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Pharmacokinetic and Pharmacodynamic Modeling of Romiplostim in Animals

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Abstract

Purpose

Romiplostim is a novel thrombopoiesis-stimulating peptibody that targets the thrombopoietin c-Mpl receptor, resulting in increased platelet production. The pharmacodynamic-mediated disposition (PDMDD) and its stimulatory effect on platelet production in Sprague-Dawley rats, rhesus monkeys, and cynomolgus monkeys following IV bolus and SC administration at various dose levels were determined.

Methods

The pharmacokinetic (PK) profile was described by a PDMDD model that accounts for romiplostim binding to the c-Mpl receptor. The PD model contained a series of aging compartments for precursor cells in bone marrow and platelets. The stimulatory function was described by an on-and-off function operating on the fractional receptor occupancy (RO). The threshold effect, ROthr, and KD parameters were determinants of drug potency, whereas Smax reflected drug efficacy.

Results

The model implicated that receptor-mediated clearance was negligible. ROthr estimated occupancies were 0.288, 0.385, 0.771 for rats, rhesus, and cynomolgus monkeys, respectively. The analogous estimated values of KD were 4.05, 2320, and 429 ng/mL, implying that romiplostim was much more potent in rats, which was confirmed by a dose-response (ratio of peak platelet count to baseline) relationship.

Conclusions

The model adequately described romiplostim serum concentrations and platelet counts in rats, rhesus monkeys, and cynomolgus monkeys, and quantified linear clearance, PDMDD, and potency of romiplostim.

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Abbreviations

AUC0-∞ :

area under the curve from 0 to infinity

BaF3-Mpl cells:

Mpl-transfected cells

CFU:

colony-forming unit

CL:

clearance

CV:

coefficient of variation

DIV :

intravenous dosing

ELISA:

enzyme-linked immunosorbent assay

eTPO:

endogenous TPO

IgG1:

human immunoglobulin G subtype 1

ITS:

iterative-two-stage

rHu-TPO:

recombinant human thrombopoietin

TPO:

thrombopoietin

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Acknowledgments

This study was supported by an educational donation for the Fellowship in PK/PD Hematology from Amgen Inc. The authors wish to thank Teresa Wong for the bioanalytical support, Michelle Zakson for editing/writing assistance.

This study was funded by Amgen Inc. L Sutjandra, JJ Perez-Ruixo, B Sloey, AT Chow, and YM Wang were employees at Amgen, Inc. at the time this analysis was performed. W Krzyzanski was a consultant for Amgen, Inc, and received consultation fees for this project.

Part of the content of this manuscript was presented at a poster podium session: Y. Wang, W. Krzyzanski, J. Xiao, B. Jaramilla, A. Chow, Pharmacokinetic and Pharmacodynamic modeling of AMG 531, a thrombopoiesis stimulating Fc fusion protein (peptibody), in rats and monkeys. The AAPS Journal Vol. 9, No. S2, Abstract W4407 (2007).

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, University at Buffalo, Buffalo, New York, USA

    Wojciech Krzyzanski

  2. Amgen Inc., Pharmacokinetics and Drug Metabolism, Thousand Oaks, California, USA

    Liviawati Sutjandra, Juan Jose Perez-Ruixo, Bethlyn Sloey & Andrew T. Chow

  3. Office of Clinical Pharmacology, Food and Drug Administration, Washington, District of Columbia, USA

    Yow-Ming Wang

  4. Quantitative Pharmacology Pharmacokinetics and Drug Metabolism Department, Amgen Inc., Picayo 3, Puzol, 46530, Valencia, Spain

    Juan Jose Perez-Ruixo

Authors
  1. Wojciech Krzyzanski
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  2. Liviawati Sutjandra
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  3. Juan Jose Perez-Ruixo
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  4. Bethlyn Sloey
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  5. Andrew T. Chow
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  6. Yow-Ming Wang
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Corresponding author

Correspondence to Juan Jose Perez-Ruixo.

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Krzyzanski, W., Sutjandra, L., Perez-Ruixo, J.J. et al. Pharmacokinetic and Pharmacodynamic Modeling of Romiplostim in Animals. Pharm Res 30, 655–669 (2013). https://doi.org/10.1007/s11095-012-0894-2

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  • DOI: https://doi.org/10.1007/s11095-012-0894-2

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