Fosamprenavir

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.

Fosamprenavir
Clinical data
Trade namesLexiva, Telzir
AHFS/Drugs.comMonograph
MedlinePlusa604012
License data
Pregnancy
category
  • US: C (Risk not ruled out)
    Routes of
    administration    		Oral
    ATC code
    Legal status
    Legal status
    Pharmacokinetic data
    BioavailabilityUnknown
    Protein binding90%
    MetabolismHydrolysed to amprenavir and phosphate in GI tract epithelium
    Elimination half-life7.7 hours
    ExcretionFecal (as metabolites of amprenavir)
    Identifiers
    CAS Number
    PubChem CID
    DrugBank
    ChemSpider
    UNII
    KEGG
    ChEMBL
    NIAID ChemDB
    CompTox Dashboard (EPA)
    Chemical and physical data
    FormulaC25H36N3O9PS
    Molar mass585.608 g/mol
    623.700 g/mol (calcium salt) g·mol−1
    3D model (JSmol)
     NY (what is this?)  (verify)

    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]

    References
    1. Eron J Jr; Yeni P; Gathe J Jr; et al. (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.
    2. Jasek, W, ed. (2007). Austria-Codex (in German) (62nd ed.). Vienna: Österreichischer Apothekerverlag. pp. 8009–17. ISBN 978-3-85200-181-4.
    3. Drugs.com: Lexiva Monograph.
    4. Shen, C. H.; Wang, Y. F.; Kovalevsky, A. Y.; Harrison, R. W.; Weber, I. T. (2010). "Amprenavir complexes with HIV-1 protease and its drug-resistant mutants altering hydrophobic clusters". FEBS Journal. 277 (18): 3699–3714. doi:10.1111/j.1742-4658.2010.07771.x. PMC 2975871. PMID 20695887.
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