141W94 (VX-478) was synthesized by Vertex Pharmaceuticals, Inc. and has been licensed for development by Glaxo Wellcome, Inc. and Kissei Pharmaceuticals. It is a potent and specific inhibitor of HIV protease with in vitro IC 5 0 s of 0.084 and 0.080 μM against HIV-1 I I I B in MT-4 cells and PBLs, respectively, and mean IC 5 0 s of 0.012 and 0.019 μM against six zidovudine-sensitive and three zidovudine-resistant clinical isolates, respectively, evaluated in PHA-stimulated PBLs. In a previous clinical study, 141W94 was well tolerated by HIV-infected volunteers at single, oral doses between 150 and 1200 mg. The present study is an open-label, Phase I/II trial designed to evaluate the pharmacokinetics of multiple doses of 141W94 administered alone for four weeks to patients with CD 4 lymphocyte counts between 150 and 400 cells/mm 3 . Plasma samples were obtained 0 (per-dose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 hours after the first dose of 141W94. Subsequent doses were withheld until after the 24 hour plasma sample. After three weeks of multiple-dose treatment, plasma samples were obtained over a steady-state dosing interval at 0 (pre-dose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, and 12 hours after dosing. The 10 and 12 hour samples are collected only from patients receiving 141W94 b.i.d. Samples are assayed for 141W94 using a validated HPLC method and pharmacokinetic parameters calculated by model-independent methods. Comparisons of AUC 0 → ∞ after the first dose with AUC s s at steady-state provide information that can be used to select dosing regimens for subsequent studies. Data will be presented from a full cohort of ten HIV-infected patients, all of whom have now completed four weeks of therapy with 141W94 at 300 mg b.i.d. These data constitute the first report of multiple dosing of 141W94 in HIV-infected patients.