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 (IC₅₀: 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.