James Lu (1), Katrin Hübner (2), Norman Mazer (1)
(1) Modeling and Simulation, Translational Research Sciences, F. Hoffman-La Roche Ltd., Basel, Switzerland; (2) Department of Modeling Biological Processes, BioQuant, University of Heidelberg, Heidelberg, Germany
Objectives: The Cholesterol Ester Transfer Protein (CETP) mediates the transfer of cholesteryl esters (CE) and triglycerides (TG) between lipoprotein particles and hence plays a critical role in reverse cholesterol transport. In order to better understand as well as predict the effects of CETP inhibitors and modulators on lipid profiles, a more precise characterization of the lipid transfer mechanism is needed.
Methods: We have implemented a previously published, mechanistic model that describes lipid transfer processes at the level of individual lipoprotein particles [1]. Given a set of values for the kinetic rate parameters, the model can then be simulated stochastically using a variant of the Next Reaction Method, from which the stationary density profiles of the lipoprotein particles and their constituents are obtained by averaging the particle distribution over time. The flexibility of the modelling framework enables a precise formulation of the mechanisms of particle interactions and hence allows one to explore different hypotheses.
In order to simulate pharmacological effects of CETP inhibitors and modulators on the lipid profiles, we first need to differentiate between the existing candidate mechanisms of lipid transfer. To explore the plausibility of various CETP transfer mechanisms, we additionally compared model predictions to literature data on cholesterol fluxes between HDL, VLDL and LDL particles, cholesterol (C) levels in CETP deficiency states and the effects of hypertriglyceridemia on HDL-C levels.
Results: While both the uncoupled exchange and coupled (swapping) mechanisms of CETP mediated transfer can reproduce both the lipid concentrations in HDL and ApoB-containing particles as well as the flux measurement data, the former cannot explain the observed inverse relationship between HDL-C and TG levels in hypertriglyceridemic patients. Analysis of the model with the swapping mechanism suggests that some form of coupling between the CE and TG transfers is needed in the CETP module.
Conclusions: The lipid concentration data from CETP deficient and hypertriglyceridemic patients can discriminate between different mechanisms of CETP mediated lipid transfer within our model of lipoprotein metabolism and kinetics. Once the LMK model is fully calibrated, we plan to translate its detailed, stochastic description to an ODE representation within NONMEM in order to analyse clinical data.
References:
[1] Hübner K et al. PLoS Comput Biol. 2008 May 23;4(5).
Reference: PAGE 21 (2012) Abstr 2386 [www.page-meeting.org/?abstract=2386]
Poster: Other Drug/Disease Modelling