Pharmacodynamics of romiplostim alone and in combination with pegfilgrastim on acute radiation-induced thrombocytopenia and neutropenia in non-human primates

Abstract

Purpose: Evaluation of the pharmacodynamics (PD) and pharmacokinetics (PK) of romiplostim alone and in combination with pegfilgrastim in a non-human primate (NHP) model of acute radiation syndrome (ARS).

Materials and methods: Male and female rhesus macaques were subjected to Cobalt-60 γ irradiation, at a dose of 550 cGy 24 h prior to subcutaneous administration of either romiplostim alone as a single (2.5 or 5.0 mg/kg on Day 1) or repeat dose (5.0 mg/kg on Days 1 and 8), pegfilgrastim alone as a repeat dose (0.3 µg/kg on Day 1 and 8), or a combination of both agents (romiplostim 5.0 mg/kg on Day 1; pegfilgrastim 0.3 µg/kg on Days 1 and 8). Clinical outcome, hematological parameters and PK were assessed throughout the 45 d study period post-irradiation.

Results: Administration of romiplostim, pegfilgrastim or the combination of both resulted in significant improvements in hematological parameters, notably prevention of severe thrombocytopenia, compared with irradiated, vehicle control-treated NHPs. The largest hematologic benefit was observed when romiplostim and pegfilgrastim were administered as a combination therapy with much greater effects on both platelet and neutrophil recovery following irradiation compared to single agents alone.

Conclusions: These results indicate that romiplostim alone or in combination with pegfilgrastim is effective at improving hematological parameters in an NHP model of ARS. This study supports further study of romiplostim as a medical countermeasure to improve primary hemostasis and survival in ARS.

Keywords:

• Thrombocytopenia
• medical countermeasure
• acute radiation syndrome (ARS)
• pharmacodynamics
• animal model organisms

Disclosure statement

None of the authors has any conflict of interest, other than their employment in either a contract research organization or pharmaceutical company.

Additional information

Funding

This work was funded by the National Institute of Allergy and Infectious Diseases within the National Institutes of Health (NIAID/NIH; under a prime contract #: HHSN272201500013I awarded to SRI International).

Notes on contributors

Karen Wong

Karen Wong is a Senior Research Scientist and Study Director at Citoxlab North America. She received a BSc from University Concordia.

Polly Y. Chang

Polly Y. Chang, received her PhD in Biophysics from the University of California, Berkeley. She is currently the Senior Director of Molecular and Genetic Toxicology at SRI International and is actively engaged in radiation biology research coupled with product development of medical countermeasures for radiation protection.

Mark Fielden

Mark Fielden, is a Scientific Director of Comparative Biology and Safety Sciences at Amgen Inc. Fielden conducts non-clinical safety toxicology studies to support clinical development and approval of therapeutics.

Anne Marie Downey

Anne Marie Downey is a Research Fellow and Study Director at Citoxlab North America. She holds a BSc in Biopharmaceutical Sciences (medicinal chemistry) from the University of Ottawa and a PhD in Pharmacology and Therapeutics from McGill University.

Deborah Bunin

Deborah I. Bunin, Director Molecular Toxicology at SRI Biosciences, conducts non-clinical safety toxicology and efficacy studies to advance radiation medical countermeasures, vaccines, biologics, and other therapeutics toward regulatory approval.

James Bakke

James Bakke, Research Scientist/Study Director at SRI Biosciences. Bakke conducts radiation model development, efficacy studies to advance radiation medical countermeasures and non-clinical safety toxicology of small molecule drugs, vaccines, biologics and medical devices toward regulatory approval.

Janet Gahagen

Janet Gahagen, Senior Study Director at SRI Biosciences. She conducts non-clinical safety and efficacy studies to support development and advancement of small and large molecule compounds. Contributes to radiation medical countermeasures program for Acute Radiation Syndrome. Expertise in NHP study design development and behavior.

Lalitha Iyer

Lalitha Iyer, Principal Scientist, Drug Metabolism and Pharmacokinetics at SRI Biosciences. She directs programs on in vitro metabolism and pharmacokinetic studies, performs pharmacokinetic and toxicokinetic data analysis, and interprets data on pharmacokinetic/pharmacodynamic relationships.

Sameer Doshi

Sameer Doshi, Director, Clinical Pharmacology, Modeling and Simulation, at Amgen Inc. Doshi conducts modeling and simulation studies to support clinical development and regulatory approval of therapeutics.

Wieslaw Wierzbicki

Wieslaw Wierzbicki, is a Certified Medical Radiophysicist with 20 years' experience in clinical and research radiobiology and physics. He works in radio-oncology with patients at Hôpital Maisonneuve-Rosemont, Montreal Canada and has associate member appointments with McGill University and University of Montreal.