PI-073 - MECHANISM-BASED PHARMACOKINETIC-PHARMACODYNAMIC MODELING OF ERYTHROFERRONE: OPTIMIZING RECOMBINANT HUMAN ERYTHROPOIETIN DOSING IN CKD-INDUCED ANEMIA

L. ZHANG¹, X. YAN¹; ¹The Chinese University of Hong Kong, N.T., Hong Kong.

Background: Recombinant human erythropoietin (rHuEPO) is a cornerstone treatment for anemia in chronic kidney disease (CKD) patients, although with varying responsivenesss. Hemoglobin (HGB) is the gold standard for assessing rHuEPO response. However, its delayed response can lead to excessive rHuEPO dosing and subsequent HGB overshooting. Erythroferrone (ERFE), an endogenous hormone that enhances iron availability by reducing hepcidin levels, is secreted by erythroid cells in response to erythropoietin (EPO). This study explores ERFE as a potential early biomarker for optimizing rHuEPO dosing in CKD anemic rats.

Methods: CKD anemic rats were utilized to delineate the kinetic profile of ERFE and its determinants following rHuEPO administration. Key factors influencing ERFE kinetics were characterized using mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) modeling. The correlation between ERFE and HGB changes post-rHuEPO treatment was assessed through Pearson correlation analysis. Comparative evaluations of ERFE-based versus HGB-based dose titration were conducted to verify their respective benefits.

Results: Baseline ERFE levels were significantly elevated in CKD anemic rats (RM 7.25 ng/mL, RSE 8.6%) compared to healthy controls (RM 2.38 ng/mL, RSE 8.1%), with a p value < 0.0001. ERFE induction by rHuEPO was attenuated in CKD rats, primarily due to a diminished EPO response driven by underlying inflammation, as evidenced by a higher rHuEPO concentration required to induce 50% of the maximum ERFE induction in CKD rats (EC50 1360 mIU/mL, RSE 69.9%) relative to healthy rats (EC50 466 mIU/mL, RSE 38.3%). Notably, maximum ERFE induction at 4 hours post-rHuEPO administration was predictive of HGB response in CKD rats (R = 0.65, p value = 0.059). ERFE-based dosing strategies resulted in a 12% reduction in cumulative rHuEPO dose and mitigated the risk of HGB overshooting compared to HGB-based dosing.

Conclusion: ERFE emerges as a promising early biomarker for guiding dose adjustments during the early stages of rHuEPO treatment in CKD anemic rats. These findings hold significant clinical implications, potentially enabling reduced rHuEPO dosages and minimizing the risk of HGB overshooting in anemic patients.