Cassatt David R, Fazenbaker Christine A, Kifle Gizachew, Bachy Christine M
Department of Molecular Biology/Biochemistry, MedImmune, Inc, Gaithersburg, MD 20878, USA.
Semin Oncol. 2003 Dec;30(6 Suppl 18):31-9. doi: 10.1053/j.seminoncol.2003.11.039.
The chemo- and radioprotectant drug amifostine (Ethyol; MedImmune, Inc, Gaithersburg, MD) is approved for intravenous (IV) administration; however, the subcutaneous (SC) route is being explored as a practical alternative. We have previously reported equivalence between IV and SC administration using a rat model of radioprotection and active metabolite (WR-1065) tissue pharmacokinetics. To examine the more clinically relevant fractionated and hyperfractionated radiation schedules and the effects of variations in the time of amifostine administration, we expanded these studies to include radioprotection and pharmacokinetic studies of WR-1065 using multiple dosing. To measure radioprotection using a fractionated radioprotection model, rats were given amifostine over a 1-week period at various doses (25 mg/kg, 50 mg/kg, 100 mg/kg; or 162.5 mg/m(2), 325 mg/m(2), 650 mg/m(2), respectively) IV or SC daily 30 minutes before exposure to 7.5 Gy/dose. Rats were fully protected from mucositis at the highest amifostine dose, with protection diminishing as the amifostine was decreased. Equivalent protection was observed whether the drug was given IV or SC. When the number of days of amifostine administration was reduced, protection was diminished. Amifostine also protected against radiation delivered using a 1-week hyperfractionated schedule (4.5 Gy/exposure twice daily), with optimal protection occurring when the drug was administered bid 30 minutes before each exposure (50 mg/kg) or every day before the morning exposure (100 mg/kg). The need for daily dosing to achieve optimal radioprotection was consistent with the tissue pharmacokinetics of the active metabolite. We found that WR-1065 did not accumulate in tissues or in SC-implanted tumors when amifostine was administered daily for 3 weeks. In addition, tissue and tumor levels of WR-1065 declined to baseline 24 hours after each amifostine dose. In a monkey pharmacokinetic model, plasma levels of WR-1065 (characterized by a pronounced spike of WR-1065 immediately after IV administration that was absent when the drug was given SC) were similar to those of humans; however, levels of WR-1065 in the tissues were higher 30 minutes following SC administration and were equivalent 60 minutes following IV or SC administration. These results suggest that maximum tissue levels and protection occur when amifostine is given 30 to 60 minutes before radiation exposure, that treatment breaks reduce the radioprotection by amifostine, and that protection from hyperfractionated radiation is dependent on amifostine dose and schedule.
化疗和放疗防护药物氨磷汀（Ethyol；MedImmune公司，马里兰州盖瑟斯堡）已获批用于静脉注射给药；然而，皮下注射途径正作为一种切实可行的替代方法进行探索。我们之前曾报道，在大鼠辐射防护模型和活性代谢产物（WR - 1065）组织药代动力学方面，静脉注射和皮下注射给药具有等效性。为了研究更具临床相关性的分次和超分次放疗方案以及氨磷汀给药时间变化的影响，我们扩展了这些研究，纳入了使用多次给药的WR - 1065辐射防护和药代动力学研究。为了使用分次辐射防护模型测量辐射防护效果，在1周时间内，以不同剂量（分别为25 mg/kg、50 mg/kg、100 mg/kg；或162.5 mg/m²、325 mg/m²、650 mg/m²）每日在暴露于7.5 Gy/剂量前30分钟经静脉或皮下给予大鼠氨磷汀。在氨磷汀最高剂量时，大鼠完全免受黏膜炎影响，随着氨磷汀剂量降低，防护效果减弱。无论药物经静脉还是皮下给药，均观察到等效的防护效果。当氨磷汀给药天数减少时，防护效果减弱。氨磷汀也能防护采用1周超分次放疗方案（每次照射4.5 Gy，每日两次）的辐射，当在每次照射前30分钟（50 mg/kg）或每天早晨照射前（100 mg/kg）给予药物时，可实现最佳防护效果。实现最佳辐射防护需要每日给药，这与活性代谢产物的组织药代动力学一致。我们发现，当每日给予氨磷汀3周时，WR - 1065不会在组织或皮下植入的肿瘤中蓄积。此外，每次氨磷汀给药后24小时，WR - 1065的组织和肿瘤水平降至基线。在猴药代动力学模型中，WR - 1065的血浆水平（静脉注射后立即出现明显的WR - 1065峰值，皮下给药时则无此现象）与人类相似；然而，皮下给药后30分钟，组织中WR - 1065的水平较高，静脉注射或皮下给药后60分钟时两者相当。这些结果表明，在辐射暴露前30至60分钟给予氨磷汀时可达到最大组织水平和防护效果，治疗中断会降低氨磷汀的辐射防护效果，并且超分次辐射的防护效果取决于氨磷汀的剂量和给药方案。
