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Novel Formulation Strategy to Improve the Feasibility of Amifostine Administration

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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.

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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

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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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Authors and Affiliations

  1. Department of Plastic Surgery, University of Michigan, 1540 E. Hospital Dr., Floor 4, Suite 4-730, Ann Arbor, Michigan, 48105, USA

    Kavitha Ranganathan, Jeremy Lynn, Alicia Snider, Yu Zhang, Noah Nelson, Alexis Donneys, Lauren Buchman & Steven R. Buchman

  2. Therapeutic Systems Research Laboratories, Inc., Ann Arbor, Michigan, USA

    Eric Simon, Dawn Reyna & Elke Lipka

  3. Department of Plastic Surgery, Carilion Clinic, Roanoke, Virginia,, USA

    Jose Rodriguez

Authors
  1. Kavitha Ranganathan
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  2. Eric Simon
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  3. Jeremy Lynn
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  5. Yu Zhang
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  6. Noah Nelson
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  7. Alexis Donneys
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  9. Lauren Buchman
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  10. Dawn Reyna
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  11. Elke Lipka
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Corresponding author

Correspondence to Steven R. Buchman.

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Ranganathan, K., Simon, E., Lynn, J. et al. Novel Formulation Strategy to Improve the Feasibility of Amifostine Administration. Pharm Res 35, 99 (2018). https://doi.org/10.1007/s11095-018-2386-5

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  • DOI: https://doi.org/10.1007/s11095-018-2386-5

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