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Abstract: FR-PO177

Quantitative Systems Pharmacology Model of Metabolic Bone Disorder and Vascular Calcification in CKD

Session Information

Category: Bone and Mineral Metabolism

  • 402 Bone and Mineral Metabolism: Clinical

Authors

  • Mcbride, Devin Elise, University of Louisville, Louisville, Kentucky, United States
  • Gaweda, Adam E., University of Louisville, Louisville, Kentucky, United States
  • Brier, Michael E., University of Louisville, Louisville, Kentucky, United States
  • Lederer, Eleanor D., University of Louisville; Robley Rex VA Medical Center, Louisville, Kentucky, United States
Background

Changes in Calcium (Ca) and Phosphorus (P) metabolism in patients with Chronic Kidney Disease (CKD) and the associated Mineral Bone Disorder (MBD) and Vascular Calcification (VC) pose significant morbidity and mortality risk in this patient population. We propose a Quantitative Systems Pharmacology (QSP) model of CKD-related MBD / VC to enable precision dosing of pharmacologic agents used in treatment of these conditions.

Methods

Based on the published data, we developed a QSP model of Ca / P metabolism. The model represents the movement of Ca and P between serum, gut, bone, kidney, and the soft tissue. The model also includes the FGF23 pathway and the effects of calcimimetic, vitamin D, and P binders. We validated the model against recently published clinical data describing the effect of CKD on the markers of MBD progression. We also investigated the ability of the model to predict different treatment effects in a virtual CKD patient.

Results

The impact of kidney function decline on Ca, P, PTH, Calcitriol, FGF23, and the Ca fluxes between serum, bone, and soft tissue predicted by the model is shown in the six plots below. The model correctly captures the decrease in serum Ca and the increase in P and PTH. In addition, the model correctly identifies the changes in Calcitriol and FGF23. Predicted changes in bone-to-serum and serum-to-soft tissue Ca fluxes are consistent with the pathophysiology of CKD-MBD/VC. The effects of combined P binder, Calcitriol, and a calcimimetic administration are consistent with the expected mechanism of action.

Conclusion

We propose a QSP model of Ca / P homeostasis and their effect on bone and vascular health. Validation against published clinical data proves the feasibility of the model. The model will be used to benchmark personalized treatment options to minimize the impact of MBD/VC in CKD patients.

Predicted levels of Ca, P, PTH, Calcitriol, FGF23, and the Ca fluxes between serum, bone, and soft tissue at different levels of CKD.

Funding

  • Veterans Affairs Support