title: Analysis of "On/Off" Kinetics of a CETP Inhibitor Using a Mechanistic Model of Lipoprotein Metabolism and Kinetics.
abstract: 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.
authors.affiliation: Roche Pharma Research and Early Development, Clinical Pharmacology, Roche Innovation Center Basel, F. Hoffmann-La Roche Basel, Switzerland.
authors.forename: J
authors.initials: J
authors.lastname: Lu
authors.affiliation: Roche Pharma Research and Early Development, Clinical Pharmacology, Roche Innovation Center Basel, F. Hoffmann-La Roche Basel, Switzerland.
authors.forename: Y
authors.initials: Y
authors.lastname: Cleary
authors.affiliation: Roche Pharma Research and Early Development, Neuroscience, Ophthalmology and Rare Diseases Discovery and Translational Area, Roche Innovation Center Basel, F. Hoffmann-La Roche Basel, Switzerland.
authors.forename: C
authors.initials: C
authors.lastname: Maugeais
authors.affiliation: Global Medical Affairs, F. Hoffmann-La Roche Basel, Switzerland.
authors.forename: C I
authors.initials: CI
authors.lastname: Kiu Weber
authors.affiliation: Roche Pharma Research and Early Development, Clinical Pharmacology, Roche Innovation Center Basel, F. Hoffmann-La Roche Basel, Switzerland.
authors.forename: N A
authors.initials: NA
authors.lastname: Mazer