Optimization of Amifostine Administration for Radioprotection.

Amifostine;Pharmacy and Pharmacology;Health Sciences;Pharmaceutical Sciences

Lu, ZhengNormolle, Daniel Paul ;

University of Michigan

关键词: Amifostine;    Pharmacy and Pharmacology;    Health Sciences;    Pharmaceutical Sciences;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/57589/zlu_1.pdf?sequence=2&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

Amifostine has been shown in randomized trials to protect normal tissues from radiation. It is a thiophosphate prodrug that is dephosphorylated to the active free thiol metabolite, WR-1065, by plasma membrane-bound alkaline phosphatase. Selectivity of amifostine may be due to differences between the microenvironment of normal tissues and tumor (e.g., pH and enzymatic activity) and different uptake processes. We proposed to optimize the use of amifostine as a radiation protector of normal liver, which will permit the safe delivery of higher doses of radiation for patients with both focal and diffuse disease. We carried out nonclinical studies to optimize amifostine selectivity (i.e., the concentration of WR-1065 in liver to tumor) in a rat xenograft model with different dosing routes of drug (systemic vs regional and IV vs SC). The pharmacokinetics of amifostine and WR-1065 were evaluated in a phase I trial of dose-escalating radiation therapy with systemic amifostine for liver cancer patients. Following intravenous dosing of amifostine, the concentrations of WR-1065 in liver and blood were highest at the earliest sampling time and higher doses, while tumor levels were relatively constant with respect to time. Based on our response surface regression model, no significant difference was observed between systemic and regional administrations of amifostine. After subcutaneous dosing of amifostine, optimal selectivity was sustained for a period of 5-20 min. While the liver and tumor concentrations of WR-1065 were initially low and increased steadily over time, blood levels were relatively constant over time. These findings recommend that the highest intravenous dose of amifostine tolerated be administered, and that radiotherapy begin shortly after dosing for liver cancer patients. A subcutaneous dose, which is an easier administration route, may be a reasonable substitute when dosed 5-20 min before radiotherapy. Clinical pharmacokinetic results indicated that amifostine has a short half-life, a small volume of distribution and a large clearance. WR-1065 has a much longer half-life, and larger volume of distribution and clearance as compared to amifostine. In conclusion, amifostine was converted to WR-1065 rapidly and confined to extracellular fluid in the body. WR-1065 was extensively bound in tissues and converted quickly to disulfides.