PHASE I II STUDY OF THE TOXICITY, PHARMACOKINETICS, AND ACTIVITY OF THE HIV PROTEASE INHIBITOR SC-52151/

SC-52151, an HN-I protease inhibitor, was developed as an ethanol-base d elixir and subsequently as a self-emulsifying drug delivery, system (SEDDS) to improve bioavailability. To evaluate formulation and treatm ent regimen effects, we conducted a four-arm, phase I/II study using t he highest previously tested daily dose, 2250 mg, Forty-nine patients received the elixir or SEDDS at a dosage of 750 mg three times daily o r 1125 mg twice daily for 14 days. One patient developed hypertriglyce ridemia, and one had fever and dyspnea. The SEDDS formulation compared with the elixir resulted in a larger area under the concentration-tim e curve (AUC, p < 0.001), peak (Cmax, p = 0.041) and trough (Cmin, p = 0.025). Twice-daily administration compared with administration three times daily produced a higher cumulative AUC (p = 0.008). Both SEDDS regimens produced mean plasma concentrations above the 90% inhibitory concentration (IC90) for HN. A mean decline of 0.03 log(10) RNA copies (SEDDS) and an increase of 0.15 log(10) (elixir were observed. Althou gh SC-52151 was well tolerated and the SEDDS formulation resulted in p lasma concentrations above the IC90 for viral replication, no antivira l activity was produced.