FOSAMPRENAVIR

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C25H36N3O9PS
Molecular Weight	585.607
Optical Activity	UNSPECIFIED
Defined Stereocenters	3 / 3
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CC(C)CN(C[C@@H](OP(O)(O)=O)[C@H](CC1=CC=CC=C1)NC(=O)O[C@H]2CCOC2)S(=O)(=O)C3=CC=C(N)C=C3

InChI

InChIKey=MLBVMOWEQCZNCC-OEMFJLHTSA-N

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

HIDE SMILES / InChI

Description
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2002/21007s11,21039s10lbl.pdf
Curator's Comment: Description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/23519392 | https://www.ncbi.nlm.nih.gov/pubmed/11152018 | https://www.ncbi.nlm.nih.gov/pubmed/15341507

Amprenavir is an inhibitor of HIV-1 protease. Amprenavir binds to the active site of HIV-1 protease and thereby prevents the processing of viral gag and gag-pol polyprotein precursors, resulting in the formation of immature non-infectious viral particles. Amprenavir-containing combination regimens have shown virological efficacy, and have generally been well tolerated, in patients with HIV infection (primarily treatment-naive or protease inhibitor-naive). Fosamprenavir (GW433908, Lexiva, Telzir) is an oral prodrug of amprenavir, with a reduced daily pill burden. The use of protease inhibitors has also been associated with dyslipidemia and an increased risk of cardiovascular disease. Amprenavir activates Pregnane X receptor to mediate dyslipidemia.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Pregnane X receptor 35 Target ID: CHEMBL3401 Sources: https://www.ncbi.nlm.nih.gov/pubmed/23519392	Agonist 2678	8.6 µM [EC50]
Cytochrome P450 3A 22 Target ID: CHEMBL2364675 Sources: https://www.ncbi.nlm.nih.gov/pubmed/10952482	Inhibitor 8297	2.5 µM [IC50]
Human immunodeficiency virus type 1 protease 35 Target ID: CHEMBL243 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2002/21007s11,21039s10lbl.pdf	Inhibitor 8297

Conditions

Condition	Modality	Targets	Highest Phase	Product
HIV-1 infection 151 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2002/21007s11,21039s10lbl.pdf	Primary		Approved 8429	AGENERASE Approved Use AGENERASE (amprenavir) is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection. Launch Date 1999

C_max

Value	Dose	Analyte	Population
5.36 μg/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/1999/21007lbl.pdf	1200 mg 2 times / day multiple, oral dose: 1200 mg route of administration: Oral experiment type: MULTIPLE co-administered:	AMPRENAVIR plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
6.18 μg/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/1999/21007lbl.pdf	1200 mg single, oral dose: 1200 mg route of administration: Oral experiment type: SINGLE co-administered:	AMPRENAVIR plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: HIGH-FAT
9.72 μg/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/1999/21007lbl.pdf	1200 mg single, oral dose: 1200 mg route of administration: Oral experiment type: SINGLE co-administered:	AMPRENAVIR plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: FASTED
6.77 μg/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/1999/21007lbl.pdf	20 mg/kg bw 2 times / day multiple, oral dose: 20 mg/kg bw route of administration: Oral experiment type: MULTIPLE co-administered:	AMPRENAVIR plasma	Homo sapiens population: UNHEALTHY age: CHILD sex: UNKNOWN food status: UNKNOWN
3.99 μg/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/1999/21007lbl.pdf	15 mg/kg bw 3 times / day multiple, oral dose: 15 mg/kg bw route of administration: Oral experiment type: MULTIPLE co-administered:	AMPRENAVIR plasma	Homo sapiens population: UNHEALTHY age: CHILD sex: UNKNOWN food status: UNKNOWN

AUC

Value	Dose	Analyte	Population
18.5 μg × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/1999/21007lbl.pdf	1200 mg 2 times / day multiple, oral dose: 1200 mg route of administration: Oral experiment type: MULTIPLE co-administered:	AMPRENAVIR plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
22.06 μg × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/1999/21007lbl.pdf	1200 mg single, oral dose: 1200 mg route of administration: Oral experiment type: SINGLE co-administered:	AMPRENAVIR plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: HIGH-FAT
28.05 μg × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/1999/21007lbl.pdf	1200 mg single, oral dose: 1200 mg route of administration: Oral experiment type: SINGLE co-administered:	AMPRENAVIR plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: FASTED
15.46 μg × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/1999/21007lbl.pdf	20 mg/kg bw 2 times / day multiple, oral dose: 20 mg/kg bw route of administration: Oral experiment type: MULTIPLE co-administered:	AMPRENAVIR plasma	Homo sapiens population: UNHEALTHY age: CHILD sex: UNKNOWN food status: UNKNOWN
8.73 μg × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/1999/21007lbl.pdf	15 mg/kg bw 3 times / day multiple, oral dose: 15 mg/kg bw route of administration: Oral experiment type: MULTIPLE co-administered:	AMPRENAVIR plasma	Homo sapiens population: UNHEALTHY age: CHILD sex: UNKNOWN food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
8.85 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/1999/21007lbl.pdf	1200 mg 2 times / day multiple, oral dose: 1200 mg route of administration: Oral experiment type: MULTIPLE co-administered:		AMPRENAVIR plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
10% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/1999/21007lbl.pdf	1200 mg 2 times / day multiple, oral dose: 1200 mg route of administration: Oral experiment type: MULTIPLE co-administered:		AMPRENAVIR plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
1200 mg 2 times / day multiple, oral Recommended Dose: 1200 mg, 2 times / day Route: oral Route: multiple Dose: 1200 mg, 2 times / day Co-administed with:: lamivudine, po(150 mg, BID) zidovudine, po(300 mg, BID) Sources: https://pubmed.ncbi.nlm.nih.gov/11192131 Page: p.1387	unhealthy, 21-62 n = 113 Health Status: unhealthy Condition: HIV-1 infection Age Group: 21-62 Sex: M+F Population Size: 113 Sources: https://pubmed.ncbi.nlm.nih.gov/11192131 Page: p.1387	Disc. AE: Nausea, Vomiting... AEs leading to discontinuation/dose reduction: Nausea (12%) Vomiting (6%) Loose stools (3%) Abdominal pain (2%) Abdominal discomfort (2%) Rash (3%) Sources: https://pubmed.ncbi.nlm.nih.gov/11192131 Page: p.1387
1200 mg single, oral Recommended Dose: 1200 mg Route: oral Route: single Dose: 1200 mg Sources: https://pubmed.ncbi.nlm.nih.gov/10390223 Page: p.1688	unhealthy, 33+/-6.7 n = 12 Health Status: unhealthy Condition: HIV-1 infection Age Group: 33+/-6.7 Sex: M+F Population Size: 12 Sources: https://pubmed.ncbi.nlm.nih.gov/10390223 Page: p.1688	Sources: https://pubmed.ncbi.nlm.nih.gov/10390223 Page: p.1688
1200 mg 2 times / day multiple, oral Recommended Dose: 1200 mg, 2 times / day Route: oral Route: multiple Dose: 1200 mg, 2 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021007s017lbl.pdf Page: p.11	unhealthy Health Status: unhealthy Condition: HIV-1 infection Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021007s017lbl.pdf Page: p.11	Disc. AE: Reaction skin, Stevens-Johnson syndrome... AEs leading to discontinuation/dose reduction: Reaction skin (grade 3-4) Stevens-Johnson syndrome (grade 3-4) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021007s017lbl.pdf Page: p.11

AEs

AE	Significance	Dose	Population
Nausea	12% Disc. AE	1200 mg 2 times / day multiple, oral Recommended Dose: 1200 mg, 2 times / day Route: oral Route: multiple Dose: 1200 mg, 2 times / day Co-administed with:: lamivudine, po(150 mg, BID) zidovudine, po(300 mg, BID) Sources: https://pubmed.ncbi.nlm.nih.gov/11192131 Page: p.1387	unhealthy, 21-62 n = 113 Health Status: unhealthy Condition: HIV-1 infection Age Group: 21-62 Sex: M+F Population Size: 113 Sources: https://pubmed.ncbi.nlm.nih.gov/11192131 Page: p.1387
Abdominal discomfort	2% Disc. AE	1200 mg 2 times / day multiple, oral Recommended Dose: 1200 mg, 2 times / day Route: oral Route: multiple Dose: 1200 mg, 2 times / day Co-administed with:: lamivudine, po(150 mg, BID) zidovudine, po(300 mg, BID) Sources: https://pubmed.ncbi.nlm.nih.gov/11192131 Page: p.1387	unhealthy, 21-62 n = 113 Health Status: unhealthy Condition: HIV-1 infection Age Group: 21-62 Sex: M+F Population Size: 113 Sources: https://pubmed.ncbi.nlm.nih.gov/11192131 Page: p.1387
Abdominal pain	2% Disc. AE	1200 mg 2 times / day multiple, oral Recommended Dose: 1200 mg, 2 times / day Route: oral Route: multiple Dose: 1200 mg, 2 times / day Co-administed with:: lamivudine, po(150 mg, BID) zidovudine, po(300 mg, BID) Sources: https://pubmed.ncbi.nlm.nih.gov/11192131 Page: p.1387	unhealthy, 21-62 n = 113 Health Status: unhealthy Condition: HIV-1 infection Age Group: 21-62 Sex: M+F Population Size: 113 Sources: https://pubmed.ncbi.nlm.nih.gov/11192131 Page: p.1387
Loose stools	3% Disc. AE	1200 mg 2 times / day multiple, oral Recommended Dose: 1200 mg, 2 times / day Route: oral Route: multiple Dose: 1200 mg, 2 times / day Co-administed with:: lamivudine, po(150 mg, BID) zidovudine, po(300 mg, BID) Sources: https://pubmed.ncbi.nlm.nih.gov/11192131 Page: p.1387	unhealthy, 21-62 n = 113 Health Status: unhealthy Condition: HIV-1 infection Age Group: 21-62 Sex: M+F Population Size: 113 Sources: https://pubmed.ncbi.nlm.nih.gov/11192131 Page: p.1387
Rash	3% Disc. AE	1200 mg 2 times / day multiple, oral Recommended Dose: 1200 mg, 2 times / day Route: oral Route: multiple Dose: 1200 mg, 2 times / day Co-administed with:: lamivudine, po(150 mg, BID) zidovudine, po(300 mg, BID) Sources: https://pubmed.ncbi.nlm.nih.gov/11192131 Page: p.1387	unhealthy, 21-62 n = 113 Health Status: unhealthy Condition: HIV-1 infection Age Group: 21-62 Sex: M+F Population Size: 113 Sources: https://pubmed.ncbi.nlm.nih.gov/11192131 Page: p.1387
Vomiting	6% Disc. AE	1200 mg 2 times / day multiple, oral Recommended Dose: 1200 mg, 2 times / day Route: oral Route: multiple Dose: 1200 mg, 2 times / day Co-administed with:: lamivudine, po(150 mg, BID) zidovudine, po(300 mg, BID) Sources: https://pubmed.ncbi.nlm.nih.gov/11192131 Page: p.1387	unhealthy, 21-62 n = 113 Health Status: unhealthy Condition: HIV-1 infection Age Group: 21-62 Sex: M+F Population Size: 113 Sources: https://pubmed.ncbi.nlm.nih.gov/11192131 Page: p.1387
Reaction skin	grade 3-4 Disc. AE	1200 mg 2 times / day multiple, oral Recommended Dose: 1200 mg, 2 times / day Route: oral Route: multiple Dose: 1200 mg, 2 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021007s017lbl.pdf Page: p.11	unhealthy Health Status: unhealthy Condition: HIV-1 infection Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021007s017lbl.pdf Page: p.11
Stevens-Johnson syndrome	grade 3-4 Disc. AE	1200 mg 2 times / day multiple, oral Recommended Dose: 1200 mg, 2 times / day Route: oral Route: multiple Dose: 1200 mg, 2 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021007s017lbl.pdf Page: p.11	unhealthy Health Status: unhealthy Condition: HIV-1 infection Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021007s017lbl.pdf Page: p.11

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:40050	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:40050
ChemicalBook	CB4186139	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB4186139
MolPort	MolPort-000-883-856	https://www.molport.com/shop/molecule-link/MolPort-000-883-856
Selleck Chemicals	Amprenavir-(Agenerase)	http://www.selleckchem.com/products/Amprenavir-(Agenerase).html
ZINC	ZINC000003809192	http://zinc15.docking.org/substances/ZINC000003809192
eMolecules	877446	https://www.emolecules.com/cgi-bin/more?vid=877446

PubMed

Title	Date	PubMed
Principles and practice of HIV-protease inhibitor pharmacoenhancement.	2001 Apr	11737387
HIV and drug allergy.	2001 Aug	11964706
Genotypic correlates of resistance to HIV-1 protease inhibitors on longitudinal data: the role of secondary mutations.	2001 Dec	11878405
Combination of protease inhibitors for the treatment of HIV-1-infected patients: a review of pharmacokinetics and clinical experience.	2001 Dec	11878403
Therapeutic drug monitoring of HIV protease inhibitors using high-performance liquid chromatography with ultraviolet or photodiode array detection.	2001 Dec	11802104
Human immunodeficiency virus type 1 hypersusceptibility to amprenavir in vitro can be associated with virus load response to treatment in vivo.	2001 Dec 15	11700580
Amprenavir: new preparation. Another HIV protease inhibitor: no proven advance.	2001 Jun	11718166
Resistant to everything.	2001 May	11682786
From amprenavir to GW433908.	2001 Nov	11740410
Anti-human immunodeficiency virus drugs are ineffective against Pneumocystis carinii in vitro and in vivo.	2001 Nov 15	11679930
Pharmacokinetics of amprenavir and lopinavir in combination with nevirapine in highly pretreated HIV-infected patients.	2001 Nov 23	11698713
In vitro activity of amprenavir against Pneumocystis carinii.	2001 Sep	11708264
Retroviral proteases.	2002	11983066
Interaction potential of lercanidipine, a new vasoselective dihydropyridine calcium antagonist.	2002	11963641
New dosing regimen approved.	2002 Apr	12015873
Simultaneous determination of the six HIV protease inhibitors (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir) plus M8 nelfinavir metabolite and the nonnucleoside reverse transcription inhibitor efavirenz in human plasma by solid-phase extraction and column liquid chromatography.	2002 Apr	11897976
In-vitro and in-vivo pharmacokinetic interactions of amprenavir, an HIV protease inhibitor, with other current HIV protease inhibitors in rats.	2002 Feb	11848286
A potent human immunodeficiency virus type 1 protease inhibitor, UIC-94003 (TMC-126), and selection of a novel (A28S) mutation in the protease active site.	2002 Feb	11773409
HIV-1 genotype and phenotype correlate with virological response to abacavir, amprenavir and efavirenz in treatment-experienced patients.	2002 Feb 15	11834950
Amino acid substitutions in Gag protein at non-cleavage sites are indispensable for the development of a high multitude of HIV-1 resistance against protease inhibitors.	2002 Feb 22	11741936
Central nervous system toxicity and amprenavir oral solution.	2002 Jan	11816252
Clinical pharmacology and pharmacokinetics of amprenavir.	2002 Jan	11816239
Beta-strand mimicking macrocyclic amino acids: templates for protease inhibitors with antiviral activity.	2002 Jan 17	11784141
[Advances in the domain of HIV].	2002 Jan 19	11850992
Determination of amprenavir, a HIV-1 protease inhibitor, in human seminal plasma using high-performance liquid chromatography-tandem mass spectrometry.	2002 Jan 25	11824819
Unfavourable interaction of amprenavir and lopinavir in combination with ritonavir?	2002 Jan 25	11807318
Longitudinal use of phenotypic resistance testing to HIV-1 protease inhibitors in patients developing HAART failure.	2002 Jul	12116020
In vitro antiviral interaction of lopinavir with other protease inhibitors.	2002 Jul	12069982
Dual vs single protease inhibitor therapy following antiretroviral treatment failure: a randomized trial.	2002 Jul 10	12095381
The pharmacokinetics of amprenavir, zidovudine, and lamivudine in the genital tracts of men infected with human immunodeficiency virus type 1 (AIDS clinical trials group study 850).	2002 Jul 15	12134255
Determination of lopinavir and nevirapine by high-performance liquid chromatography after solid-phase extraction: application for the assessment of their transplacental passage at delivery.	2002 Jul 15	12076682
Synthesis and antiviral activity of new anti-HIV amprenavir bioisosteres.	2002 Jul 18	12109915
New developments in anti-HIV chemotherapy.	2002 Jul 18	12084468
High-performance liquid chromatographic method for the simultaneous determination of the six HIV-protease inhibitors and two non-nucleoside reverse transcriptase inhibitors in human plasma.	2002 Jun	12021635
Sensitive and simultaneous determination of HIV protease inhibitors in rat biological samples by liquid chromatography-mass spectrometry.	2002 Jun	11933027
Fosamprenavir. Vertex Pharmaceuticals/GlaxoSmithKline.	2002 Mar	12054084
Lipodystrophy update.	2002 Mar	12038302
Resistance testing in children changing human immunodeficiency virus type 1 protease inhibitor.	2002 Mar	12005085
Drug interactions between HIV protease inhibitors based on physiologically-based pharmacokinetic model.	2002 Mar	11920753
Efavirenz-induced skin eruption and successful desensitization.	2002 Mar	11895054
The utility of inhibitory quotients in determining the relative potency of protease inhibitors.	2002 Mar 29	11964541
Delavirdine increases drug exposure of ritonavir-boosted protease inhibitors.	2002 Mar 29	11964540
Drug interaction between amprenavir and lopinavir/ritonavir in salvage therapy.	2002 Mar 29	11964539
FDA approves new dosing for amprenavir and ritonavir combination.	2002 Mar 8	11965920
Parallel decline of CD8+/CD38++ T cells and viraemia in response to quadruple highly active antiretroviral therapy in primary HIV infection.	2002 Mar 8	11873002
Salvage therapy with amprenavir and ritonavir: prospective study in 17 heavily pretreated patients.	2002 Mar-Apr	11976990
Prevalence of the HIV protease mutation N88S causing hypersensitivity to amprenavir.	2002 May 1	11941567
Amprenavir-resistant HIV-1 exhibits lopinavir cross-resistance and reduced replication capacity.	2002 May 3	11953467
Select HIV protease inhibitors alter bone and fat metabolism ex vivo.	2002 May 31	11937496
Therapeutic vaccination in primary HIV infection, the Quest trial.	2002 May 6	11983263

Patents

Sample Use Guides

In Vivo Use Guide

Adults: The recommended oral dose of AGENERASE Capsules for adults is 1200 mg (eight 150-mg capsules) twice daily in combination with other antiretroviral agents. Concomitant Therapy: If AGENERASE and ritonavir are used in combination, the recommended dosage regimens are: AGENERASE 1200 mg with ritonavir 200 mg once daily or AGENERASE 600 mg with ritonavir 100 mg twice daily. Pediatric Patients: For adolescents (13 to 16 years), the recommended oral dose of AGENERASE Capsules is 1200 mg (eight 150-mg capsules) twice daily in combination with other antiretroviral agents. For patients between 4 and 12 years of age or for patients 13 to 16 years of age with weight of <50 kg, the recommended oral dose of AGENERASE Capsules is 20 mg/kg twice daily or 15 mg/kg 3 times daily (to a maximum daily dose of 2400 mg) in combination with other antiretroviral agents.

Route of Administration: Oral

In Vitro Use Guide

The in vitro antiviral activity of amprenavir was evaluated against HIV-1 IIIB in both acutely and chronically infected lymphoblastic cell lines (MT-4, CEM-CCRF, 43 H9) and in peripheral blood lymphocytes. The 50% inhibitory concentration (IC50) of amprenavir ranged from 0.012 to 0.08 µM in acutely infected cells and was 0.41 µM in chronically infected cells (1 µM = 0.50 mcg/mL).

Name

Type

Language

FOSAMPRENAVIR

Official Name

English

GW433908

Code

English

(3S)-TETRAHYDRO-3-FURYL ((.ALPHA.S)-.ALPHA.-((1R)-1-HYDROXY-2-(N1-ISOBUTYLSULFANILAMIDO)ETHYL)PHENETHYL)CARBAMATE PHOSPHATE (ESTER)

Common Name

English

fosamprenavir [INN]

Common Name

English

FOSAMPRENAVIR [MI]

Common Name

English

GW433908A

Code

English

GW-433908

Code

English

CARBAMIC ACID, ((1S,2R)-3-(((4-AMINOPHENYL)SULFONYL)(2-METHYLPROPYL)AMINO)-1-(PHENYLMETHYL)-2-(PHOSPHONOOXY)PROPYL)-, C-(3S)-TETRAHYDRO-3-FURANYL) ESTER

Systematic Name

English

Fosamprenavir [WHO-DD]

Common Name

English

FOSAMPRENAVIR [VANDF]

Common Name

English

FOSAMPRENAVIR [HSDB]

Common Name

English

Classification Tree Code System Code

NCI_THESAURUS

C97366