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

Wong, Karen; Chang, Polly Y.; Fielden, Mark R.; Downey, Anne Marie; Bunin, Deborah I.; Bakke, James; Gahagen, Janet; Iyer, Lalitha; Doshi, Sameer; Wierzbicki, W; Authier, Simon

doi:10.1080/09553002.2019.1625488

Cited by 40 publications

(36 citation statements)

References 31 publications

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“…It may be the case in receptor binding that once the receptors are saturated, a higher dose will not be effective, but a longer duration of dosing could be important, so Neulasta might achieve that. Similarly, repeat dosing of Nplate did not give greater benefit than was found for a single dose in mice (73) and NHPs (74). It may be possible that use of more than one growth factor (e.g., addition of a mobilization factor) with filgrastim might reduce the amount of G-CSF needed to provide benefit (113); however, this outcome may depend on the dose of radiation received.…”

Section: Science Of Cytokinesmentioning

confidence: 93%

“…When compared to Neulasta, an existing known intervention for ARS, survival curves for a single dose of Nplate overlapped with those from a single dose of Neulasta or the combination. These promising mouse data led investigators to proceed with a different model system and pursue PK and PD studies in NHPs with the goal of understanding the PK/PD in the NHP model and determining the dose for eventual pivotal efficacy studies (74). Two different doses and treatment regimens were studied, alone or in combination with Neulasta.…”

Section: Session 2: Pre-licensure Researchmentioning

confidence: 99%

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Use of Growth Factors and Other Cytokines for Treatment of Injuries During a Radiation Public Health Emergency

et al. 2019

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Radiation oncology, military medicine, radiation protection a Speakers had the opportunity to review this meeting report prior to journal submission. b CBRNE ¼ chemical, biological, radiological, nuclear and explosive. 2 https://bit.ly/2ZJO9KH. 3 https://bit.ly/2U8OwdE 4 https://bit.ly/2XYai6h. 5 https://bit.ly/2OWDKpK. 6 https://bit.ly/2P28xl9. 7 https://bit.ly/2I8r7aI. 8 https://bit.ly/2uXqrfQ. 9 https://bit.ly/2I6Dq7r. 10 Where pre-publication data are discussed, the first initial and last name of the presenter who provided the information is shown in parentheses.

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Section: Science Of Cytokinesmentioning

confidence: 93%

Section: Session 2: Pre-licensure Researchmentioning

confidence: 99%

Use of Growth Factors and Other Cytokines for Treatment of Injuries During a Radiation Public Health Emergency

et al. 2019

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“…In another study, the maximal survival enhancement of ∼40% was achieved after a single 30 µg/kg dose of Romiplostim [72]. Administration of PEGfilgrastim and Romiplostim or the combination of both agents resulted in improvements in hematological parameters compared with irradiated control NHPs [73]. The most hematologic advantage in respect to platelet and neutrophil was noted when PEGfilgrastim and Romiplostim were dispensed as a combination therapy.…”

Section: Biologicsmentioning

confidence: 96%

“…Some of the agents which have been combined with amifostine or its derivatives to improve efficacy are G-CSF, metformin, selenium, vitamin-E, gamma-tocotrienol, prostaglandin E2, β-glucan, and roncho-Vaxom [199]. Similarly, there are reports for the combination of flagellin and IL-1β [200], gamma-tocotrienol and Simvastatin/pentoxifylline [201,202], filgrastim and α-tocopherol succinate [203], and PEGfilgrastim and Romiplostim [73].…”

Section: Poly-pharmacy and Repurposing Approachesmentioning

confidence: 99%

Pharmacological management of ionizing radiation injuries: current and prospective agents and targeted organ systems

Singh

Seed²

2020

Expert Opinion on Pharmacotherapy

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Introduction: There is a limited array of currently available medicinals that are useful for either the prevention, mitigation or treatment of bodily injuries arising from ionizing radiation exposure. Area covered: In this brief article, the authors review those pharmacologic agents that either are currently being used to counter the injurious effects of radiation exposure, or those that show promise and are currently under development. Expert opinion: Although significant, but limited progress has been made in the development and fielding of safe and effective pharmacotherapeutics for select types of acute radiation-associated injuries, additional effort is needed to broaden the scope of drug development so that overall health risks associated with both short-and long-term injuries in various organ systems can be reduced and effectively managed. There are several promising radiation countermeasures that may gain regulatory approval from the government in the near future for use in clinical settings and in the aftermath of nuclear/radiological exposure contingencies. ARTICLE HISTORY

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“…10) The radio-mitigative effects of RP have also been reported by other groups. 11,12) Especially, Wong et al have demonstrated the radiation damage reduction effect of RP in non-human primates. 12) However, the mechanism of action of RP cannot be explained only by signal transduction via TPOR, and the involvement of antioxidant mechanism is also speculated.…”

Section: Introductionmentioning

confidence: 99%

Regulation of Antioxidant Stress-Responsive Transcription Factor Nrf2 Target Gene in the Reduction of Radiation Damage by the Thrombocytopenia Drug Romiplostim

Chiba

Kawabata

Yamaguchi

et al. 2020

Biological & Pharmaceutical Bulletin

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Ionizing radiation induces severe oxidative stress, resulting in individual death by acute radiation syndrome. The nuclear factor-erythroid-2-related factor 2 (Nrf2) plays an important role in the antioxidant response pathway. Recently, romiplostim (RP), an idiopathic thrombocytopenic purpura therapeutic drug, was reported to completely rescue mice exposed to lethal total-body irradiation (TBI). However, the details underlying the mechanism for reducing radiation damage remain largely unknown. To elucidate the involvement of the master redox regulator Nrf2 in the radio-mitigative efficacy of RP on TBI-induced oxidative stress, expression of Nrf2 target genes in hematopoietic tissues such as bone marrow, spleen, and lung from mice treated with RP for three consecutive days after 7 Gy of X-ray TBI was analyzed. RP promoted the recovery of bone marrow cells from day 10 and the significant up-regulation of reduced nicotinamide adenine dinucleotide phosphate (NAD(P)H) dehydrogenase quinone 1 (Nqo1), glutamate-cysteine ligase catalytic subunit (Gclc) and glutamate-cysteine ligase modifier subunit (Gclm) was observed compared to the TBI mice. RP also promoted the recovery of splenic cells on day 18, and the significant up-regulation of Nqo1, Gclc and Gclm in spleen both on day 10 and 18 and Nqo1 and Gclm in lung on day 10 was observed compared to the TBI mice. The present study suggests that the radio-mitigative effects of RP indicates on the activation of Nrf2 target genes involved in redox regulation and the antioxidative function, especially Nqo1, Gclc and Gclm. It is indicating the importance of these genes in the maintenance of biological homeostasis in response to radiation-induced oxidative stress. Key words accute radiation syndrome; romiplostim; radio-mitigative effect; nuclear factor-erythroid-2-related factor 2 (Nrf2) target gene; reduced nicotinamide adenine dinucleotide phosphate dehydrogenase quinone 1 (Nqo1); glutamate-cysteine ligase modifier subunit (Gclm)

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

Cited by 40 publications

References 31 publications

Use of Growth Factors and Other Cytokines for Treatment of Injuries During a Radiation Public Health Emergency

Use of Growth Factors and Other Cytokines for Treatment of Injuries During a Radiation Public Health Emergency

Pharmacological management of ionizing radiation injuries: current and prospective agents and targeted organ systems

Regulation of Antioxidant Stress-Responsive Transcription Factor Nrf2 Target Gene in the Reduction of Radiation Damage by the Thrombocytopenia Drug Romiplostim

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