Mechanism-based pharmacokinetic-pharmacodynamic modeling of short-term erythroferrone response and long-term efficacy of erythropoietin in chemotherapy-induced anemia rats
Lin Zhang (1), Peng Xu (1), Xiaoyu Yan (1)
(1) School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR.
Introduction: Chemotherapy-induced anemia is commonplace among cancer patients. Recombinant human erythropoietin (rHuEPO) has been used to treat CIA patients with hemoglobin (HGB) levels of 10g/dL or below [1], although with varying responsiveness and a long titration period [2]. Erythroferrone (ERFE), an endogenous hormone, increases iron availability for erythropoiesis by lowering hepcidin levels [3]. ERFE is produced by erythroid cells in response to erythropoietin (EPO) and correlated with long-term HGB response, thus could potentially serve as an early biomarker to allow for early dose titration and prediction of rHuEPO responsiveness.
Objectives: The current study aims to 1) develop a mechanism-based PK/PD model to quantify ERFE and HGB response to rHuEPO treatment in CIA rats 2) investigate the correlation between ERFE and HGB and the predictive ability of ERFE in predicting rHuEPO responsiveness.
Methods: A single dose of rHuEPO (1350 IU/kg and 450 IU/kg) was given to carboplatin-induced anemia in rats. To simultaneously quantify both ERFE and HGB responses to rHuEPO, a pharmacokinetics and pharmacodynamics (PKPD) model was developed. A previously developed chemotherapy-induced myelosuppression model [4] was used as the starting point to build a CIA model by including the ERFE model. The model was fitted simultaneously to ERFE and HGB data. To investigated if there is a linear correlation between the change of ERFE and HGB after rHuEPO treatment, we then performed correlation analysis. Receiver operating characteristics (ROC) curve analysis was performed to test the predictive power of ERFE in predicting EPO responsiveness.
Results: The PK model that best described EPO and Carboplatin was a two-compartment model with nonlinear elimination and a three-compartment model with linear elimination, respectively. The PD model included two sub-models, i.e., a CIA model that is linked by a series of transit compartments representing maturing erythroid cells at different stages, and an ERFE model that is linked to the last transit compartment representing the main cells that produce ERFE. The ERFE response to EPO was best described by an indirect response model with dual-input (i.e., a circadian input assuming cosine behavior and a first-order input) and a linear elimination. The estimated input rate constant (θkin) for ERFE was 1.4 /h. The estimated circadian mesor (θRm) for ERFE was 3.53 ng/mL, representing the mean ERFE baseline of 3.53 ng/mL in CIA rats. The estimated circadian amplitude (θRa) for ERFE was 1.13 ng/mL, representing the absolute ERFE change from baseline in the cosine function. The change of ERFE at 10 h after treatment was significantly correlated with the change of HGB by Day 6 in CIA rats after rHuEPO treatment (R square = 0.77, P-value = 0.01). The change of ERFE at 10 h after treatment was a significant predictor of rHuEPO responsiveness (AUC = 0.88).
Conclusions: The time course of ERFE and HGB following rHuEPO treatment in CIA rats was successfully characterized by a mechanism-based PK/PD model. We demonstrated the potential of using ERFE to predict HGB response to rHuEPO and rHuEPO responsiveness in CIA rats. This mechanism-based PK/PD model can be used to further optimize the design of short-term biomarker-based prediction of long-term response following EPO therapy in CIA.
References: [1] Abdel-Razeq H, Hashem H. Recent update in the pathogenesis and treatment of chemotherapy and cancer induced anemia. Crit Rev Oncol Hematol 2020; 145: 102837.
[2] Ingrasciotta Y, Lacava V, Marciano I, Giorgianni F, Tripepi G, G DA, Chinellato A, Ugo Tari D, Santoro D, Trifiro G. In search of potential predictors of erythropoiesis-stimulating agents (ESAs) hyporesponsiveness: a population-based study. BMC Nephrol 2019; 20: 359.
[3] Kautz L, Jung G, Nemeth E, Ganz T. Erythroferrone contributes to recovery from anemia of inflammation. Blood 2014; 124: 2569-74.
[4] Friberg LE, Henningsson A, Maas H, Nguyen L, Karlsson MO. Model of chemotherapy-induced myelosuppression with parameter consistency across drugs. J Clin Oncol 2002; 20: 4713-21.