A Quantitative Systems Pharmacology Model Provides Insights into Phosphate Homoeostasis through Multiple Interacting Pathways
Kirill Peskov (1), Artem Demidenko (1), Aleksander Dorodnov (1),Oleg Demin (1), and Balaji Agoram (2)
(1) Institute for Systems Biology SPb, Moscow, Russia; (2) MedImmune
Objectives: Phosphate is an important mineral required for numerous cellular functions such as DNA and membrane lipid synthesis, generation of high energy phosphate esters, and intracellular signalling. However, an integrated understanding of phosphate regulation, the various control mechanisms, and interactions between the mechanisms is not available yet. We describe here the first attempt, to our knowledge, to develop an integrated quantitative understanding of the factors responsible for endogenous phosphate regulation.
Methods: Based on Bergwitz (2010), a minimal model consisting of bone, serum, parathyroids, intestine, and kidney tissues and fibroblast growth factor (FGF) 23, parathyroid hormone (PTH), VitaminD, and phosphate entities was developed. The known dependencies (Ben-Gov 2007) were hypothesised based on literature and quantitatively characterised based on available data. The individual submodels were integrated to provide a unified model of phosphate homoeostasis. Model predictions were verified with available literature data on therapies known to impact phosphate levels (e.g. FGF23, and FGFR modulators) and from human genetic disorders. We then used the model to simulate single and multiple dose phosphate changes for different FGFR modulators that can potentially alter endogenous phosphate levels.
Results: All individual submodels provided adequate descriptions of isolated interactions. The magnitude, but not time course of Vit D changes after FGFR modulation was predicted correctly. The integrated model provided good descriptions of literature-reported changes in phosphate, and Vit D levels after FGFR therapy. FGFR-subtype specific modulators had generally different VitD and phosphate effects. The contribution of PTH to overall phosphate homoeostasis was found to be not significant compared to that of bone (through FGF23).
Conclusions: A minimal quantitative system pharmacology model of phosphate homoeostasis was developed. The model can be used to evaluate the potential effect of various therapeutic options affecting the phosphate homoeostasis pathway.
 Bergwitz and Juppner Annu Rev Med (2010) 2. Ben-Gov J. Clin Inv (2007).