O'Reilly S, Rowinsky E, Slichenmyer W, Donehower R C, Forastiere A, Ettinger D, Chen T L, Sartorius S, Bowling K, Smith J, Brubaker A, Lubejko B, Ignacio V, Grochow L B
Johns Hopkins Oncology Center, Baltimore, MD, USA.
J Natl Cancer Inst. 1996 Jun 19;88(12):817-24. doi: 10.1093/jnci/88.12.817.
Topotecan, a topoisomerase I inhibitor that has demonstrated anticancer activity toward leukemias and solid tumors in clinical trials, is eliminated via hepatic and renal routes. However, dosing guidelines for the administration of topotecan to patients with impaired hepatic function have not yet been established.
We compared the maximum tolerated doses (MTDs), the toxic effects, and the pharmacokinetics and pharmacodynamics of topotecan in patients who had refractory, malignant, solid tumors and who either had or lacked hepatic injury. The potential role of three substrate markers of liver function (indocyanin green [ICG]-- a marker of hepatic blood flow; lorazepam--a substrate marker of hepatic glucuronidation; and antipyrine--a substrate marker for cytochrome P450 activity) in optimizing topotecan doses for patients with liver injury was also evaluated.
Twenty-one cancer patients, 14 of whom had hepatic injury due to metastatic disease, biliary obstruction, or cirrhosis, were treated with intravenously delivered courses of topotecan consisting of 0.5, 1.0, or 1.5 mg/m2 of drug per day for 5 days. Most patients received more than one course of treatment, with new courses initiated at 3-week intervals. Patient responses (evaluated by tumor measurements) and treatment-induced toxic effects were assessed. Prior to the initiation of topotecan treatment, patients were given intravenous injections of ICG, lorazepam, and antipyrine to determine the plasma pharmacokinetics of these compounds. The pharmacokinetics of topotecan (both the lactone and the carboxylate forms) were determined by analysis of plasma and urine samples collected on the first day of the first course of drug treatment. Scatter plots of area under the plasma concentration versus time curves in relation to percent decreases in either absolute neutrophil count or platelet count were used to explore the pharmacodynamics of topotecan. The Student's t test and the Mann-Whitney U test were used to compare pharmacokinetic parameters between patients with and without abnormal hepatic function. Correlations were assessed using the Spearman's rank correlation coefficient (rs). Reported P values are based on two-tailed tests of significance.
Patients with hepatic injury tolerated topotecan doses up to 1.5 mg/m2, i.e., the MTD of this drug established in previous studies. The nature and severity of treatment-induced toxic effects and the pharmacokinetics of topotecan were similar in patients with and without liver injury. No differences were observed in the urinary excretion of topotecan between the two patient groups. Clearances of total topotecan and its lactone species correlated only with clearance of ICG (rs = .64, P = .004; and rs = .68, P = .0017, respectively). The pharmacodynamic effects of topotecan were not altered by liver dysfunction.
Cancer patients with hepatic injury can be treated with topotecan at a starting dose of 1.5 mg/m2, given daily for 5 days and administered every 3 weeks. Topotecan dose modifications do not appear to be required for patients with hepatic dysfunction and normal renal function.
拓扑替康是一种拓扑异构酶I抑制剂，在临床试验中已显示出对白血病和实体瘤具有抗癌活性，它通过肝脏和肾脏途径消除。然而，尚未确立针对肝功能受损患者使用拓扑替康的给药指南。
我们比较了拓扑替康在患有难治性恶性实体瘤且有或无肝损伤的患者中的最大耐受剂量（MTD）、毒性作用以及药代动力学和药效学。还评估了三种肝功能底物标志物（吲哚菁绿[ICG]——肝血流标志物；劳拉西泮——肝葡萄糖醛酸化底物标志物；安替比林——细胞色素P450活性底物标志物）在为肝损伤患者优化拓扑替康剂量方面的潜在作用。
21名癌症患者，其中14名因转移性疾病、胆道梗阻或肝硬化而有肝损伤，接受静脉注射拓扑替康疗程治疗，每天给予0.5、1.0或1.5mg/m²药物，共5天。大多数患者接受了不止一个疗程的治疗，新疗程每隔3周开始。评估患者反应（通过肿瘤测量评估）和治疗引起的毒性作用。在开始拓扑替康治疗前，给患者静脉注射ICG、劳拉西泮和安替比林以确定这些化合物的血浆药代动力学。通过分析在第一个疗程药物治疗第一天采集的血浆和尿液样本确定拓扑替康（内酯和羧酸盐形式）的药代动力学。使用血浆浓度-时间曲线下面积相对于绝对中性粒细胞计数或血小板计数百分比下降的散点图来探索拓扑替康的药效学。使用学生t检验和曼-惠特尼U检验比较肝功能正常和异常患者之间的药代动力学参数。使用Spearman等级相关系数（rs）评估相关性。报告的P值基于双侧显著性检验。
肝损伤患者耐受高达1.5mg/m²的拓扑替康剂量，即先前研究中确定的该药物的MTD。有或无肝损伤患者中治疗引起的毒性作用的性质和严重程度以及拓扑替康的药代动力学相似。两组患者之间拓扑替康的尿排泄未观察到差异。总拓扑替康及其内酯形式的清除率仅与ICG清除率相关（rs分别为0.64，P = 0.004；和rs = 0.68，P = 0.0017）。肝功能障碍未改变拓扑替康的药效学作用。
有肝损伤的癌症患者可以接受拓扑替康治疗，起始剂量为1.5mg/m²，每天给药5天，每3周给药一次。对于肝功能障碍且肾功能正常的患者，似乎无需调整拓扑替康剂量。
