New Dosing Regimens for Amifostine: A Pilot Study to Compare the Relative Bioavailability of Oral and Subcutaneous Administration with Intravenous Infusion

Abstract

A phase I clinical trial was conducted to assess thefeasibility of a more convenient and safe dosing regime for the cytoprotective drug amifostine. Two alternative routes of administration, oral and subcutaneous (s.q.), each with a dose of 500 mg, were compared to a 7.5-minute intravenous (i.v.) infusion, with a dose of 200 mg/m2, in normal, healthy volunteers (N = 12). Bioavailability of amifostine (parent drug) and its pharmacologically active metabolite, WR-1065, was evaluated by comparing the area under the concentration-time curve (AUC) derived from HPLC analysis of amifostine and both protein-free and protein-bound WR-1065 in all three routes of administration. Results showed that SQ (but not oral) administration of amifostine could provide a more effective dosing regimen, in terms of both a reasonable AUC for the bound form of WR-1065 and decreased toxicity, compared to i.v. delivery. These data suggest that the protein-bound form of WR-1065 plays an important role in contributing to the bioavailability of this clinically useful cytoprotective drug.