CONCISE COMMUNICATION Hollow-Fiber Unit Evaluation of a New Human Immunode®ciency Virus Type 1 Protease Inhibitor, BMS-232632, for Determination of the Linked Pharmacodynamic Variable

BMS-232632 is a potent human immunode®ciency type 1 (HIV-1) protease inhibitor with a half-life that allows for once-daily dosing. A concentration of 4 times the viral 50 % effective concentration (EC50 [i.e., »EC95]) administered as a continuous infusion in vitro provides virtually complete suppression of viral replication. This exposure, modeled in vitro as once-daily administration with oral absorption, allows ongoing viral replication. An exposure 4 times as large was calculated to be necessary to provide virus suppression equivalent to the continuous-infusion exposure. These experiments demonstrated that concentration above a threshold ( ) is the pharmacodynamically linked variable for this HIV-1 pro-time 1 4 3 EC50 tease inhibitor. Protein-binding experiments demonstrated that the EC50 was increased 13.4 times by the addition of human binding proteins. Monte Carlo simulation of protein bind-ing±adjusted pharmacokinetic data from volunteers demonstrated that 64%±70 % of a simu-lated population ( ) would achieve virus suppression with 400±600 mg of BMS-232632n p 3000 given once daily, if the viral EC50 were <1 nM. BMS-232632 is a new human immunode®ciency virus type 1 (HIV-1) protease inhibitor with potent activity and activit