisotopic: 585.190986967
Chemical Formula
C25H36N3O9PS
InChI Key
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
IUPAC Name
{[(2R,3S)-1-[N-(2-methylpropyl)4-aminobenzenesulfonamido]-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

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.

Associated Conditions
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.

TargetActionsOrganism
AHuman immunodeficiency virus type 1 protease
inhibitor
Human immunodeficiency virus 1
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
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe metabolism of (R)-warfarin can be decreased when combined with Fosamprenavir.
(S)-WarfarinThe metabolism of (S)-Warfarin can be decreased when combined with Fosamprenavir.
2,4-thiazolidinedioneThe therapeutic efficacy of 2,4-thiazolidinedione can be decreased when used in combination with Fosamprenavir.
3,5-diiodothyropropionic acidThe metabolism of 3,5-diiodothyropropionic acid can be decreased when combined with Fosamprenavir.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with Fosamprenavir.
5-androstenedioneThe metabolism of 5-androstenedione can be decreased when combined with Fosamprenavir.
6-Deoxyerythronolide BThe metabolism of Fosamprenavir can be decreased when combined with 6-Deoxyerythronolide B.
6-O-benzylguanineThe metabolism of 6-O-benzylguanine can be decreased when combined with Fosamprenavir.
AbemaciclibThe serum concentration of Abemaciclib can be increased when it is combined with Fosamprenavir.
AbirateroneThe metabolism of Abiraterone can be decreased when combined with Fosamprenavir.
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.

References

Synthesis Reference
US6559815
General References
  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. doi: 10.1186/1742-6405-5-5. [PubMed:18373851]
  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:18042502]
  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:15341507]
  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:14982766]
  5. Sension M: Initial therapy for human immunodeficiency virus: broadening the options. HIV Clin Trials. 2004 Mar-Apr;5(2):99-111. [PubMed:15116286]
  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:14693528]
  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:12162471]
  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:16485915]
External Links
Human Metabolome Database
HMDB0015416
PubChem Compound
131536
PubChem Substance
46504901
ChemSpider
116245
ChEBI
82941
ChEMBL
CHEMBL1664
Therapeutic Targets Database
DAP000707
PharmGKB
PA10084
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Fosamprenavir
ATC Codes
J05AE07 — Fosamprenavir
AHFS Codes
  • 08:18.08.08 — HIV Protease Inhibitors
FDA label
Download (374 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentHealthy Volunteers2
1CompletedTreatmentHepatitis C Viral Infection / Human Immunodeficiency Virus (HIV) / Telaprevir1
1CompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections2
1CompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections / Infections, Fungal1
1CompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections / Opioid Dependency1
1CompletedTreatmentInfections, Human Immunodeficiency Virus and Herpesviridae1
1TerminatedTreatmentHealthy Volunteers1
2Active Not RecruitingTreatmentHuman Immunodeficiency Virus (HIV) Infections1
2CompletedNot AvailableHealthy Volunteers1
2CompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections3
2CompletedTreatmentInfection, Human Immunodeficiency Virus I1
2, 3CompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections1
3CompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections5
3CompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections / Infection, Human Immunodeficiency Virus I1
3CompletedTreatmentInfection, Human Immunodeficiency Virus I1
3TerminatedTreatmentHuman Immunodeficiency Virus Type 1 (HIV-1)1
3Unknown StatusTreatmentHuman Immunodeficiency Virus (HIV) Infections3
4CompletedNot AvailableHuman Immunodeficiency Virus (HIV) Infections1
4CompletedNot AvailableHuman Immunodeficiency Virus (HIV) / Proteinuria1
4CompletedTreatmentChronic Infection With HIV / HCV Coinfection1
4CompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections1
4CompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections / Hypertriglyceridemias1
Not AvailableCompletedNot AvailableHealthy Volunteers2
Not AvailableCompletedNot AvailableHuman Immunodeficiency Virus (HIV) Infections1
Not AvailableCompletedNot AvailableInfection, Human Immunodeficiency Virus I1
Not AvailableCompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • A-S Medication Solutions LLC
  • Dept Health Central Pharmacy
  • GlaxoSmithKline Inc.
  • Physicians Total Care Inc.
  • Remedy Repack
  • ViiV Healthcare ULC
Dosage forms
FormRouteStrength
SuspensionOral50 mg/1mL
Tablet, film coatedOral700 mg/1
SuspensionOral50 mg/ml
SuspensionOral50 mg
TabletOral700 mg
Tablet, film coatedOral700 mg
Prices
Unit descriptionCostUnit
Lexiva 700 mg tablet14.78USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
CA2224738No2002-08-272016-06-28Canada
CA2231700No2005-08-092018-03-10Canada
US6436989Yes2002-08-202018-06-24Us
US6514953Yes2003-02-042020-01-15Us

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.685 mg/mLALOGPS
logP0.84ALOGPS
logP1.92ChemAxon
logS-2.9ALOGPS
pKa (Strongest Acidic)1.22ChemAxon
pKa (Strongest Basic)2.45ChemAxon
Physiological Charge-2ChemAxon
Hydrogen Acceptor Count8ChemAxon
Hydrogen Donor Count4ChemAxon
Polar Surface Area177.72 Å2ChemAxon
Rotatable Bond Count13ChemAxon
Refractivity144.95 m3·mol-1ChemAxon
Polarizability57.77 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.6363
Blood Brain Barrier+0.5379
Caco-2 permeable+0.6992
P-glycoprotein substrateSubstrate0.6482
P-glycoprotein inhibitor IInhibitor0.7374
P-glycoprotein inhibitor IINon-inhibitor0.7819
Renal organic cation transporterNon-inhibitor0.8671
CYP450 2C9 substrateSubstrate0.5877
CYP450 2D6 substrateSubstrate0.6061
CYP450 3A4 substrateSubstrate0.5805
CYP450 1A2 substrateNon-inhibitor0.7454
CYP450 2C9 inhibitorNon-inhibitor0.6627
CYP450 2D6 inhibitorNon-inhibitor0.8835
CYP450 2C19 inhibitorNon-inhibitor0.6591
CYP450 3A4 inhibitorNon-inhibitor0.6317
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.6969
Ames testNon AMES toxic0.598
CarcinogenicityNon-carcinogens0.78
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.5018 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9846
hERG inhibition (predictor II)Non-inhibitor0.8356
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as aminobenzenesulfonamides. These are organic compounds containing a benzenesulfonamide moiety with an amine group attached to the benzene ring.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Benzenesulfonamides
Direct Parent
Aminobenzenesulfonamides
Alternative Parents
Phenylbutylamines / Amphetamines and derivatives / Benzenesulfonyl compounds / Phosphoethanolamines / Aniline and substituted anilines / Monoalkyl phosphates / Organosulfonamides / Tetrahydrofurans / Aminosulfonyl compounds / Propargyl-type 1,3-dipolar organic compounds
show 7 more
Substituents
Aminobenzenesulfonamide / Phenylbutylamine / Amphetamine or derivatives / Benzenesulfonyl group / Phosphoethanolamine / Aniline or substituted anilines / Monoalkyl phosphate / Organic phosphoric acid derivative / Phosphoric acid ester / Organosulfonic acid amide
show 24 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
sulfonamide (CHEBI:82941)

Targets

Kind
Protein
Organism
Human immunodeficiency virus 1
Pharmacological action
Yes
Actions
Inhibitor
General Function
Aspartic-type endopeptidase activity
Specific Function
Not Available
Gene Name
pol
Uniprot ID
Q72874
Uniprot Name
Pol polyprotein
Molecular Weight
10778.7 Da
References
  1. 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:18042502]
  2. 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:14982766]
  3. Sension M: Initial therapy for human immunodeficiency virus: broadening the options. HIV Clin Trials. 2004 Mar-Apr;5(2):99-111. [PubMed:15116286]
  4. 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:14693528]
  5. Wire MB, Shelton MJ, Studenberg S: Fosamprenavir : clinical pharmacokinetics and drug interactions of the amprenavir prodrug. Clin Pharmacokinet. 2006;45(2):137-68. [PubMed:16485915]
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
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 react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
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:16485915]
  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. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256]

Drug created on June 30, 2007 11:17 / Updated on November 16, 2018 08:03