Multicentre phase II pharmacological evaluation of rhizoxin
Multicentre phase II pharmacological evaluation of rhizoxin
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DOI：
10.1038/bjc.1996.657
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发表时间：
1996-12-01
影响因子：
8.8
通讯作者：
Verweij, J
中科院分区：
文献类型：
--
作者：
McLeod, HL;Murray, LS;Verweij, J
根霉毒素是一种大环内酯化合物，可与微管蛋白结合并抑制微管组装。Rhizoxin对多种人类肿瘤细胞系和异种移植模型表现出临床前抗肿瘤活性。第一阶段的评估发现，最大耐受剂量为2.6毫克米（-2），与可逆的，但剂量限制，粘膜炎，白细胞减少症和腹泻。随后，EORTC ECSG启动了黑色素瘤、乳腺癌、头颈癌和非小细胞肺癌的临床试验，推荐的II期剂量为2 mg m（-2）。药理学研究与II期试验一起进行，以补充I期试验中有限的药代动力学数据。从69至103名符合条件的患者中获得了II期根霉素研究的血液样本，这些样本可用于36名患者的药代动力学分析。采用高效液相色谱法（HPLC）测定血浆中根霉素浓度，并采用一室模型估计分布后药代动力学参数。根霉毒素从血浆中迅速消除，中位全身清除率为8.41 min（-1）m（-2），消除半衰期为10.4 min。获得部分缓解或病情稳定的患者的根霉毒素浓度-时间曲线下面积（AUC）高于病情进展的患者（中位314 vs 222 nl ml（-1）min; P=0.03）。根据先前的研究预测，观察到血液学和胃肠道毒性，但不能证明与根霉素AUC相关。本研究证明了根霉素从体循环中的快速和可变消除。药效学关系的存在和低水平的全身毒性表明，未来的试验与替代剂量或治疗方案的根霉素是必要的。
Rhizoxin is a macrocyclic lactone compound that binds to tubulin and inhibits microtubule assembly. Rhizoxin demonstrated preclinical anti-tumour activity against a variety of human tumour cell lines and xenograft models. Phase I evaluation found a maximum tolerated rhizoxin dose of 2.6 mg m(-2), with reversible, but dose-limiting, mucositis, leucopenia and diarrhoea. Clinical trials were then initiated by the EORTC ECSG in melanoma, breast, head and neck, and non-small-cell lung cancers with the recommended phase II rhizoxin dose of 2 mg m(-2). Pharmacological studies were instituted with the phase II trials to complement the limited pharmacokinetic data available from the phase I trial. Blood samples were obtained from 69 to 103 eligible patients enrolled in phase II rhizoxin studies, and these were evaluable for pharmacokinetic analysis in 36 patients. Plasma rhizoxin concentrations were determined by high-performance liquid chromatography (HPLC), and post-distribution pharmacokinetic parameters were estimated by a one-compartment model. Rhizoxin was rapidly eliminated from plasma, with a median systemic clearance of 8.41 min(-1) m(-2) and elimination half-life of 10.4 min. Rhizoxin area under the concentration-time curve (AUC) was higher in patients obtaining a partial response or stable disease than in those with progressive disease (median 314 vs 222 nl ml(-1) min; P=0.03). A predicted from previous studies, haematological and gastrointestinal toxicity was observed, but could not be shown to be related to rhizoxin AUC. This study demonstrated the rapid and variable elimination or rhizoxin from the systemic circulation. The presence of pharmacodynamic relationships and the low level of systemic toxicity suggest that future trials of rhizoxin with alternative dosage or treatment schedules are warranted.