Hollow-fiber unit evaluation of a new human immunodeficiency virus type 1 protease inhibitor, BMS-232632, for determination of the linked pharmacodynamic variable

BMS- 232632 is a potent human immunodeficiency 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., similar to 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 (time > 4 x EC50) is the pharmacodynamically linked variable for this HIV-1 pro-time 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 binding- adjusted pharmacokinetic data from volunteers demonstrated that 64%- 70% of a simulated population (n = 3000) would achieve virus suppression with 400-600 mg of BMS-232632 given once daily, if the viral EC50 were less than or equal to 1 nM.