Case Study: Fosamprenavir: A Prodrug of Amprenavir

Abstract

Fosamprenavir (Lexiva^®) is a phosphate ester prodrug of the antiretroviral protease inhibitor amprenavir (Agenerase^®). Amprenavir is a white-to-cream-colored solid with a solubility of approximately 0.04 mg/mL in water at 25°C. It was originally marketed as an oral solution at a concentration of 15 mg/mL that included a variety of excipients, such as acesulfame potassium, artificial grape bubblegum flavor, citric acid, TPGS, menthol, natural peppermint flavor, polyethylene glycol 400, propylene glycol, saccharin sodium, sodium chloride, and sodium citrate (GlaxoSmithKline, 2004). Because the recommended amprenavir regimen is 1200 mg twice daily (equal to 80 mL b.i.d.), the large amount of excipients (propylene glycol in particular) in the oral solution posed potential toxicity problems and prohibited its usage in infants and children under the age of 4 years and in certain other patient populations. Amprenavir is also formulated as capsules in strengths of 50 and 150 mg (GlaxoSmithKline, 2002). The content of vitamin E as TPGS in amprenavir capsules (daily dose of 1744 IU) far exceeds the Reference Daily Intake (adults 30 IU, pediatrics 10 IU). Patients are advised not to take additional vitamin E. To reduce the excipient intake and the burden of 8 capsules twice daily, fosamprenavir was designed as a more watersoluble prodrug (0.31 mg/mL in water at 25°C) of amprenavir (Gatell, 2001), which required only two tablets twice a day.