| Autor: |
Singh I; Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo Buffalo, New York, USA., Nagiec EE; Exploratory Drug Safety, Drug Safety Research and Development (DSRD), Pfizer Cambridge, Massachusetts, USA., Thompson JM; Inflammation Biology, Pfizer, Chesterfield, Missouri, USA; Pharmacokinetics-Dynamics and Metabolism (PDM), Pfizer Cambridge, Massachusetts, USA., Krzyzanski W; Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo Buffalo, New York, USA., Singh P; Pharmacokinetics & Drug Metabolism, Amgen Thousand Oaks, California, USA. |
| Abstrakt: |
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 (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 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. |
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