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DOI: 10.1007/s11095-012-0894-2Pages: 655-669

Pharmacokinetic and Pharmacodynamic Modeling of Romiplostim in Animals

1. University at Buffalo, Department of Pharmaceutical Sciences

2. Amgen Inc., Pharmacokinetics and Drug Metabolism

3. Office of Clinical Pharmacology, Food and Drug Administration

4. Amgen Inc., Quantitative Pharmacology Pharmacokinetics and Drug Metabolism Department

Correspondence to:
Juan Jose Perez-Ruixo
Tel: +34-96-1423095
Fax: +34-96-1423095
Email: juanjose@amgen.com

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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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  • Accepted: Sep 24, 2012
  • Online: Dec 19, 2012

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