Pharmaceutical Research

, Volume 30, Issue 3, pp 655–669

Pharmacokinetic and Pharmacodynamic Modeling of Romiplostim in Animals

Authors

  • Wojciech Krzyzanski
    • Department of Pharmaceutical SciencesUniversity at Buffalo
  • Liviawati Sutjandra
    • Amgen Inc., Pharmacokinetics and Drug Metabolism
    • Amgen Inc., Pharmacokinetics and Drug Metabolism
    • Quantitative Pharmacology Pharmacokinetics and Drug Metabolism DepartmentAmgen Inc.
  • Bethlyn Sloey
    • Amgen Inc., Pharmacokinetics and Drug Metabolism
  • Andrew T. Chow
    • Amgen Inc., Pharmacokinetics and Drug Metabolism
  • Yow-Ming Wang
    • Office of Clinical Pharmacology, Food and Drug Administration
Research Paper

DOI: 10.1007/s11095-012-0894-2

Cite this article as:
Krzyzanski, W., Sutjandra, L., Perez-Ruixo, J.J. et al. Pharm Res (2013) 30: 655. doi:10.1007/s11095-012-0894-2

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.

KEY WORDS

c-Mpl receptorpeptibodypharmacodynamics-mediated drug disposition (PDMDD)pharmacokinetic and pharmacodynamic modeling

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

Copyright information

© Springer Science+Business Media, LLC 2012