GAITHERSBURG, Maryland-Animal studies of amifostine(Drug information on amifostine) (Ethyol) are being used to explore optimal subcutaneous (SC) treatment and to refine approaches to dosing and scheduling of the radioprotectant. David R. Cassatt, PhD, of MedImmune, Inc., Gaithersburg, Maryland, described current preclinical work with amifostine.
"There are several unresolved issues regarding amifostine use," he said. "First we need to protect normal tissues and not protect tumors from radiotherapy or chemotherapy. Second we need to reduce the severity of amifostine side effects such as hypotension. We also need to improve the ease of administration. The IV formulation is effective but difficult, especially in the radiotherapy setting. Finally, we want to expand the indications for amifostine beyond xerostomia and nephrotoxicity. Currently amifostine is approved for intravenous administration, to prevent nephrotoxicity associated with cisplatin(Drug information on cisplatin) (Platinol) and xerostomia associated with radiotherapy."
Also being studied are effects of amifostine on mucositis, esophagitis, pneumonitis, protection of bone-marrow cells, and myelodysplastic syndrome. "The approved indication for radiotherapy is for prevention of xerostomia only. Mucositis would be an important additional indication," Dr. Cassatt said.
IV vs SC Routes
One limitation to amifostine use is the need for intravenous administration. Dr. Cassatt said that the initial intravenous bolus dose spike is sometimes associated with hypotension.
The goals of Dr. Cassatt’s preclinical studies are to determine whether SC administration is equivalent to IV administration, to explore mucositis as an endpoint, and to define markers that predict protection against radiation injury. Radioprotection against salivary gland damage is being studied in rats. Protection against mucositis is being studied in mice and dogs.
"We give rats amifostine intra-enously or subcutaneously, and at certain periods after the administration, we anesthetize and restrain the rats, put a shield around everything except the head and the neck to get exposure only to the local area, and give 15.3 Gy of gamma irradiation. Over a period of 10 days or so we examine the rats daily using the Parkins mucositis scale, looking at erythema and looking at edema," Dr. Cassatt said. Differences in degree of mucositis are readily apparent in this model. The main questions being asked are whether subcutaneous amifostine can protect against radiation-induced mucositis and how long the effective pretreatment interval is.