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.
Drusano
G L
GL
Division of Clinical Pharmacology, Clinical Research Institute, Albany Medical College, Albany, NY 12208, USA. gldrusano@aol.com
Bilello
J A
JA
Preston
S L
SL
O'Mara
E
E
Kaul
S
S
Schnittman
S
S
Echols
R
R
D000328:Adult; D000069446:Atazanavir Sulfate; D004305:Dose-Response Relationship, Drug; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D017320:HIV Protease Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D009010:Monte Carlo Method; D009842:Oligopeptides / Q000493:pharmacokinetics / Q000494:pharmacology*; D011725:Pyridines / Q000493:pharmacokinetics / Q000494:pharmacology*; D019562:Viral Load; D014779:Virus Replication / Q000187:drug effects
D017320:HIV Protease Inhibitors; D009842:Oligopeptides; D011725:Pyridines; D000069446:Atazanavir Sulfate