Prediction of the Biological Effect of PEG-rHuEPO Candidates in Chronic Kidney Disease Patients using a Middle-out Translation Approach
Authors: Fernandez Gledys Reynaldo , Rodriguez-Vera Leyanis , Mehta Parsshava , Amaro-Gonzalez Daniel , Solozabal Joaquin , Duconge Jorge , Mangas-Sanjuan Victor , Troconiz Iñaki , Azeredo Francine Johansson , Vozmediano Valvanera 
Published: February 2025

Objectives: Recombinant human erythropoietin (rHuEPO) is indicated to treat anemia in chronic kidney disease (CKD) [1]. Nevertheless, due to its short half-life requires frequent administration. Pegylation is an efficient method to improve therapeutic proteins' pharmacokinetics (PK). However, pegylation can also affect protein biologic properties, including potency [2]. A semi-mechanistic PK/PD model was previously developed to evaluate four rHuEPO (ior®EPOCIM, MIRCERA®, and PEG-EPO 32 and 40 kDa) in rabbits [3]. To select the best candidate and anticipate their human biological effect, the model was scaled by distinguishing drug and biological system parameters both in healthy subjects and patients with CKD. Methods: A semi-mechanistic PK/PD model describing the effect of the four formulations on the time course of hematopoiesis was used as a starting point for the extrapolation [3]. PK parameters were extrapolated by allometric scaling. Drug-specific parameters related to the pharmacological effect (slope of the linear model and amplification factor) were considered identical between species, considering the high degree of homology of receptors between species. System-specific parameters (hematopoiesis mean transit time; baseline reticulocytes, red blood cells, hemoglobin) were extrapolated using human physiological values. The ability of the model to predict human behavior was evaluated using published data from MIRCERA®. Simulations were then performed at the MIRCERA® efficacious doses to evaluate HGB concentrations 90 days after administration in patients with different degrees of CKD. Results: All the pegylated formulations showed similar exposures in humans and rabbits at the different evaluated doses. The half-life of PEG-EPO 32 increased in ~52 h and ~1.44 h with respect to ior®EPOCIM and MIRCERA®, respectively. The half-life of PEG-EPO 40 increased in ~94 h and ~3 h with respect to ior®EPOCIM and MIRCERA®, respectively. After 3 months of a single dose administration MIRCERA®, PEG-EPO 32 and PEG-EPO 40, there was a significant increase on the RBC count and HGB levels concerning ior®EPOCIM. However, no significant differences were found between these three formulations. Conclusions: The results suggest that PEG-EPO 32 and PEG-EPO 40 will present similar behaviors in humans to MIRCERA® and a significant prolongation of the pharmacological effect for ior®EPOCIM. These promising formulations would significantly decrease the frequency of administrations up to approximately one month, even in patients with severe CKD. The strict distinction between drug- and system-dependent parameters is a key feature of PK/PD models allowing a more realistic interspecies extrapolation than empirical approaches. Based on the simulations, PEG-EPO 32 would be a better candidate for FIH trials due to the lower content of PEG (and thus lower production cost) and similar duration of the effect with respect to PEG-EPO 40.Citations: [1] Label Mircera® (methoxy polyethylene glycol-epoetin beta) injection, for intravenous or subcutaneous use) revised 04/2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/125164s089lbl.pdf[2] Páez R, Amaro D, Castro F, Hernández Y, Ruiz G. Conjugate comprising erythropoietin and a branched polymer structure. Google Patents; 2016.[3] Reynaldo-Fernández G, Solozábal J, Amaro D, Fernández-Sánchez EM, Rodríguez-Vera L, Bermejo M, Mangas-Sanjuan V, Troconiz IF. Semi-mechanistic Pharmacokinetic/Pharmacodynamic model of three pegylated rHuEPO and ior®EPOCIM in New Zealand rabbits. Eur J Pharmaceutical Sciences, 2018(120) 123–132. [4] Jiu-Hong Li, Jun-Feng Luo,Ying Jiang, Yong-Jian Ma, Yong-Qiang Ji, Guo-Liang Zhu, Cong Zhou, Hong-Wei Chu, Hou-De Zhang. Red Blood Cell Lifespan Shortening in Patients with Early-Stage Chronic Kidney Disease. Kidney Blood Press Res 2019;44: 1158–1165.