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Novel Formulation Strategy to Improve the Feasibility of Amifostine Administration

  • Kavitha Ranganathan
  • Eric Simon
  • Jeremy Lynn
  • Alicia Snider
  • Yu Zhang
  • Noah Nelson
  • Alexis Donneys
  • Jose Rodriguez
  • Lauren Buchman
  • Dawn Reyna
  • Elke Lipka
  • Steven R. Buchman
Research Paper

Abstract

Purpose

Amifostine (AMF), a radioprotectant, is FDA-approved for intravenous administration in cancer patients receiving radiation therapy (XRT). Unfortunately, it remains clinically underutilized due to adverse side effects. The purpose of this study is to define the pharmacokinetic profile of an oral AMF formulation potentially capable of reducing side effects and increasing clinical feasibility.

Methods

Calvarial osteoblasts were radiated under three conditions: no drug, AMF, and WR-1065 (active metabolite). Osteogenic potential of cells was measured using alkaline phosphatase staining. Next, rats were given AMF intravenously or directly into the jejunum, and pharmacokinetic profiles were evaluated. Finally, rats were given AMF orally or subcutaneously, and blood samples were analyzed for pharmacokinetics.

Results

WR-1065 preserved osteogenic potential of calvarial osteoblasts after XRT to a greater degree than AMF. Direct jejunal AMF administration incurred a systemic bioavailability of 61.5%. Subcutaneously administrated AMF yielded higher systemic levels, a more rapid peak exposure (0.438 vs. 0.875 h), and greater total systemic exposure of WR-1065 (116,756 vs. 16,874 ng*hr/ml) compared to orally administered AMF.

Conclusions

Orally administered AMF achieves a similar systemic bioavailability and decreased peak plasma level of WR-1065 compared to intravenously administered AMF, suggesting oral AMF formulations maintain radioprotective efficacy without causing onerous side effects, and are clinically feasible.

Key words

amifostine head and neck cancer hypotension radiation 

Abbreviations

%F

Systemic bioavailability

ALP

Alkaline Phosphatase

alpha-MEM

Alpha-modified minimal essential medium

AMF

Amifostine

AUC

Areas under curve

Cmax

Maximum concentration

EC-AMF

Enteric-coated AMF

HNC

Head and neck cancer

IV

Intravenous

LC-MS

Liquid chromatography-mass spectrometry

MC3T3 cells

Calvarial osteoblasts

MS

Mass spectrometry

ODM

Osteogenic differentiation medium

PBS

Phosphate Buffered Saline

PK

Pharmacokinetic

PO

Oral

SC

Subcutaneous

UPLC

Ultra performance liquid chromatography

WR-1065

Active Amifostine metabolite

WR-1065-EMI

WR-1065 N-ethylmaleimide

WR-1065-MMI

Modified WR-1065 N-methymaleimide

XRT

Radiation therapy

Notes

Acknowledgments and Disclosures

This work was support by R01 CA 125187 awarded to Steven R. Buchman, MD by the Nation Institutes of Health (NIH).

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Kavitha Ranganathan
    • 1
  • Eric Simon
    • 2
  • Jeremy Lynn
    • 1
  • Alicia Snider
    • 1
  • Yu Zhang
    • 1
  • Noah Nelson
    • 1
  • Alexis Donneys
    • 1
  • Jose Rodriguez
    • 3
  • Lauren Buchman
    • 1
  • Dawn Reyna
    • 2
  • Elke Lipka
    • 2
  • Steven R. Buchman
    • 1
  1. 1.Department of Plastic SurgeryUniversity of MichiganAnn ArborUSA
  2. 2.Therapeutic Systems Research Laboratories, Inc.Ann ArborUSA
  3. 3.Department of Plastic SurgeryRoanokeUSA

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