Schilder R J, LaCreta F P, Perez R P, Johnson S W, Brennan J M, Rogatko A, Nash S, McAleer C, Hamilton T C, Roby D
Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia 19111-2497.
Cancer Res. 1994 Feb 1;54(3):709-17.
Ormaplatin (tetraplatin, NSC 363812) is a platinum(IV) analogue that is active against cisplatin-resistant cell lines in preclinical models. A schedule previously shown to be active and well tolerated for cisplatin was evaluated in 26 patients. Ormaplatin was administered over a dose range of 4.4-60.8 mg/m2 i.v. given over 30 min on a day 1 and day 8 schedule every 28 days. Twenty-three patients had received prior chemotherapy, and the median performance status was 1. Nausea/vomiting (> or = grade 2) occurred in 40% of patients but was well controlled with standard antiemetic therapy. One patient had grade 2 renal toxicity and 1 patient had grade 3 hepatotoxicity (grade 2 pretreatment). No toxicity limited the dose given during the first course. With repeated drug administration delayed severe neurotoxicity developed in 4 patients, manifested as a sensory polyneuropathy in 3 patients and a possible autonomic neuropathy in one. Prospective nerve conduction studies did not detect subclinical neuropathy prior to the onset of symptoms. Patients who received cumulative doses above 200 mg/m2 were at increased risk for developing neurotoxicity. Plasma elimination of ultrafilterable platinum (measured by atomic absorption spectrometry) was biphasic with a harmonic mean terminal half-life of 15.8 h. The mean total body clearance and renal clearance of ultrafilterable platinum were 173 and 29.8 ml/min/m2, respectively. Thus, renal clearance accounted for 16% of total clearance suggesting that extensive protein/tissue binding was responsible for the majority of platinum clearance. Approximately 60% of the platinum is protein bound (one-half irreversibly) at the end of the infusion. Pharmacokinetic parameters were not dose dependent. No pharmacokinetic parameters were more predictive of neurotoxicity than the cumulative ormaplatin dose. A phase II dose cannot be recommended on this schedule because severe and unpredictable neurotoxicity precludes the administration of more than three cycles at the three highest doses levels tested.
奥马铂（四铂，NSC 363812）是一种铂（IV）类似物，在临床前模型中对顺铂耐药细胞系具有活性。对26例患者评估了一种先前显示对顺铂有活性且耐受性良好的给药方案。奥马铂静脉注射剂量范围为4.4 - 60.8mg/m²，于第1天和第8天给药，每次30分钟，每28天一个疗程。23例患者曾接受过化疗，中位体能状态为1。40%的患者出现恶心/呕吐（≥2级），但通过标准止吐治疗得到良好控制。1例患者出现2级肾毒性，1例患者出现3级肝毒性（治疗前为2级）。在第一个疗程中，没有毒性限制给药剂量。随着药物的重复给药，4例患者出现延迟性严重神经毒性，3例表现为感觉性多发性神经病，1例可能为自主神经病变。前瞻性神经传导研究在症状出现前未检测到亚临床神经病变。接受累积剂量超过200mg/m²的患者发生神经毒性的风险增加。通过原子吸收光谱法测量的可超滤铂的血浆消除呈双相性，谐波平均终末半衰期为15.8小时。可超滤铂的平均全身清除率和肾清除率分别为173和29.8ml/min/m²。因此，肾清除率占总清除率的16%，这表明大量的蛋白质/组织结合是铂清除的主要原因。输注结束时，约60%的铂与蛋白质结合（其中一半不可逆）。药代动力学参数与剂量无关。没有药代动力学参数比奥马铂累积剂量更能预测神经毒性。在此给药方案下不能推荐II期剂量，因为严重且不可预测的神经毒性使得在测试的三个最高剂量水平下无法给药超过三个疗程。
