A Systems Pharmacology Model of Erythropoiesis in Mice Induced by Small Molecule Inhibitor of Prolyl Hydroxylase Enzymes

Mammalian erythropoiesis is a conserved process tightly controlled by the hypoxia-inducible factor (HIF1) pathway. In this study, a small molecule inhibitor (PHI-1) of prolyl-hydroxylase-2 (PHD2) enzyme involved in regulating HIF1α levels was orally administered to male BALB/c mice at 10 and 30 mg/kg. A systems pharmacology model was developed based on the measured PHI-1 plasma exposures, kidney HIF1α, kidney erythropoietin (EPO) mRNA, plasma EPO, reticulocyte counts, red blood cells, and hemoglobin levels. The model fit resulted in the estimation of drug potency (IC(50): 1.7μM), and systems parameters such as EPO mRNA turnover (k(deg_EPOmRNA): 0.43 hr(-1)) and mean lifespan of reticulocytes (T(r): 81 hours). The model correctly described the observed 30–40-fold increase in kidney HIF1α protein, ∼1,000 fold increase in EPO mRNA and 2–3-fold increase in the reticulocytes at 30 mg/kg. This study presents the first parsimonious systems model of erythropoiesis to quantitatively describe the in vivo effects of PHD2 inhibition.