PHASE-I TRIAL WITH PHARMACOKINETICS OF CB10-277 GIVEN BY 24 HOURS CONTINUOUS INFUSION
PHASE-I TRIAL WITH PHARMACOKINETICS OF CB10-277 GIVEN BY 24 HOURS CONTINUOUS INFUSION
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DOI：
10.1038/bjc.1993.67
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发表时间：
1993-02-01
影响因子：
8.8
通讯作者：
CALVERT, AH
中科院分区：
文献类型：
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作者：
FOSTER, BJ;NEWELL, DR;CALVERT, AH
达卡巴嗪类似物 CB10-277 的短期输注试验的剂量限制性毒性是恶心和呕吐，这似乎与母药的血浆峰值水平有关。此外，根据小鼠研究，这些剂量限制性毒性发生在单甲基代谢物低于最佳水平时，而单甲基代谢物是抗肿瘤活性所需的假定物质。考虑了一种替代方案，该方案可以避免短时间输注的母药血浆峰值水平，同时可能允许增加产生的单甲基代谢物的量。因此，探索了每 21 天重复一次的 24 小时连续输注方案。22 名患者接受了 42 个疗程，剂量范围为 4,700-15,000 mg m-2。剂量限制性毒性是骨髓抑制（白细胞减少和血小板减少）。尽管也发生恶心和呕吐，但通过常规止吐治疗可以控制。其他毒性包括腹泻、幻觉、不适、肌肉疼痛、头痛和潮红，所有毒性均低于或等于 WHO 2 级。药代动力学研究共进行了 13 个疗程，其中包括所有剂量水平。母体药物的平均 t1/2 为 178 分钟。母体药物和单甲基代谢物最高剂量下的浓度 x 时间曲线下面积 (AUC) 分别为 2,350 和 9 mM x 分钟。与 CB10-277 短期输注试验的结果相比，这种单甲基代谢物 AUC 和相关的骨髓抑制与小鼠中确定的临床前数据相比显示出更有利的结果。因此，该药物的推荐II期剂量和方案为12,000 mg m-2，24小时连续输注。
The dose limiting toxicities of the short infusion trial of the dacarbazine analog, CB10-277, were nausea and vomiting which appeared to be related to the peak plasma level of the parent drug. In addition, based on mouse studies, these dose limiting toxicities occurred at a less than optimal level of the monomethyl metabolite, the presumed species required for antitumour activity. An alternative schedule that would avoid the parent drug peak plasma levels of short infusion, while possibly allowing an increase in the amount of monomethyl metabolite produced was considered. Thus, a 24 h continuous infusion schedule, repeated every 21 days was explored.Twenty-two patients received 42 courses with a dose range of 4,700-15,000 mg m-2. The dose limiting toxicity was myelosuppression (leucopenia and thrombocytopenia). Although nausea and vomiting also occurred, it was managable with routine antiemetic therapy. Other toxicities included diarrhoea, hallucinations, malaise, muscle ache, headache and flushing and all were less-than-or-equal-to WHO grade 2. Pharmacokinetic studies were performed with 13 courses which included all dose levels. The mean t1/2 of the parent drug was 178 min. Area under the concentration x time curve (AUC) at the highest dose for the parent drug and the monomethyl metabolite were 2,350 and 9 mM x minutes, respectively. This monomethyl metabolite AUC and the associated myelosuppression showed a more favourable comparison to the preclinical data determined in mice than the results from the short infusion trial of CB10-277. Therefore, the recommended Phase II dose and schedule of this drug was 12,000 mg m-2 given by 24 h continuous infusion.