A Semi-Physiologic Model of Postprandial Triglyceride Response following Anti-Obesity Therapy
Jennifer Leohr(1), Michael Heathman(1), and Maria C. Kjellsson(2)
(1) Pharmacokinetics/Pharmacodynamics and Pharmacometrics, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 462852 (2)Pharmacometrics Research Group, Department of Pharmaceutical Biosciences, Uppsala University, Sweden
Objectives: Obesity is a disorder of chronic positive energy balance, whereby excess of energy intake beyond energy utilization leads to an increase in adipose tissue. The ability of an anti-obesity agent to induce weight loss requires transport of fat from storage depots to sites of utilization. Therefore, a model of triglyceride (TG) transport would further increase understanding of the dynamics of these lipids and improve determination of drug efficacy, the selection of the appropriate dose level for future studies, as well as patient identification. The aim of this study was to quantify the postprandial TG response of chylomicrons (CHO) and large very low-density lipoprotein V6 particles (VLDL-V6) following a high fat meal, as biomarkers of drug pharmacology using a mechanistic PKPD modeling approach. LY was found to cause weight loss by reducing food intake and increasing the oxidation of TG in rodents.
Methods: Data was collected from a single-center, double-blind, randomized, placebo-controlled study evaluating the safety and tolerability of single, escalating, 7 oral doses of LY (5–130mg) in a total of 17 healthy obese subjects (BMI:27.6-37.8 kg/m). The drug exposure data and TG response following the test meal was used to develop the model. Nonlinear mixed-effect modeling was used to analyze the TG in CHO and large VLDL-V6, using NONMEM® and Perl-speaks-NONMEM as the modeling environment.
Results: The LY data was best described by a two-compartment model with first-order elimination. The values of population parameter estimates for CL, V1, Q and V2 were 73.4 L/h, 676 L, 79.6 L/h and 585 L respectively. A model describing the TG data consisted of four compartments: two transit compartments for the lag between meal consumption and appearance of TG in the blood and turn-over models for the CHO and large VLDL-V6, respectively. The rate constants for the absorption of TG (0.62 h-1) and elimination of large VLDL-V6 (1.4 h-1) along with the conversion rate of CHO to large VLDL-V6 (9.3 h-1) were well determined. HOMA-IR was found to be a significant covariate on the conversion rate of CHO to large VLDL-V6. The drug effect of LY was found to decrease the conversion from CHO to VLDL-V6.
Conclusions: This is the first PKPD model that describes the absorption of TG from dietary fats into the blood and identifies the anti-obesity pharmacology on the dynamics of TG in CHO and large VLDL-V6 in obese subjects.