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


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 HIF1? 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 HIF1?, 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: 1.7?M), and systems parameters such as EPO mRNA turnover (kdeg_EPOmRNA: 0.43 hr(-1)) and mean lifespan of reticulocytes (Tr : 81 hours). The model correctly described the observed 30-40-fold increase in kidney HIF1? 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.

SUBMITTER: Singh I 

PROVIDER: S-EPMC4360669 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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

Singh I I   Nagiec E E EE   Thompson J M JM   Krzyzanski W W   Singh P P  

CPT: pharmacometrics & systems pharmacology 20150211 2


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 hemogl  ...[more]

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