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This study intends to elucidate the underlying mechanisms for the double peaks of ERFE dynamics and further determine whether early ERFE measurements can predict haemoglobin responses to rHuEPO.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>By using the purified recombinant rat ERFE protein and investigating its deposition in rats, the production of ERFE was deconvoluted. To explore the role of iron in ERFE production, we monitored short\u2010term changes of iron status after injection of rHuEPO or deferiprone. Pharmacokinetic\/pharmacodynamic (PK\/PD) modelling was used to confirm the mechanisms and examine the predictive ability of ERFE for long\u2010term haemoglobin responses.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>The rRatERFE protein was successfully purified. The production of ERFE was deconvoluted and showed two independent peaks (2 and 8\u2009h). Transient iron decrease was observed at 4\u2009h after rHuEPO injection and deferiprone induced significant increases of ERFE. Based on this mechanism, the PK\/PD model could characterize the complex dynamics of ERFE. In addition, the model predictions further revealed a stronger correlation between ERFE and haemoglobin peak values than that for observed values.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions and Implications<\/jats:title>\n                    <jats:p>The complex dynamics of ERFE should be composited by an immediate release and transient iron deficiency\u2010mediated secondary production of ERFE. The early peak values of ERFE, which occur within a few hours, can predict haemoglobin responses several weeks after ESA treatment.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.16396","type":"journal-article","created":{"date-parts":[[2024,4,23]],"date-time":"2024-04-23T19:18:50Z","timestamp":1713899930000},"page":"2833-2850","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Early erythroferrone levels can predict the long\u2010term haemoglobin responses to erythropoiesis\u2010stimulating agents"],"prefix":"10.1111","volume":"181","author":[{"given":"Peng","family":"Xu","sequence":"first","affiliation":[{"name":"School of Pharmacy The Chinese University of Hong Kong  HKSAR China"},{"name":"Phase I Clinical Trial Center, Taihe Hospital Hubei University of Medicine  Shiyan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raymond S. 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