Hollow‐Fiber Unit Evaluation of a New Human Immunodeficiency Virus Type 1 Protease Inhibitor, BMS‐232632, for Determination of the Linked Pharmacodynamic Variable

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Abstract
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., ∼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×EC50) is the pharmacodynamically linked variable for this HIV-1 protease 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 ⩽1 nM

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