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• W2107681929 abstract "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. CPT Pharmacometrics Syst. Pharmacol. (2015) 4, 106–115; doi: 10.1002/psp4.12 ; published online on 11 February 2015." @default.
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• W2107681929 date "2015-02-01" @default.
• W2107681929 modified "2023-10-06" @default.
• W2107681929 title "A Systems Pharmacology Model of Erythropoiesis in Mice Induced by Small Molecule Inhibitor of Prolyl Hydroxylase Enzymes" @default.
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• W2107681929 doi "https://doi.org/10.1002/psp4.12" @default.
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