A phase I trial of the pharmacokinetics, toxicity, and activity of KNI-272, an inhibitor of HIV-1 protease, in patients with AIDS or symptomatic HIV infection

The pharmacokinetics, toxicity, and activity of KNI-272, a transition state inhibitor of HIV-1 protease, was assessed in a phase 1 trial. After an ini tial phase in which the pharmacokinetics were assessed, 37 patients with AI DS or symptomatic HIV infection and 100-400 CD4 cells/mm(3) were entered in an escalating dose study. KNI-272 was administered four times daily for up to 12 weeks. Oral bioavailability ranged from 22 to 55% and was not apprec iably different in the fasting and post-prandial state. The dose limiting t oxicity was hepatic transaminase elevation; this could be reduced by escala ting the dose over 4 weeks. When administered this way, the maximum tolerat ed oral dose was 40 mg:kg per day. At the highest two tolerated doses (26.4 and 40 mg/kg per day), there was some evidence of an anti-HIV effect with median decreases of 0.2-0.3 log(10) copies:ml plasma HIV RNA; these decreas es persisted through 7-8 weeks of treatment. There was an upward trend in t he CD4 count at the 40 mg/kg per day dose but not at other doses. Additiona l studies focused on approaches to improve the therapeutic index of KNI-272 may be warranted. (C) 1999 Elsevier Science B.V. All rights reserved.