Preclinical Pharmacology and Pharmacokinetics of GW433908 a Water-Soluble Prodrug of the Human Immunodeficiency Virus Protease Inhibitor Amprenavir

摘要

is the water-soluble, phosphate ester prodrug of the human immunodeficiency virus type 1 protease inhibitor amprenavir (APV). A high-yield synthesis of is achieved by phosphorylation of the penultimate precursor of APV with phosphorous oxychloride (POCl3) in pyridine. A single-dose pharmacokinetic study of sodium salt in dogs showed that APV exposure was similar to that achieved with an equivalent molar dose of the APV clinical formulation (Agenerase) and that systemic exposure to the prodrug was minimal (0.3% of the APV exposure). However, the sodium salt of was a hygroscopic, amorphous solid and thus not suitable for pharmaceutical development. The calcium salt was a developable crystalline solid, but oral dosing afforded only 24% of the APV exposure in dogs compared with Agenerase. Acidification of the dog stomach by coadministration of HCl increased the bioavailability of the calcium salt to levels near those of the sodium salt. Single-dose administration of calcium salt in dogs and rats produced portal vein concentrations that were maximally 1.72 and 0.79% of those of APV concentrations, respectively. Furthermore, had poor transepithelial flux and APV showed significant flux across human-derived Caco-2 cell monolayers (a model of intestinal permeability). Taken together, these results suggest that is primarily metabolized to APV at or in the epithelial cells of the intestine and that the prodrug is not substantially absorbed. Based in part on these findings, was advanced to clinical development.