Fosamprenavir

Fosamprenavir
Clinical data
Trade names	Lexiva, Telzir
AHFS/Drugs.com	Monograph
MedlinePlus	a604012
License data	EU EMA: by INN;
Pregnancy; category	US: C (Risk not ruled out) ;
Routes of; administration	Oral
ATC code	J05AE07 (WHO) ;
Legal status
Legal status	UK: POM (Prescription only) ; US: ℞-only ;
Pharmacokinetic data
Bioavailability	Unknown
Protein binding	90%
Metabolism	Hydrolysed to amprenavir and phosphate in GI tract epithelium
Elimination half-life	7.7 hours
Excretion	Fecal (as metabolites of amprenavir)
Identifiers
	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;
CAS Number	226700-81-8 ;
PubChem CID	131536;
DrugBank	DB01319 ;
ChemSpider	116245 ;
UNII	WOU1621EEG;
KEGG	D02497 ;
ChEMBL	ChEMBL1664 ;
NIAID ChemDB	082186;
CompTox Dashboard (EPA)	DTXSID2048296 ;
Chemical and physical data
Formula	C25H36N3O9PS
Molar mass	585.608 g/mol; 623.700 g/mol (calcium salt) g·mol−1
3D model (JSmol)	Interactive image;
	SMILES O=C(O[C@H]1CCOC1)N[C@@H](Cc2ccccc2)[C@H](OP(=O)(O)O)CN(CC(C)C)S(=O)(=O)c3ccc(N)cc3;
	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 ; Key:MLBVMOWEQCZNCC-OEMFJLHTSA-N ;
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Fosamprenavir (marketed by ViiV Healthcare as the calcium salt under the trade names Lexiva in the U.S. and Telzir in Europe) is a drug for the treatment of HIV infections. It is a pro-drug of the protease inhibitor and antiretroviral drug amprenavir. The FDA approved it October 20, 2003, while the EMA approved it on July 12, 2004. The human body metabolizes fosamprenavir in order to form 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.

A head-to-head study with lopinavir[1] showed the two drugs to have comparable potency, but patients on fosamprenavir tended to have a higher serum cholesterol. Fosamprenavir's main advantage over lopinavir is that it is cheaper.

Medical uses

Fosamprenavir is used for the treatment of HIV-1 infections, typically but not necessarily in combination with low-dose ritonavir or other antiviral drugs.[2][3]

Adverse effects

The most common adverse effect is diarrhea. Other common side effects include headache, dizziness and exanthema, which is usually transient. Severe allergic reactions (Stevens–Johnson syndrome) are rare.[2]

Interactions

Amprenavir (the active metabolite of fosamrenavir, which is found in blood plasma, liver and other organs) is metabolized via the liver enzyme CYP3A4 and also weakly inhibits this enzyme. This means that combination with drugs that are also metabolized by CYP3A4 can increase their plasma concentrations and thus side effects; and combination with drugs that inhibit CYP3A4 can increase amprenavir concentrations.[2]

When combining fosamprenavir with low doses of the CYP3A4 inhibitor ritonavir, this interaction is intended as it allows for application of lower fosamprenavir doses.[2]

Pharmacology

Fosamprenavir is quickly activated to amprenavir, even before it reaches the circulation. Amprenavir is a HIV protease inhibitor.[2]

HIV-1 protease dimer with amprenavir (sticks) bound in the active site. PDB entry 3nu3[4]

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References

Eron J, Yeni P, Gathe J, Estrada V, DeJesus E, Staszewski S, et al. (August 2006). "The KLEAN study of fosamprenavir-ritonavir versus lopinavir-ritonavir, each in combination with abacavir-lamivudine, for initial treatment of HIV infection over 48 weeks: a randomised non-inferiority trial". Lancet. 368 (9534): 476–82. doi:10.1016/S0140-6736(06)69155-1. PMID 16890834.
Jasek W, ed. (2007). Austria-Codex (in German) (62nd ed.). Vienna: Österreichischer Apothekerverlag. pp. 8009–17. ISBN 978-3-85200-181-4.
Lexiva. Drugs.com (Report). Monograph.
Shen CH, Wang YF, Kovalevsky AY, Harrison RW, Weber IT (September 2010). "Amprenavir complexes with HIV-1 protease and its drug-resistant mutants altering hydrophobic clusters". The FEBS Journal. 277 (18): 3699–714. doi:10.1111/j.1742-4658.2010.07771.x. PMC 2975871. PMID 20695887.

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[1] Eron J, Yeni P, Gathe J, Estrada V, DeJesus E, Staszewski S, et al. (August 2006). "The KLEAN study of fosamprenavir-ritonavir versus lopinavir-ritonavir, each in combination with abacavir-lamivudine, for initial treatment of HIV infection over 48 weeks: a randomised non-inferiority trial". Lancet. 368 (9534): 476–82. doi:10.1016/S0140-6736(06)69155-1. PMID 16890834.

[Austria-Codex-2] Jasek W, ed. (2007). Austria-Codex (in German) (62nd ed.). Vienna: Österreichischer Apothekerverlag. pp. 8009–17. ISBN 978-3-85200-181-4.

[3] Lexiva. Drugs.com (Report). Monograph.

[4] Shen CH, Wang YF, Kovalevsky AY, Harrison RW, Weber IT (September 2010). "Amprenavir complexes with HIV-1 protease and its drug-resistant mutants altering hydrophobic clusters". The FEBS Journal. 277 (18): 3699–714. doi:10.1111/j.1742-4658.2010.07771.x. PMC 2975871. PMID 20695887.