Improved Aqueous Solubility

For compounds suffering from dissolution rate or solubility limited absorption due to low aqueous solubility and/or high therapeutic dose introduction of a hydrophilic moiety may prove beneficial for the oral bioavailability. The most appealing type of prodrugs to overcome solubility problems are the phosphate esters because they are generally chemically stable and at the same time enzymati-cally labile and, furthermore, because the solubility increase obtained by phosphate esters can be of several orders of magnitude.

The protease inhibitor amprenavir suffers from a combination of low aqueous solubility (0.04 mg/mL) and high dose requirements (1200 mg BID corresponding to eight capsules of the marketed product). Thus, Vertex Pharmaceuticals together with GlaxoSmithKline developed the phosphate ester prodrug fosamprenavir (Figure 9.8) with the aim of increasing the oral bioavailability of the parent drug. Fosamprenavir is rapidly and extensively hydrolyzed by alkaline phos-phatases at the brush border of the gastrointestinal tract during or after absorption to yield the parent active drug, amprenavir. Only minimal amounts of intact fosamprenavir reach the systemic circulation. The development of fosamprenavir has reduced the "pill burden" for HIV patients considerably and the prodrug can be administered without any food or water restrictions.

FIGURE 9.8 Fosamprenavir.

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