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 (EC(50) [i.e., approximately EC(95)]) 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 > 4xEC50) is the pharmacodynamically linked variable for this HIV-1 protease inhibitor. Protein-binding experiments demonstrated that the EC(50) 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 EC(50) were < or = 1 nM.