Pharmacokinetic and pharmacodynamic modeling of erythropoietin and romiplostim combination therapy in rats with chemotherapy-induced anemia and thrombocytopenia
Xiaoqing Fan (1), Wojciech Krzyzanski (2), Raymond S. M. Wong (3), Xiaoyu Yan (1)
(1) School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, China SAR. (2) Department of Pharmaceutical Sciences, The State University of New York at Buffalo, Buffalo, NY, USA. (3) Division of Hematology, Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, China SAR.
Introduction: Chemotherapy-induced damage of hematopoietic stem and progenitor cells (HSPCs) in bone marrow is a major cause of anemia and thrombocytopenia (CIAT) in cancer patients[1, 2]. We have previously shown that romiplostim, a thrombopoietin receptor agonist that could stimulate the expansion of HSPCs, could synergize with recombinant human erythropoietin (rHuEPO) to promote erythropoiesis in addition to stimulating platelet production, whereas rHuEPO could influence the platelet count within the normal physiological range through HSPCs competition[3]. Therefore, we hypothesize that a combination of romiplostim with rHuEPO can alleviate CIAT simultaneously while minimizing the risk of thrombosis.
Objectives:
- To investigate pharmacokinetics (PK) and pharmacodynamics (PD) of rHuEPO and romiplostim as monotherapy and combination therapy to alleviate CIAT simultaneously
- To develop a novel PK-PD model to quantify the effects of rHuEPO and romiplostim on megakaryopoiesis and erythropoiesis in CIAT
- To apply this model to explain potential mechanisms of the combination therapy to alleviate CIAT
Methods: Romiplostim (30 μg/kg, once weekly, subcutaneous) and rHuEPO (100, 450 or 1350 IU/kg, thrice weekly, intravenous) were administered as monotherapy and combination therapy in a multiple dosing regimen in an orthotopic rat model with carboplatin-induced anemia and thrombocytopenia. A mechanism-based PK-PD model was developed to quantify the effects of the two drugs. The carboplatin PK data in rats following single IV dose (60 mg/kg) were fitted by a three-compartment model[4], while a two-compartment model and a one-compartment model were used to describe the time course of rHuEPO and romiplostim, respectively[3]. The PD model for the effect of rHuEPO and romiplostim on erythropoiesis and thrombopoiesis in CIAT were described by using a catenary indirect response model [3]. The carboplatin concentration is assumed to reduce the proliferation rate of HSPCs. Romiplostim stimulates the proliferation of HSPCs and megakaryopoiesis, while rHuEPO recruits the HSPCs into the erythroid lineage and further promotes erythropoiesis. The model was implemented in NONMEM 7.5.1 (ICON LLC) where the ordinary differential equations were solved by ADVAN13 subroutine, and the FOCEI algorithm was used for parameter estimation.
Results: The red blood cells and hemoglobin (Hgb) concentration recovered faster, and the secondary thrombocytopenia was alleviated in the rHuEPO and romiplostim combination therapy groups compared with the corresponding rHuEPO monotherapy groups. The rebound phenomenon of platelet was inhibited compared with the romiplostim monotherapy group. There was no PK interaction between rHuEPO and romiplostim in the combination groups at the dosing regimens adopted. The combination index value of 0.97<1 for 1350 IU/kg rHuEPO+romiplostim vs. romiplostim, calculated using the area under the effect over time curve of Hgb, suggested a synergistic effect between rHuEPO and romiplostim. The estimated RBC0, PLT0, TRET, and TPLT were 6.163×1012 cells/L, 1.173 ×1012 cells/L, 85.28 h, and 139.8 h, respectively, which were close to the physiologic values[3]. The values for the rHuEPO-related parameters SC50E, SmaxE1, and SmaxE2 are 7477 mIU/mL, 252.6, and 11.09, respectively. The values for the romiplostim-related parameters SC50RM, SmaxRM1, and SmaxRM2 are 13.4 ng/mL, 1.11, and 0.21. All PD parameters were estimated with reasonable precision, except for drug related parameters SmaxRM1, SmaxE1, SC50RM, and SC50E which had RSE% of 661.9, 92.91, 1069, and 107.2%, respectively. This result was expected, because there is only one dose level for romiplostim in the present study. The PK-PD model adequately described the observed PK and PD data after administration of rHuEPO and/or romiplostim. The goodness of fit plots and visual predictive check results qualified the model and confirmed the predictive performance.
Conclusions: RHuEPO and romiplostim combination therapy can alleviate CIAT simultaneously in rats while minimizing the risk of thrombosis, indicating that combination therapy might be superior to monotherapy in the supportive therapy of cancer patients undergoing chemotherapy. The established PK-PD model provides mechanistic insights regarding rHuEPO and romiplostim combination therapy on CIAT and may also serve as a valuable tool to assist in the dosing selection of the combination therapy in future studies.
References:
[1] H. Al-Samkari, G.A. Soff, (2021) Clinical challenges and promising therapies for chemotherapy-induced thrombocytopenia, Expert Rev Hematol, 14(5): 437-448. [2] H. Abdel-Razeq, H. Hashem, (2020) Recent update in the pathogenesis and treatment of chemotherapy and cancer induced anemia, Crit Rev Oncol Hematol, 145: 102837. [3] X. Fan, W. Krzyzanski, R.S.M. Wong, X. Yan, (2022) Fate determination role of erythropoietin and romiplostim in the lineage commitment of hematopoietic progenitors, J Pharmacol Exp Ther, 382(1): 31-43. [4] S. Woo, W. Krzyzanski, W.J. Jusko, (2008) Pharmacodynamic model for chemotherapy-induced anemia in rats, Cancer Chemother Pharmacol, 62(1): 123-33.
