Zhang Lin, Xu Peng, Yan Xiaoyu
Guangdong-Hong Kong-Macao Joint Laboratory for New Drug Screening, School of Pharmacy, The Chinese University of Hong Kong, Shatin 999077, Hong Kong SAR, P. R. China.
ACS Pharmacol Transl Sci. 2024 Dec 11;8(1):189-202. doi: 10.1021/acsptsci.4c00575. eCollection 2025 Jan 10.
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.
红细胞生成素铁蛋白（ERFE）已成为重组人促红细胞生成素（rHuEPO）治疗后红细胞生成反应的一种潜在生物标志物。虽然在非贫血状态下，ERFE与rHuEPO的血红蛋白（HGB）反应之间的关联已得到充分证实，但在贫血状态下这种相关性及ERFE动力学仍不清楚。我们采用了两种贫血大鼠模型，即慢性肾脏病（CKD）贫血模型和化疗诱导贫血（CIA）模型，来确定rHuEPO给药后ERFE的动力学及其与HGB反应的相关性。使用药代动力学/药效学（PK/PD）建模方法对影响ERFE动力学的关键因素进行了表征，并通过实验加以支持。与健康大鼠相比，贫血大鼠注射rHuEPO后ERFE的诱导减弱，这主要归因于前体细胞数量减少和rHuEPO反应性受损。给药后4小时ERFE的早期升高使得能够迅速预测贫血大鼠的HGB反应和rHuEPO低反应性。因此，基于ERFE的剂量调整在CKD大鼠中产生了rHuEPO节约效应。预计该策略可转化应用于贫血患者，有可能减少rHuEPO剂量并减轻HGB过度升高。
