Physiologically based pharmacokinetics of KNI-272, a tripeptide HIV-1 protease inhibitor.
The effects of dose on the pharmacokinetic characteristics of KNI-272 were evaluated in rats after intravenous (iv) administration. The plasma kinetics of KNI-272 were dose-independent within a dose range of 1.0 to 10.0 mg/kg. However, when the dose was increased to 50.0 mg/kg, the area under the plasma concentration-time curve (AUC)/dose significantly increased and the total plasma clearance (Cl(tot)) significantly decreased, possibly due to saturation of hepatic metabolism. On the other hand, the terminal elimination half-life (t(1/2,lambda(z))) was independent of dose. Using biochemical and physiological parameters obtained from in vitro and in vivo studies, we developed a physiologically based pharmacokinetic (PBPK) model for KNI-272 in rats in which concentration-dependent nonlinear hepatic metabolism (Michaelis-Menten type metabolism) was considered. Using this PBPK model, plasma KNI-272 concentration-time profiles were simulated. From these profiles it was demonstrated that the terminal elimination phase was proportional to the dose at lower doses. However, as the dose increased to 50.0 mg/kg, the simulated plasma concentrations at the terminal elimination phase increased more than the increase of dose in the same way as the observed data. Accordingly, the dose-dependent plasma kinetics observed after a 50.0 mg/kg dose was considered to be attributable in part to concentration-dependent hepatic metabolism in rats.
Kiriyama
A
A
Department of Pharmacokinetics, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8414, Japan.
Nishiura
T
T
Yamaji
H
H
Takada
K
K
D000818:Animals; D019380:Anti-HIV Agents / Q000097:blood / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D017320:HIV Protease Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D008954:Models, Biological; D009842:Oligopeptides / Q000097:blood / Q000493:pharmacokinetics*; D011237:Predictive Value of Tests; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution
D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D009842:Oligopeptides; C077822:kynostatin 272