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
First Online:
Received:
Accepted:
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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.

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

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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).

References

  1. 1.
    Cohen EM, Schapira L. Head and Neck Cancer: Statistics. Cancer.net.; 2017 September. Available from: http://www.cancer.net/cancer-types/head-and-neck-cancer/statistics
  2. 2.
    Moreau MF, Gallois Y, Baslé MF, Chappard D. Gamma irradiation of human bone allografts alters medullary lipids and releases toxic compounds for osteoblast-like cells. Biomaterials. 2000;21(4):369–76.CrossRefPubMedGoogle Scholar
  3. 3.
    Marx RE. Osteoradionecrosis: a new concept of its pathophysiology. J Oral Maxillofac Surg. 1983;41(5):283–8.CrossRefPubMedGoogle Scholar
  4. 4.
    Marx RE, Johnson RP. Studies in the radiobiology of osteoradionecrosis and their clinical significance. Oral Surg Oral Med Oral Pathol. 1987;64(4):379–90.CrossRefPubMedGoogle Scholar
  5. 5.
    Monson LA, Nelson NS, Donneys A, Farberg AS, Tchanque-Fossuo CN, Deshpande SS, et al. Amifostine treatment mitigates the damaging effects of radiation on distraction osteogenesis in the murine mandible. Ann Plast Surg. 2016;77(2):164–8.CrossRefPubMedGoogle Scholar
  6. 6.
    Donneys A, Nelson NS, Page EE, Deshpande SS, Felice PA, Tchanque-Fossuo CN, et al. Targeting angiogenesis as a therapeutic means to reinforce osteocyte survival and prevent nonunions in the aftermath of radiotherapy. Head Neck. 2015;37(9):1261–7.CrossRefPubMedGoogle Scholar
  7. 7.
    Wu HY, Hu ZH, Jin T. Sustained-release microspheres of amifostine for improved radio-protection, patient compliance, and reduced side effects. Drug Deliv. 2016;23(9):3704–11.CrossRefPubMedGoogle Scholar
  8. 8.
    Kamran MZ, Ranjan A, Kaur N, Sur S, Tandon V. Radioprotective agents: strategies and translational advances. Med Res Rev. 2016;36(3):461–93.CrossRefPubMedGoogle Scholar
  9. 9.
    Kouvaris JR, Kouloulias VE, Vlahos LJ. Amifostine: the first selective-target and broad-Spectrum Radioprotector. Oncologist. 2007;12(6):738–47.CrossRefPubMedGoogle Scholar
  10. 10.
    Felice PA, Gong B, Ahsan S, Deshpande SS, Nelson NS, Donneys A, et al. Raman spectroscopy delineates radiation-induced injury and partial rescue by amifostine in bone: a murine mandibular model. J Bone Miner Metab. 2015;33(3):279–84.CrossRefPubMedGoogle Scholar
  11. 11.
    Tchanque-Fossuo CN, Donneys A, Razdolsky ER, Monson LA, Farberg AS, Deshpande SS, et al. Quantitative histologic evidence of Amifostine-induced Cytoprotection in an irradiated murine model of mandibular distraction osteogenesis. Plast Reconstr Surg. 2012;130(6):1199–207.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Donneys A, Tchanque-Fossuo CN, Blough JT, Nelson NS, Deshpande SS, Buchman SR. Amifostine preserves osteocyte number and osteoid formation in fracture healing following radiotherapy. J Oral Maxillofac Surg. 2014;72(3):559–66.CrossRefPubMedGoogle Scholar
  13. 13.
    Page EE, Deshpande SS, Nelson NS, Felice PA, Donneys A, Rodriguez JJ, et al. Prophylactic administration of Amifostine protects vessel thickness in the setting of irradiated bone. J Plast Reconstr Aesthet Surg. 2015;68(1):98–103.CrossRefPubMedGoogle Scholar
  14. 14.
    Sarhaddi D, Tchanque-Fossuo CN, Poushanchi B, Donneys A, Deshpande SS, Weiss DM, et al. Amifostine protects vascularity and improves Union in a Model of irradiated mandibular fracture healing. Plast Reconstr Surg. 2013;132(6):1542–9.CrossRefPubMedGoogle Scholar
  15. 15.
    Polyatskaya Y, Nelson NS, Rodriguez JJ, Zheutlin AR, Deshpande SS, Felice PA, et al. Prophylactic amifostine prevents a pathologic vascular response in a murine model of expander-based breast reconstruction. J Plast Reconstr Aesthet Surg. 2016;69(2):234–40.CrossRefPubMedGoogle Scholar
  16. 16.
    Tchanque-Fossuo CN, Gong B, Poushanchi B, Donneys A, Sarhaddi D, Gallagher KK, et al. Raman spectroscopy demonstrates Amifostine induced preservation of bone mineralization patterns in the irradiated murine mandible. Bone. 2013;52(2):712–7.CrossRefPubMedGoogle Scholar
  17. 17.
    Felice PA, Ahsan S, Perosky JE, Deshpande SS, Nelson NS, Donneys A, et al. Prophylactic Amifostine preserves the biomechanical properties of irradiated bone in the murine mandible. Plast Reconstr Surg. 2014;133(3):314e–21e.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Tchanque-Fossuo CN, Donneys A, Deshpande SS, Nelson NS, Boguslawski MJ, Gallagher KK, et al. Amifostine remediates the degenerative effects of radiation on the mineralization capacity of the murine mandible. Plast Reconstr Surg. 2012;129(4):646e–55e.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    US Food and Drug Administration. Ethyol® (amifostine) for injection. Washington, D.C.Google Scholar
  20. 20.
    Calabro-Jones PM, Fahey RC, Smoluk GD, Ward JF. Alkaline phosphatase promotes radioprotection and accumulation of WR-1065 in V79-171 cells incubated in medium containing WR-2721. Int J Radiat Biol Relat Stud Phys Chem Med. 1985;47(1):23–7.CrossRefPubMedGoogle Scholar
  21. 21.
    Ryan SV, Carrithers SL, Parkinson SJ, Shurk C, Nuss C, Pooler PM. Hypotensive mechanisms of amifostine. J Clin Pharmacol. 1996;36(4):365–73.CrossRefPubMedGoogle Scholar
  22. 22.
    Gula A, Ren L, Zhou Z, Lu D, Wang S. Design and evaluation of biodegradable enteric microcapsules of amifostine for oral delivery. Int J Pharm. 2013;453(2):441–7.CrossRefGoogle Scholar
  23. 23.
    Oppenheimer AJ, Rhee ST, Goldstein SA, Buchman SR. Force-induced craniosynostosis in the murine sagittal suture. Plast Reconstr Surg. 2009;124(6):1840–8.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Rickard DJ, Kassem M, Hefferan TE, Sarkar G, Spelsberg TC, Riggs BL. Isolation and characterization of osteoblast precursor cells from human bone marrow. J Bone Miner Res. 2009;11(3):312–24.CrossRefGoogle Scholar
  25. 25.
    Calabro-Jones PM, Aquilera JA, Ward JF, Smoluk GD, Fahey RC. Uptake of WR-2721 derivatives by cells in culture: identification of the transported form of the drug. Cancer Res. 1988;48:3634–40.PubMedGoogle Scholar
  26. 26.
    Akbulut S, Sevmis S, Karakayali H, Bayraktar N, Unlukaplan M, Oksuz E, et al. Amifostine enhances the antioxidants and hepatoprotective effects of UW and HTK preservation solutions. World J Gastroenterol. 2014;20(34):12292–300.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Santini V, Giles FJ. The potential of amifostine: from cytoprotectant to therapeutic agent. Haematologica. 1999;84(11):1035–42.PubMedGoogle Scholar
  28. 28.
    Verstappen CC, Postma TJ, Geldof AA, Heimans JJ. Amifostine protects against chemotherapy-induced neurotoxicity: an in vitro investigation. Anticancer Res. 2004;24(4):2337–41.PubMedGoogle Scholar
  29. 29.
    Jellema AP, Slotman BJ, Muller MJ, Leemans CR, Smeele EL, Hoekman K, et al. Radiotherapy alone, versus radiotherapy with amifostine 3 times weekly, versus radiotherapy with amifostine 5 times weekly. Cancer. 2006;107(3):544–53.CrossRefPubMedGoogle Scholar
  30. 30.
    Akbulut S, Elbe H, Eric C, Dogan Z, Toprak G, Otan E, et al. Cytoprotective effects of amifostine, ascorbic acid and N-acetylcysteine against methotrexate-induced hepatotoxicity in rats. World J Gastroenterol. 2014;20(29):10158–65.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Mandal TK, Bostanian LA, Graves RA, Chapman SR, Womack I. Development of biodegradable microcapsules as carrier for oral controlled delivery of amifostine. Drug Dev Ind Pharm. 2002;28(3):339–44.CrossRefPubMedGoogle Scholar
  32. 32.
    Pamujula S, Kishore V, Rider B, Fermin CD, Graves RA, Agrawal KC, et al Radioprotection in mice following oral delivery of amifostine nanoparticles. Int J Radiat Biol. 2005;81(3):251–7.CrossRefPubMedGoogle Scholar

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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