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A Novel Combination Therapy of Erythropoietin and Thrombopoietin to Treat Erythropoietin-Resistance anemia

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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.

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Abbreviations

AUC:

Area under the curve

AUEC:

The area under the effect curve

BFU-E:

Burst forming unit-erythroid

CFU-E:

Colony forming unit-erythroid

CKD:

Chronic kidney disease

CWRES:

Conditional weighted residual

EPO/rHuEPO:

Erythropoietin/recombinant human erythropoietin

ESA:

Erythropoiesis-stimulating agents

HGB:

Hemoglobin

HIF-PHIs:

Hypoxia-inducible factor prolyl hydroxylase enzyme inhibitors

HSC:

Hematopoietic stem cell

IOV:

Inter-occasion variability

IV:

Intravenous

MCH:

Mean corpuscular hemoglobin

MEP:

Megakaryocyte-erythroid progenitors

MK:

Megakaryocyte

M-M:

Michaelis-Menten saturable kinetics

NCA:

The noncompartmental analysis

PD:

Pharmacodynamic

PK:

Pharmacokinetic

PLT:

Platelet

PPARα:

Peroxisome proliferator-activated receptor alpha

RBC:

Red blood cell

RET:

Reticulocyte

SC:

Subcutaneous

TGF-β:

Transforming growth factor-beta

TPO/rHuTPO:

Thrombopoietin/recombinant human thrombopoietin

TPO-RA:

Thrombopoietin receptor agonist

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ACKNOWLEDGMENTS AND DISCLOSURES

The authors declared no conflicts of interest.

Funding

This work was supported by the Direct Grant for Research (4054573) from The Chinese University of Hong Kong and the research grants from the Hong Kong Research Grants Council, Early Career Scheme (24103120).

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Authors and Affiliations

  1. School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR

    Huixi Zou, Peng Xu & Xiaoyu Yan

  2. Division of Hematology, Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR

    Raymond S. M. Wong

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  1. Huixi Zou
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  2. Peng Xu
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  3. Raymond S. M. Wong
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  4. Xiaoyu Yan
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Contributions

HZ designed the study, analyzed the data, developed the model and drafted the manuscript. HZ and XP conducted animal experiments. RW and XY designed the study. XY supervised model development and revised the manuscript.

Corresponding author

Correspondence to Xiaoyu Yan.

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Zou, H., Xu, P., Wong, R.S.M. et al. A Novel Combination Therapy of Erythropoietin and Thrombopoietin to Treat Erythropoietin-Resistance anemia. Pharm Res 39, 1249–1265 (2022). https://doi.org/10.1007/s11095-022-03304-z

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  • DOI: https://doi.org/10.1007/s11095-022-03304-z

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