A phase I and pharmacokinetic study of didox administered by 36 hour infusion. The Cancer Research Campaign Phase I/II Clinical Trials Committee.
A phase I and pharmacokinetic study of didox administered by 36 hour infusion. The Cancer Research Campaign Phase I/II Clinical Trials Committee.
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DOI：
10.1038/bjc.1990.98
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发表时间：
1990-03
影响因子：
8.8
通讯作者：
Harris AL
中科院分区：
文献类型：
--
作者：
Carmichael J;Cantwell BM;Mannix KA;Veale D;Elford HL;Blackie R;Kerr DJ;Kaye SB;Harris AL
12例患者给予新型核糖核苷酸还原酶抑制剂地多昔单抗36h静脉滴注。最大耐受量为6gm-2，超过该剂量可观察到剂量限制性肝毒性。与使用30分钟输液的患者相比，使用36小时输液的患者耐受性明显更好；特别是，没有恶心或呕吐的报告。在这些患者中没有看到任何反应。在6 g m~(-2)的剂量下，对4名患者的36小时和30分钟的输液进行了详细的药代动力学比较。母药AUC值在36小时输注时较低，为67.8微克毫升-1小时-1，而在30分钟输注时为232微克毫升-1小时-1。输注36h后，3-羟基代谢物的AUC值要高得多：55.4，而18.6微克·ml-1h-1。相反，输注36h后未检测到酰胺代谢物，但输注30min后AUC值为23微克ml-1h-1。30分钟输注6g·m-2后，平均峰值血浆浓度为72微克·m~(-1)，而长时间输注后为2.8微克·ml~(-1)。输注36h后清除量较高：97.6vs24.4h-1。
Twelve patients were treated with didox, a new ribonucleotide reductase inhibitor, by 36 h infusion. The maximum tolerated dose was 6 g m-2, above which dose-limiting hepatic toxicity was observed. Patient tolerance was significantly better using the 36 h infusion compared to patients receiving the drug by a 30 min infusion; in particular, there were no reports of nausea or vomiting. No responses were seen in these patients. Detailed pharmacokinetics were performed at 6 g m-2 comparing the 36 h and 30 min infusions in four patients. Parent drug AUC values were lower for the 36 h infusion, 67.8 micrograms ml-1 h-1 compared to 232 micrograms ml-1 h-1 for the 30 min infusion. AUC values for the 3-hydroxy metabolite were much higher following the 36 h infusion: 55.4 compared to 18.6 micrograms ml-1 h-1. In contrast, the amide metabolite was not detected following the 36 h infusion, but AUC values of 23 micrograms ml-1 h-1 were seen after the 30 min infusion. The mean peak plasma level was 72 micrograms ml-1 following 6 g m-2 given by a 30 min infusion compared to 2.8 micrograms ml-1 following the prolonged infusion. Clearance was higher following the 36 h infusion: 97.6 versus 24.4 l h-1.