New dosing regimens for amifostine: a pilot study to compare the relative bioavailability of oral and subcutaneous administration with intravenous infusion.
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.
Bonner
H S
HS
Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia 19104, USA.
Shaw
L M
LM
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D004999:Amifostine / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D018592:Cross-Over Studies; D004311:Double-Blind Method; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D007279:Injections, Subcutaneous; D008297:Male; D010865:Pilot Projects; D011485:Protein Binding; D011837:Radiation-Protective Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*
D011837:Radiation-Protective Agents; D004999:Amifostine