(416c) A PK/PD Model of ACE Inhibition in Kidney Cells for Treatment of Diabetic Tissue Damage

Diabetes is the primary cause of chronic kidney disease (CKD). High glucose conditions have been known to initiate and exacerbate the pathophysiology of CKD particularly through damage to podocytes. Podocytes are terminally differentiated renal cells that play a key role in maintaining the structure and function of the kidneys. Podocytes express a local renin-angiotensin system (RAS) that is altered in diabetes. Studies have shown that Angiotensin II (ANG II), a blood pressure regulating hormone, produced by the RAS is upregulated in diabetic conditions and triggers podocyte injury and apoptosis. Angiotensin converting enzymes (ACE) inhibitor drugs inhibit the production of ANG II. However, these drugs are not well characterized for use in CKD. The progression of CKD could be slowed by controlling the ANG II levels to prevent irreversible podocyte loss. Due to sparse experimental evidence for glucose-dose-dependency of ANG II, especially for podocytes, we propose and parameterize a mathematical model to describe the glucose-stimulated RAS in podocytes that produces ANG II. The model can connect drug concentration to the inhibition of the ANG II in RAS in podocytes for the ACE inhibitor drugs in the cases of normal and impaired renal function.

We define a model for the pharmacokinetic RAS network that triggers the synthesis of ANG II and the pharmacodynamic physiological response to ACE inhibitors in a time and dose-dependent manner for normal and impaired kidney. The model takes glucose dynamics and drug dosage as the input. The glucose-sensitive podocyte RAS pathway is represented by a system of ordinary differential equations to track ANG II and other RAS peptides. Glucose-dependence is added through different enzyme activity parameters. A one-compartment model with first-order absorption from the site of administration and first-order elimination is used here for the oral administration of ACE inhibitor drugs. Previous experimental studies are used to estimate the unknown parameters and kinetic constants for the model. The parameters are analyzed by local and global sensitivity analyses along with other validation cases. MATLAB is used to solve the system of ordinary differential equations, fit parameters to data, and to develop a graphical user interface (GUI).

The model fits a mathematical function to experimental data for glucose dynamics and uses it to predict the corresponding change in ANG II concentrations with the pharmacokinetic RAS network model. The pharmacodynamic part of the model shows that ANG II concentration is lowered by the drugs. The model is used to explore the effects of different drug dosage on the levels of the diacid form of the drug and ANG II in diabetic or normal patients with normal or impaired kidney function over time. 

We have developed a physiologically relevant PK/PD model for ACE inhibition parameterized for local RAS in podocytes for drugs in normal and impaired renal conditions. The model can use experimental data for glucose dynamics from normal and diabetic subjects and predict the dosage for each drug in normal or impaired kidney to control the ANG II levels. The model is packaged as a MATLAB app to facilitate reuse for research and educational purposes. The result of this work will enable further studies on the impacts of ACE inhibition in chronic kidney disease or other diseases.