Novel Formulation Strategy to Improve the Feasibility of Amifostine Administration
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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.
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.
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.
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 wordsamifostine head and neck cancer hypotension radiation
Alpha-modified minimal essential medium
Areas under curve
Head and neck cancer
Liquid chromatography-mass spectrometry
- MC3T3 cells
Osteogenic differentiation medium
Phosphate Buffered Saline
Ultra performance liquid chromatography
Active Amifostine metabolite
Modified WR-1065 N-methymaleimide
Acknowledgments and Disclosures
This work was support by R01 CA 125187 awarded to Steven R. Buchman, MD by the Nation Institutes of Health (NIH).
- 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
- 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
- 19.US Food and Drug Administration. Ethyol® (amifostine) for injection. Washington, D.C.Google Scholar