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Pharmacodynamics of Recombinant Human Erythropoietin in Murine Bone Marrow

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Abstract

Purpose

Originally approved for three times/week dosing, recombinant human erythropoietin (rhEPO) is now often used at weekly intervals. We have studied rhEPO in mice to better understand why the extended dosing interval retains efficacy.

Methods

C57Bl/6 mice received a single sc. dose of rhEPO (3,000 IU/kg). Bone marrow and blood were collected at 8 h and 1, 2, 5 and 7 days. Staining for TER-119 and CD71, pulse labeling with bromodeoxyuridine, annexin-V binding and vital staining with 7-aminoactinomycin d were used cell cycle and apoptosis in erythroblasts by four color flow cytometry.

Results

A wave of proliferation and/or maturation progressed through all erythroblasts, resulting in the emigration of immature reticulocytes into the periphery. An increase in the fraction of erythroblasts in S and G2M was found, but suppression of apoptosis was not.

Conclusions

Most of the effects of rhEPO occurred 48 h after dosing, when the concentration of rhEPO was less than 1% of Cmax, suggesting that the processes set in motion by rhEPO can continue after rhEPO concentrations fall. Our observation of apoptosis in erythroblasts even when rhEPO concentrations were high suggests that regulatory mechanisms which down-regulate erythropoiesis are also engaged.

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Acknowledgements

This work was supported in its entirety by Centocor, a wholly owned subsidiary of Johnson & Johnson, Inc.

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Authors and Affiliations

  1. Discovery Research, Centocor Research & Development, Inc., Radnor, SP, 19087, USA

    Peter J. Bugelski, Thomas Nesspor, Amy Volk, Joanne O’Brien, Dorie Makropoulos, Kim Shamberger, Paul W. Fisher, Ian James & Renold J. Capocasale

  2. Clinical Pharmacology and Experimental Medicine, Centocor Research & Development, Inc., Radnor, SP, 19087, USA

    Danielle Graden

  3. Experimental Pathology, Centocor, R-4-2, 145 King of Prussia Road, Radnor, SP, 19087, USA

    Peter J. Bugelski

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  1. Peter J. Bugelski
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Correspondence to Peter J. Bugelski.

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Bugelski, P.J., Nesspor, T., Volk, A. et al. Pharmacodynamics of Recombinant Human Erythropoietin in Murine Bone Marrow. Pharm Res 25, 369–378 (2008). https://doi.org/10.1007/s11095-007-9372-7

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  • DOI: https://doi.org/10.1007/s11095-007-9372-7

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