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 eCollection Date: 2025-01-10 DOI:10.1021/acsptsci.4c00575

Lin Zhang, Peng Xu, 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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基于机制的红铁素在慢性肾病和化疗性贫血大鼠中的药代动力学/药效学建模：血红蛋白反应和rHuEPO低反应的早期生物标志物

红细胞铁素（ERFE）已成为重组人红细胞生成素（rHuEPO）治疗后红细胞生成反应的潜在生物标志物。虽然在非贫血条件下ERFE和血红蛋白（HGB）对rHuEPO的反应之间的关联是公认的，但这种相关性和贫血状态下ERFE动力学仍不清楚。我们采用两种大鼠贫血模型，慢性肾脏疾病（CKD）贫血和化疗性贫血（CIA），测定rHuEPO给药后ERFE动力学及其与HGB反应的相关性。采用PK/PD建模方法对影响ERFE动力学的关键因素进行了表征，并得到了实验的支持。注射rHuEPO后，与健康大鼠相比，贫血大鼠的ERFE诱导减弱，主要是由于前体细胞数量减少和rHuEPO反应性受损。在给药后4小时ERFE的早期升高可以快速预测贫血大鼠的HGB反应和rHuEPO低反应。因此，以erfe为基础的剂量调整导致CKD大鼠rhuepo节约效应。这一策略有望应用于贫血患者，有可能减少rHuEPO剂量并减轻HGB过调。

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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.