Preclinical Studies Support Use of Subcutaneous Amifostine Prior to Radiation Therapy to Protect Against Mucositis

GAITHERSBURG, Maryland-Animal studies of 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 (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.

"Rats that were irradiated but not treated show scores of about 3.5. Rats given IV amifostine ½ hour, 2 hours, or 4 hours before radiation had no mucositis. Amifostine given 8 hours before radiation did not prevent mucositis," Dr. Cassatt said.

Subcutaneous amifostine had similar time points. "The conclusion is that amifostine will protect against gamma radiation-induced mucositis in the rat, whether administered either intravenously or subcutaneously. This dose is fairly high but has been used in xerostomia studies in the past. Mucositis can be prevented with IV amifostine given up to 4 hours before radiotherapy and by subcutaneous amifostine given up to 8 hours before radiotherapy," Dr. Cassatt said.

Additional Investigations

The investigators are also studying amifostine pharmacokinetics, particularly the plasma and tissue levels of the active free thiol (WR-1065) metabolite following IV and SC administration. WR-1065 levels in important target tissues including the parotid gland, kidney, and small intestine are being measured.

"We have found little or no difference between blood levels following IV or SC administration. Tissue levels may be somewhat higher following SC administration. Peak levels of WR-1065 occur in blood 5 to 10 minutes following administration. Peak levels of WR-1065 occur in target tissues 30 to 60 minutes following administration," Dr. Cassatt reported.

Next steps for the preclinical research group will be to confirm that amifostine does not protect solid tumors against radiation, to study protection following administration of lower doses, and to study the effects of repeated dosing with regard to protection during fractionated radiotherapy.