Pablo Morentin Gutierrez, James Yates, Catarina Nilsson
AstraZeneca
Objectives: Measuring plasma triglyceride (TAG) by means of an Oral-Lipid-Tolerance-Test (OLTT) can determine the efficiency with which the individual uses lipid components that are linked with cardiovascular diseases. However, despite the wide use of OLTT in the development of potential new treatments, very limited PK/PD analysis of this type of data has been carried limiting the precision and power of the analysis of the data generated. A novel PK/PD model that describes the magnitude and duration of the effect of AZD7687[1] in the plasma TAG during an OLTT setting in humans, rats and mice is therefore proposed
Methods: AZD7687 is an inhibitor of acyl-CoA:diacylglycerol acyltransferase (DGAT1), which is involved in lipid absorption. PK and Plasma TAG time course data during OLTT following AZD7687 treatment was obtained both in animals and in humans[2,3]. In the PK/PD model, the introduction of exogenous TAG into the system is represented by a first order process from the lipid depot compartment (assumed to be the gut) to the central compartment (plasma). In addition, there is an endogenous production and removal of TAG from plasma described with a turnover model. It is postulated that AZD7687 inhibits the contribution of exogenous TAG into circulation. 1 or 2 compartment models with first order absorption was used to describe the PK of AZD7687 for the different species. Non-linear mixed effect modelling implemented in Phoenix NLME 1.3[4] was used to fit the model to the PK and TAG data
Results: PK was well described by the models used. The magnitude and duration of the effects of AZD7687 in the plasma TAG time course in an OLTT were very well captured by the model in all the species. Inter-individual variability was also adequately captured by the model. The resulting in vivo IC50s for AZD7687 in the new model were in very good agreement with previously published values (for rat[1] and human[2]) using more limited PK/PD analysis
Conclusions: This modelling approach provides a deeper understanding of the magnitude and time course of change on the plasma TAG excursion during an OLTT after treatment of AZD7687. It also provides a numerical quantification of the “in vivo” potency of the drug allowing robust comparison of the efficacy of AZD7687 across species as well as tools to simulate the expected results under different dosing schedules. Finally, the system parameters on the model can now will facilitate simulations for other compounds
References:
[1] J.G. Barlind, U.A. Bauer, A.M. Birch, S. Birtles, L.K. Buckett, R.J. Butlin, et al. Design and Optimization of Pyrazinecarboxamide-Based Inhibitors of Diacylglycerol Acyltransferase 1 (DGAT1) Leading to a Clinical Candidate Dimethylpyrazinecarboxamide Phenylcyclohexylacetic Acid (AZD7687). J. Med. Chem. 2012, 55:10610−10629
[2] H. Denison, C. Nilsson, M. Kujacic, L. Lofgren, C. Karlsson, M. Knutsson. Proof of mechanism for the DGAT1 inhibitor AZD7687: Results from a first-time-in-human single-dose study. Diabetes, Obesity and Metabolism. 2013, 15:136-143
[3] H. Denison, C. Nilsson, L. Lofgren, A. Himmelmann, G. Martensson, M. Knutsson. Diacylglycerol acyltransferase 1 inhibition with AZD7687 alters lipid handling and hormone secretion in the gut with intolerable side effects: a randomized clinical trial. Diabetes, Obesity and Metabolism. 2014, 16: 334–343.
[4] Pharsight, Certara USA, Inc, 100 Overlook Center, Suite 101, Princeton, NJ 08540 USA
Reference: PAGE 25 (2016) Abstr 5701 [www.page-meeting.org/?abstract=5701]
Poster: Drug/Disease modeling - Other topics