Pharmacokinetics of GW433908, a Prodrug of Amprenavir, in Healthy Male Volunteers

These two Phase I, open‐label, single‐dose, randomized, crossover studies in 40 healthy male subjects investigated the pharmacokinetic and safety profiles of various formulations of the amprenavir prodrug GW433908 in the presence and absence of food compared with amprenavir capsules. GW433908 is a phosphate ester prodrug of the antiretroviral protease inhibitor amprenavir, with improved solubility over the parent molecule and a potential for reduced pill burden on current dosing regimens. The calcium salt of the prodrug, GW433908G, was selected for further investigation, as it appeared to offer the greatest potential for the development of new drug formulations. In the fasting state, (1) GW433908G tablet and suspension were bioequivalent in terms of both AUC and C max' and (2) GW433908G tablet and suspension were bioequivalent to amprenavir capsules for AUC; however, C max was lower with GW433908G. After a high‐fat meal compared with fasting, (1) the bioavailability of GW433908G suspension was decreased by 20% and C max by 41%, and (2) for GW433908G tablets, there was no influence on AUC (12% lower C max ). After a low‐fat meal compared with fasting, (1) there was bioequivalence for GW433908G tablets, but (2) bioavailability was decreased by 23% for amprenavir capsules (C max was also lower, by 46%). Overall, for GW433908G and amprenavir capsules, food had a negligible influence on plasma concentration at 12 hours postdose (C 12 ). Whether administered as tablets or suspension, GW433908G pharmacokinetics was only slightly affected by food. GW433908G tablets were well tolerated and delivered plasma amprenavir concentrations equivalent to the recommended therapeutic amprenavir dose but with fewer tablets. The possibility of a lower pill burden offered by GW433908 may be of clinical benefit in the treatment of HIV infection.