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Investigation of the Pharmacokinetics of Romiplostim in Rodents with a Focus on the Clearance Mechanism

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ABSTRACT

Purpose

Romiplostim, a treatment for adults with immune thrombocytopenia (ITP), is a novel thrombopoietin mimetic agent with a similar mechanism of action as thrombopoietin with no sequence homology. Structurally, it is a peptibody containing thrombopoietin mimetic peptides and the Fc portion of human IgG1. We investigated romiplostim pharmacokinetics in rodents with a focus on the clearance mechanism.

Methods

Studies with appropriate controls were conducted in four models: FcRn knockout mice, thrombocytopenic mice, splenectomized rats, and bilateral nephrectomized rats. Catabolic breakdown of romiplostim was investigated in normal rats. The primary analytical method determines the intact/active romiplostim concentration, and the secondary method determines the sum of romiplostim and its catabolic degradants.

Results

FcRn interaction results in prolonged exposure. Platelets are involved in the target-mediated elimination, a saturable process and more prominent at low dose. Splenectomy does not affect the romiplostim pharmacokinetics in rats, an observation not unexpected. Nephrectomy in rats results in a greater increase of romiplostim exposure at a higher romiplostim dose, a nonlinearity likely due to saturation of competing pathway. Catabolism plays a major role in romiplostim elimination.

Conclusion

Romiplostim clearance involves multiple mechanisms, including a nonlinear pathway. Consequently, the relative contribution of different mechanisms appears to be dose dependent.

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REFERENCES

  1. Cohen-Solal K, Debili N, Vainchenker W, Wendling F. Thrombopoietin (Mpl-ligand) and the regulation of platelet production. Thromb Haemost. 1997;78:37–41.

    PubMed  CAS  Google Scholar 

  2. Brown AS EJ, Martin JF. Megakaryocytopoiesis: the megakaryocyte/platelet haemostatic axis. In: Franz von Bruchhausen UW, editor. Platelets and Their Factors: Springer; 1 edition (July 15, 1997) 1997. p. 3–26.

  3. Jackson C, Arnold JT, Pestina TI, Stenberg PE. Megakaryocyte Biology. In: Kuter DJ, Hunt P, Sheridan W, Zucker-Franklin D, editors. Thromobopoiesis and Thrombopoietins; Molecular, Cellular, Preclinical, and Clinical Biology. Totowa, New Jersey.: Humana Press; 1997. p. 3–40.

    Google Scholar 

  4. Hall MP, Gegg C, Walker K, Spahr C, Ortiz R, Patel V, et al. Ligand-Binding Mass Spectrometry to Study Biotransformation of Fusion Protein Drugs and Guide Immunoassay Development: Strategic Approach and Application to Peptibodies Targeting the Thrombopoietin Receptor. AAPS J.

  5. Molineux G, Newland A. Development of romiplostim for the treatment of patients with chronic immune thrombocytopenia: from bench to bedside. Br J Haematol. 2010;150:9–20.

    PubMed  CAS  Google Scholar 

  6. Mager DE, Jusko WJ. General pharmacokinetic model for drugs exhibiting target-mediated drug disposition. J Pharmacokinet Pharmacodyn. 2001;28:507–32.

    Article  PubMed  CAS  Google Scholar 

  7. Wang B, Nichol JL, Sullivan JT. Pharmacodynamics and pharmacokinetics of AMG 531, a novel thrombopoietin receptor ligand. Clin Pharmacol Ther. 2004;76:628–38.

    Article  PubMed  CAS  Google Scholar 

  8. Li J, Xia Y, Kuter DJ. Interaction of thrombopoietin with the platelet c-mpl receptor in plasma: binding, internalization, stability and pharmacokinetics. Br J Haematol. 1999;106:345–56.

    Article  PubMed  CAS  Google Scholar 

  9. Kuter DJ, Rosenberg RD. The reciprocal relationship of thrombopoietin (c-Mpl ligand) to changes in the platelet mass during busulfan-induced thrombocytopenia in the rabbit. Blood. 1995;85:2720–30.

    PubMed  CAS  Google Scholar 

  10. Engel C, Loeffler M, Franke H, Schmitz S. Endogenous thrombopoietin serum levels during multicycle chemotherapy. Br J Haematol. 1999;105:832–8.

    Article  PubMed  CAS  Google Scholar 

  11. Geddis AE, Linden HM, Kaushansky K. Thrombopoietin: a pan-hematopoietic cytokine. Cytokine Growth Factor Rev. 2002;13:61–73.

    Article  PubMed  CAS  Google Scholar 

  12. Hoffbrand AV. Oral iron chelators in the treatment of hematologic diseases. Clin Adv Hematol Oncol. 2005;3:536–8.

    PubMed  Google Scholar 

  13. Stoelting RK, Miller Ronald D. Basics of anesthesia 5th ed. Churchill Livingstone: Elsevier; 2007. p. 338.

    Google Scholar 

  14. Chen B, Jerger K, Frechet JM, Szoka Jr FC. The influence of polymer topology on pharmacokinetics: differences between cyclic and linear PEGylated poly(acrylic acid) comb polymers. J Control Release. 2009;140:203–9.

    Article  PubMed  CAS  Google Scholar 

  15. Hansen CP, Goetze JP, Stadil F, Rehfeld JF. Excretion of progastrin products in human urine. Am J Physiol. 1999;276:G985–92.

    PubMed  CAS  Google Scholar 

  16. Ujhelyi MR, Robert S. Pharmacokinetic aspects of digoxin-specific Fab therapy in the management of digitalis toxicity. Clin Pharmacokinet. 1995;28:483–93.

    Article  PubMed  CAS  Google Scholar 

  17. Proksch JW, Gentry WB, Owens SM. Pharmacokinetic mechanisms for obtaining high renal coelimination of phencyclidine and a monoclonal antiphencyclidine antigen-binding fragment of immunoglobulin G in the rat. J Pharmacol Exp Ther. 1998;287:616–24.

    PubMed  CAS  Google Scholar 

  18. Behr T, Becker W, Hannappel E, Goldenberg DM, Wolf F. Targeting of liver metastases of colorectal cancer with IgG, F(ab')2, and Fab' anti-carcinoembryonic antigen antibodies labeled with 99mTc: the role of metabolism and kinetics. Cancer Res. 1995;55:5777s–85s.

    PubMed  CAS  Google Scholar 

  19. McQuarrie SA, Baum RP, Niesen A, Madiyalakan R, Korz W, Sykes TR, et al. Pharmacokinetics and radiation dosimetry of 99Tcm-labelled monoclonal antibody B43.13 in ovarian cancer patients. Nucl Med Commun. 1997;18:878–86.

    Article  PubMed  CAS  Google Scholar 

  20. Wang YM, Krzyzanski W, Doshi S, Xiao JJ, Perez-Ruixo JJ, Chow AT. Pharmacodynamics-Mediated Drug Disposition (PDMDD) and Precursor Pool Lifespan Model for Single Dose of Romiplostim in Healthy Subjects. AAPS J.

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ACKNOWLEDGMENTS

A portion of the reported data was presented at the 2005 ASH Annual Meeting as a poster presentation by Yu-Nien Sun, Rosalin Arends, Anthony Smithson, Ann Watson, and Janet L. Nichol. A Novel Thrombopoiesis-Stimulating Agent, AMG 531: Pharmacokinetics and Pharmacodynamics in FcRn Knock-Out and Wild Type Mice. Published in Blood (ASH Annual Meeting Abstracts), Nov 2005; 106: 3575. The authors of this manuscript (Yow-Ming C Wang, Bethlyn Sloey, Teresa Wong, Prerna Khandelwal, Rebeca Melara, and Yu-Nien Sun), are employees of Amgen Inc., which supported this study. The authors wish to thank Michelle Zakson for editing/writing assistance. We greatly appreciate the contribution of a broader Amgen team that worked on the development program of romiplostim over more than a decade of time. The team members, listed in alphabetical order, include, but are not limited to, the following: Rosalin Arends, Sharon Baughman, Beckinam Cepeda, Binodh de Silva, Lena Henday, Jessica Johnson, Janet Nichol, Jose Rodriquez, Anthony Smithson, Bing Wang, Tian Wang, Jeana Warren, Ann Watson, Lynn Wetherwax, Bing-Bing Yang and Protein Labs at Amgen PKDM.

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Authors and Affiliations

  1. Pharmacokinetics and Drug Metabolism Department, Amgen Inc., One Amgen Center Drive, 28-3-B, Thousand Oaks, California, 91320, USA

    Yow-Ming C. Wang, Bethlyn Sloey, Teresa Wong, Prerna Khandelwal, Rebeca Melara & Yu-Nien Sun

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  1. Yow-Ming C. Wang
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  2. Bethlyn Sloey
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  3. Teresa Wong
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  4. Prerna Khandelwal
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  5. Rebeca Melara
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  6. Yu-Nien Sun
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Corresponding author

Correspondence to Yow-Ming C. Wang.

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Wang, YM.C., Sloey, B., Wong, T. et al. Investigation of the Pharmacokinetics of Romiplostim in Rodents with a Focus on the Clearance Mechanism. Pharm Res 28, 1931–1938 (2011). https://doi.org/10.1007/s11095-011-0420-y

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  • DOI: https://doi.org/10.1007/s11095-011-0420-y

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