Evolving data analysis of an Oral Lipid Tolerance Test toward the standard for the Oral Glucose Tolerance Test: Cross species modeling effects of AZD7687 on plasma triacylglycerol

Abstract

We have developed a novel mechanistic pharmacokinetic-pharmacodynamic (PK/PD) model to describe the time course of plasma triglyceride (TAG) after Oral Lipid Tolerance Test (OLTT) and the effects of AZD7687, an inhibitor of diacylglycerol acyltransferase 1 (DGAT1), in humans, rats, and mice. Pharmacokinetic and plasma TAG data were obtained both in animals and in two phase I OLTT studies. In the PK/PD model, the introduction of exogenous TAG is represented by a first order process. The endogenous production and removal of TAG from plasma are described with a turnover model. AZD7687 inhibits the contribution of exogenous TAG into circulation. One or two compartment models with first order absorption was used to describe the PK of AZD7687 for the different species. Nonlinear mixed effect modeling was used to fit the model to the data. The effects of AZD7687 on the plasma TAG time course during an OLTT as well as interindividual variability were well described by the model in all three species. Meal fat content or data from single vs repeated dosing did not affect model parameter estimates. Body mass index was found to be a significant covariate on the plasma TAG baseline. The system parameters of the model will facilitate analysis for other compounds and provide tools to bring the standard of OLTT data analysis closer to the analyses of Oral Glucose Tolerance Test data maximizing knowledge gain.

Keywords: AZD7687; DGAT1; mechanistic modeling; nonlinear mixed effect modeling; oral lipid tolerance test; pharmacodynamics; pharmacokinetics; triglyceride.

Figure 1

Schematic representation of the PK/PD model. Refer to equations 1‐4 for abbreviations

Figure 2

Goodness of fit plot for plasma TAG in human SAD study treated with 60% fat SMM. Plots available for all treatment groups in SAD and MAD in supplementary section S3. 1000 data sets were simulated. Red line is the median and dotted lines are the 95% prediction intervals of the individual plasma TAG‐time profiles. Observed data is plotted as dots. In the SAD study subjects were fed the 60% fat SMM at 0h (baseline) and 28h post the first visit. Plotted by dose level (1, 2.5, 5, 10, 20 mg and placebo)

Figure 3

Goodness of fit plot for plasma TAG in rat. 1000 data sets were simulated. Red line is the median and dotted lines are the 95% prediction intervals of the individual plasma TAG‐time profiles. Observed data is plotted as dots. OLTT challenge (corn oil at 5 mL/kg) was performed 2h after compound dosing. Plotted by dose group (0.1, 0.3, 3 mg/kg, Naïve (i.e. no lipid challenge) and Vehicle)

Figure 4

Goodness of fit plot for plasma TAG in mouse. 1000 data sets were simulated. Red line is the median and dotted lines are the 95% prediction intervals of the individual plasma TAG‐time profiles. Observed data is plotted as triangles. OLTT challenge (Intralipos 20% at 10 mL/kg) was performed 0.5h after compound dosing. Plotted by dose group (0.1, 1, 3 mg/kg, and Vehicle)