Open AccessAnalysis of “On/Off” Kinetics of a CETP Inhibitor Using a Mechanistic Model of Lipoprotein Metabolism and Kinetics
Author(s) -
Lu J,
Cleary Y,
Maugeais C,
Kiu Weber CI,
Mazer NA
Publication year - 2015
Publication title -
cpt: pharmacometrics and systems pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.53
H-Index - 37
ISSN - 2163-8306
DOI - 10.1002/psp4.27
Subject(s) - cholesterylester transfer protein , kinetics , chemistry , pharmacokinetics , cholesterol , apolipoprotein b , lipoprotein , metabolism , endocrinology , medicine , high density lipoprotein , pharmacology , biochemistry , biology , physics , quantum mechanics
RG7232 is a potent inhibitor of cholesteryl‐ester transfer protein (CETP). Daily oral administration of RG7232 produces a dose‐ and time‐dependent increase in high‐density lipoprotein‐cholesterol (HDL‐C) and apolipoproteinA‐I (ApoA‐I) levels and a corresponding decrease in low‐density lipoprotein‐cholesterol (LDL‐C) and apolipoproteinB (ApoB) levels. Due to its short plasma half‐life (∼3 hours), RG7232 transiently inhibits CETP activity during each dosing interval (“on/off” kinetics), as reflected by the temporal effects on HDL‐C and LDL‐C. The influence of RG7232 on lipid‐poor ApoA‐I (i.e., pre‐ β 1 ) levels and reverse cholesterol transport rates is unclear. To investigate this, a published model of lipoprotein metabolism and kinetics was combined with a pharmacokinetic model of RG7232. After calibration and validation of the combined model, the effect of RG7232 on pre‐ β 1 levels was simulated. A dose‐dependent oscillation of pre‐ β 1 , driven by the “on/off” kinetics of RG7232 was observed. The possible implications of these findings are discussed.