ABSTRACT:
PNU-140690, a potent, non-peptidic HIV protease inhibitor, was well tolerated in healthy volunteers after single oral doses ranging from 100 to 2000 mg. In this multiple-dose study, healthy subjects aged 19 to 55 years were sequentially exposed in groups of 8 (2 as placebo) to
300, 600, 900, 1200,1600, or 2000 mg PNU-140690 disodium salt capsules as a single dose on Day 1, followed by TID dosing on Days 3-12. Safety laboratory tests, cardiac telemetry, and adverse events were recorded. Plasma samples were assayed for PNU-140690 using a validated HPLC method. PNU-140690 was generally well tolerated after 9.3 days of multiple dosing; the primary adverse events were mild to moderate diarrhea and mild nausea and abdominal cramps. In the 2000-mg TID group, two subjects reported vertigo, mood alterations, slowed thinking and movement, and lack of concentration, which resolved after discontinuation of PNU-140690. Drug concentrations after repeated dosing were lower than after a single dose, presumably due to enzyme induction. In the 300- and 600-mg TID groups, apparent oral clearance increased, on average, by two-fold after multiple dosing relative to a single dose; more modest increases in oral clearance, averaging from 2% to 41%, were observed in the higher dose groups. Steady-state trough PNU-140690 concentrations averaged above 1 micromolar, the predicted IC(90), for dose regimens of 900-mg TID and higher.
