Mechanism-Based Pharmacokinetic/Pharmacodynamic Modeling of Erythroferrone in Anemic Rats with Chronic Kidney Disease and Chemotherapy-Induced Anemia: An Early Biomarker for Hemoglobin Response and rHuEPO Hyporesponsiveness

IF 4.9 Q1 CHEMISTRY, MEDICINAL ACS Pharmacology and Translational Science Pub Date : 2024-12-11 DOI:10.1021/acsptsci.4c0057510.1021/acsptsci.4c00575

Lin Zhang, Peng Xu and Xiaoyu Yan*,

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Abstract

Erythroferrone (ERFE) has emerged as a potential biomarker for the erythropoiesis response following recombinant human erythropoietin (rHuEPO) treatment. While the association between ERFE and hemoglobin (HGB) response to rHuEPO is well-established in nonanemic conditions, such correlation and ERFE kinetics in anemic states remain unclear. We employed two rat models of anemia, chronic kidney disease (CKD) anemia and chemotherapy-induced anemia (CIA), to determine ERFE kinetics and its correlation with HGB responses after rHuEPO administration. The key factors influencing ERFE kinetics were characterized using a PK/PD modeling approach and supported by experimentation. Following rHuEPO injection, ERFE induction was diminished in anemic rats compared with that of healthy rats, primarily attributed to the reduced precursor cell mass and impaired rHuEPO responsiveness. The early increase in ERFE at 4 h post administration allows for the prompt prediction of HGB response and rHuEPO hyporesponsiveness in anemic rats. Consequently, the ERFE-based dose adjustment resulted in a rHuEPO-sparing effect in CKD rats. This strategy is expected to be translatable to anemic patients, potentially reducing rHuEPO doses and mitigating HGB overshooting.

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来源期刊

ACS Pharmacology and Translational Science Medicine-Pharmacology (medical)

CiteScore

10.00

自引率

3.30%

发文量

133

期刊介绍： ACS Pharmacology & Translational Science publishes high quality, innovative, and impactful research across the broad spectrum of biological sciences, covering basic and molecular sciences through to translational preclinical studies. Clinical studies that address novel mechanisms of action, and methodological papers that provide innovation, and advance translation, will also be considered. We give priority to studies that fully integrate basic pharmacological and/or biochemical findings into physiological processes that have translational potential in a broad range of biomedical disciplines. Therefore, studies that employ a complementary blend of in vitro and in vivo systems are of particular interest to the journal. Nonetheless, all innovative and impactful research that has an articulated translational relevance will be considered. ACS Pharmacology & Translational Science does not publish research on biological extracts that have unknown concentration or unknown chemical composition. Authors are encouraged to use the pre-submission inquiry mechanism to ensure relevance and appropriateness of research.