A phase I and pharmacokinetic study of MAG-CPT, a water-soluble polymer conjugate of camptothecin.
A phase I and pharmacokinetic study of MAG-CPT, a water-soluble polymer conjugate of camptothecin.
复制标题
DOI：
10.1038/sj.bjc.6600516
复制
发表时间：
2002-09-09
影响因子：
8.8
通讯作者：
ten Bokkel Huinink, W W
中科院分区：
文献类型：
--
作者：
Schoemaker, N E;van Kesteren, C;Rosing, H;Jansen, S;Swart, M;Lieverst, J;Fraier, D;Breda, M;Pellizzoni, C;Spinelli, R;Grazia Porro, M;Beijnen, J H;Schellens, J H M;ten Bokkel Huinink, W W
高分子药物偶联物是一类具有药代动力学前景的新型药物传递系统。抗肿瘤药物喜树碱与水溶性聚合物骨架（MAG-CPT）连接，每4周连续3天输注30分钟给恶性实体肿瘤患者。本研究的目的是确定MAG-CPT的最大耐受剂量、剂量限制性毒性、血浆和尿液药代动力学，并记录其抗肿瘤活性。起始剂量为17 mg m−2 day−1。16名患者接受了7个剂量水平的39个疗程。最大耐受剂量为68 mg m−2 day−1，剂量限制性毒性包括累积膀胱毒性。MAG-CPT和游离喜树碱在第1-3天积累，4-5周后仍可在血浆和尿液中检索到大量MAG-CPT。结合喜树碱和游离喜树碱的半衰期相等，表明游离喜树碱的动力学依赖于释放速率。综上所述，喜树碱的药代动力学发生了显著变化，表明喜树碱的长期暴露受到控制。血液毒性相对较轻，但存在严重的膀胱毒性，这是喜树碱的典型毒性，并且发现剂量有限。英国癌症杂志（2002）21,608-614。doi: 10.1038 / sj.bjc。6600516 www.bjcancer.com©2002英国癌症研究中心
Polymeric drug conjugates are a new and experimental class of drug delivery systems with pharmacokinetic promises. The antineoplastic drug camptothecin was linked to a water-soluble polymeric backbone (MAG-CPT) and administrated as a 30 min infusion over 3 consecutive days every 4 weeks to patients with malignant solid tumours. The objectives of our study were to determine the maximal tolerated dose, the dose-limiting toxicities, and the plasma and urine pharmacokinetics of MAG-CPT, and to document anti-tumour activity. The starting dose was 17 mg m−2 day−1. Sixteen patients received 39 courses at seven dose levels. Maximal tolerated dose was at 68 mg m−2 day−1 and dose-limiting toxicities consisted of cumulative bladder toxicity. MAG-CPT and free camptothecin were accumulated during days 1–3 and considerable amounts of MAG-CPT could still be retrieved in plasma and urine after 4–5 weeks. The half-lives of bound and free camptothecin were equal indicating that the kinetics of free camptothecin were release rate dependent. In summary, the pharmacokinetics of camptothecin were dramatically changed, showing controlled prolonged exposure of camptothecin. Haematological toxicity was relatively mild, but serious bladder toxicity was encountered which is typical for camptothecin and was found dose limiting. British Journal of Cancer (2002) 21, 608–614. doi:10.1038/sj.bjc.6600516 www.bjcancer.com © 2002 Cancer Research UK