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Fosamprenavir

Clinical Pharmacokinetics and Drug Interactions of the Amprenavir Prodrug

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Abstract

Fosamprenavir is one of the most recently approved HIV-1 protease inhibitors (Pis) and offers reductions in pill number and pill size, and omits the need for food and fluid requirements associated with the earlier-approved HIV-1 PIs. Three fosamprenavir dosage regimens are approved by the US FDA for the treatment of HIV-1 PI-naive patients, including fosamprenavir 1400mg twice daily, fosamprenavir 1400mg once daily plus ritonavir 200mg once daily, and fosamprenavir 700mg twice daily plus ritonavir 100mg twice daily. Coadministration of fosamprenavir with ritonavir significantly increases plasma amprenavir exposure. The fosamprenavir 700mg twice daily plus ritonavir 100mg twice daily regimen maintains the highest plasma amprenavir concentrations throughout the dosing interval; this is the only approved regimen for the treatment of HIV-1 PI-experienced patients and is the only regimen approved in the European Union.

Fosamprenavir is the phosphate ester prodrug of the HIV-1 PI amprenavir, and is rapidly and extensively converted to amprenavir after oral administration. Plasma amprenavir concentrations are quantifiable within 15 minutes of dosing and peak at 1.5–2 hours after fosamprenavir dosing. Food does not affect the absorption of amprenavir following administration of the fosamprenavir tablet formulation; therefore, fosamprenavir tablets may be administered without regard to food intake. Amprenavir has a large volume of distribution, is 90% bound to plasma proteins and is a substrate of P-glycoprotein.

With <1% of a dose excreted in urine, the renal route is not an important elimination pathway, while the principal route of amprenavir elimination is hepatic metabolism by cytochrome P450 (CYP) 3A4. Amprenavir is also an inhibitor and inducer of CYP3A4. Furthermore, fosamprenavir is commonly administered in combination with low-dose ritonavir, which is also extensively metabolised by CYP3A4, and is a more potent CYP3A4 inhibitor than amprenavir.

This potent CYP3A4 inhibition contraindicates the coadministration of certain CYP3A4 substrates and requires others to be coadministered with caution. However, fosamprenavir can be coadministered with many other antiretroviral agents, including drugs of the nucleoside/nucleotide reverse transcriptase inhibitor, non-nucleoside reverse transcriptase inhibitor and HIV entry inhibitor classes. Coadministration with other HIV-1 PIs continues to be studied.

The extensive fosamprenavir and amprenavir clinical drug interaction information provides guidance on how to coadminister fosamprenavir and fosamprenavir plus ritonavir with many other commonly coprescribed medications, such as gastric acid suppressants, HMG-CoA reductase inhibitors, antibacterials and antifungal agents.

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Notes

  1. The use of trade names is for product identification purposes only and does not imply endorsement.

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Acknowledgements

No sources of funding were used to assist in the preparation of this review. All authors are employees of Glaxo-SmithKline, the company that manufactures and markets fosamprenavir.

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  1. Division of Clinical Pharmacology & Discovery Medicine (CPDM), GlaxoSmithKline, Research Triangle Park, North Carolina, USA

    Mary Beth Wire & Mark J. Shelton

  2. Division of Drug Metabolism & Pharmacokinetics (DMPK), GlaxoSmithKline, Research Triangle Park, North Carolina, USA

    Scott Studenberg

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  1. Mary Beth Wire
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  2. Mark J. Shelton
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Correspondence to Mary Beth Wire.

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Wire, M.B., Shelton, M.J. & Studenberg, S. Fosamprenavir. Clin Pharmacokinet 45, 137–168 (2006). https://doi.org/10.2165/00003088-200645020-00002

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