topotecan的临床药物动力学。
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Herben VM,十Bokkel Huinink WW, Beijnen JH
topotecan的临床药物动力学。
Pharmacokinet。1996年8月,31 (2):85 - 102。
- PubMed ID
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8853931 (在PubMed]
- 文摘
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Topotecan (Hycamtin),喜树碱的半合成水溶性衍生物,是一种DNA拓扑异构酶的有效抑制剂体外,并演示了其鼓励各种肿瘤的抗肿瘤活性,包括卵巢癌、小细胞肺癌。现在在美国批准,topotecan已完成单第一阶段测试;II期和III期临床试验正在进行。在生理条件下的内酯一半topotecan经历了一个快速、可逆pH-dependent转换到一个羧酸盐open-ring形式,缺乏拓扑异构酶I抑制活动。在平衡pH值7.4 open-ring主导形式。Topotecan稳定注入液体的酒石酸(pH值< 4.0),但在等离子体不稳定,要求立即deproteinisation冷甲醇后提取的血液采样和存储-30摄氏度保存内酯形式。Topotecan已经在第一阶段试验管理几个注入时间从30分钟到21天。等离子体衰变topotecan浓度通常适合2-compartment模型。快速水解topotecan内酯导致等离子体羧酸盐水平超过内酯水平早在45分钟后30分钟注入的开始。血浆浓度峰值和等离子concentration-versus-time曲线下的面积(AUC)显示线性关系增加剂量。 No evidence of drug accumulation is seen with daily 30-minute infusions for 5 consecutive days. Topotecan lactone is widely distributed into the peripheral space, with a mean volume of distribution (Vd) at steady-state of 75 L/m2. The mean total body clearance of the lactone form is 30 L/h/m2, with a mean elimination half-life (t1/2 beta) of 3 hours; renal clearance accounts for approximately 40% of the administered dose with a large interindividual variability. The oral bioavailablity of topotecan is approximately 35%. The low bioavailability may be caused by hydrolysis of topotecan lactone in the gut, yielding substantial amounts of the open-ring form, which is poorly absorbed. Renal dysfunction may decrease topotecan plasma clearance. Creatinine clearance is significantly, but poorly, correlated with topotecan clearance. Hepatic impairment does not influence topotecan disposition. Indices of systemic exposure (steady-state concentrations and AUC) are correlated with the extent of myelotoxicity. Sigmoidal functions adequately describe the relationships between systemic exposure and the percentage decrease in neutrophils.