Huixi Zou1, Peng Xu1, Raymond S M Wong2, Xiaoyu Yan3. 1. School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR. 2. Division of Hematology, Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR. 3. School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR. xiaoyuyan@cuhk.edu.hk.
Abstract
PURPOSE: Treatment with recombinant human erythropoietin (rHuEPO) may correct anemia in patients with chronic kidney disease. However, up to 10% of these patients exhibit EPO resistance or hyporesponsiveness, which may be caused by the depletion of erythroid progenitor cells. Thrombopoietin (TPO) stimulates the self-renewal of stem cells and promotes the growth of early erythroid progenitor cells. The objective of this study was to determine whether the combination of recombinant human TPO (rHuTPO) and rHuEPO could correct the depletion of erythroid precursor cells to treat EPO-resistant anemia. METHODS: To test our hypothesis, pharmacokinetic (PK) and pharmacodynamic (PD) studies of rHuEPO and rHuTPO were performed in healthy rats. Rats received rHuEPO or rHuTPO alone or in combination. Plasma concentrations of rHuTPO and rHuEPO were measured. PD responses, including erythropoietic and thrombopoietic responses, were assessed in peripheral blood. RESULTS: On one hand, the results demonstrated the synergistic effect of the combination of rHuEPO and rHuTPO on erythropoiesis. Compared with rHuEPO monotherapy, the combination therapies further stimulated the production of red blood cells and hemoglobin. On the other hand, rHuEPO inhibited the platelet production induced by rHuTPO and mitigate the risk of blood clots. Furthermore, we successfully developed a mechanism-based PD model to simultaneously characterize the responses of the two molecules. CONCLUSIONS: Overall, our study indicated that a combination therapy of rHuTPO and rHuEPO could be used to treat EPO-resistant anemia and provided a quantitative basis for further optimizing the combination therapy for clinical use.
PURPOSE: Treatment with recombinant human erythropoietin (rHuEPO) may correct anemia in patients with chronic kidney disease. However, up to 10% of these patients exhibit EPO resistance or hyporesponsiveness, which may be caused by the depletion of erythroid progenitor cells. Thrombopoietin (TPO) stimulates the self-renewal of stem cells and promotes the growth of early erythroid progenitor cells. The objective of this study was to determine whether the combination of recombinant human TPO (rHuTPO) and rHuEPO could correct the depletion of erythroid precursor cells to treat EPO-resistant anemia. METHODS: To test our hypothesis, pharmacokinetic (PK) and pharmacodynamic (PD) studies of rHuEPO and rHuTPO were performed in healthy rats. Rats received rHuEPO or rHuTPO alone or in combination. Plasma concentrations of rHuTPO and rHuEPO were measured. PD responses, including erythropoietic and thrombopoietic responses, were assessed in peripheral blood. RESULTS: On one hand, the results demonstrated the synergistic effect of the combination of rHuEPO and rHuTPO on erythropoiesis. Compared with rHuEPO monotherapy, the combination therapies further stimulated the production of red blood cells and hemoglobin. On the other hand, rHuEPO inhibited the platelet production induced by rHuTPO and mitigate the risk of blood clots. Furthermore, we successfully developed a mechanism-based PD model to simultaneously characterize the responses of the two molecules. CONCLUSIONS: Overall, our study indicated that a combination therapy of rHuTPO and rHuEPO could be used to treat EPO-resistant anemia and provided a quantitative basis for further optimizing the combination therapy for clinical use.
Authors: Hsiang-Ying Lee; Xiaofei Gao; M Inmaculada Barrasa; Hu Li; Russell R Elmes; Luanne L Peters; Harvey F Lodish Journal: Nature Date: 2015-05-11 Impact factor: 49.962
Authors: Michelle Teodoro Alves; Sandra Simone Vilaça; Maria das Graças Carvalho; Ana Paula Fernandes; Luci Maria Sant'Ana Dusse; Karina Braga Gomes Journal: Rev Bras Hematol Hemoter Date: 2015-02-17