These two Phase I, open-label, single-dose, randomized, crossoverstudies in 40 healthymale 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 Cmax, and (2)
GW433908G tablet and
suspension were bioequivalent to
amprenavir capsules for AUC; however, Cmax was lower with
GW433908G. After a high-fat meal compared with fasting, (1) the bioavailability of
GW433908G suspension was decreased by 20% and Cmax by 41%, and (2) for
GW433908G tablets, there was no influence on AUC(12% lower Cmax). 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 (Cmax was also lower, by 46%). Overall, for
GW433908G and
amprenavir capsules, food had a negligible influence on plasma concentration at 12 hours postdose (C12). 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.