口服拓扑替康在晚期实体瘤及肾功能受损患者中的药效学和药代动力学
Pharmacodynamics and pharmacokinetics of oral topotecan in patients with advanced solid tumours and impaired renal function.
作者信息
Devriese Lot A, Witteveen Petronella Els O, Mergui-Roelvink Marja, Smith Deborah A, Lewis Lionel D, Mendelson David S, Bang Yung-Jue, Chung Hyun Choel, Dar Mohammed M, Huitema Alwin D R, Beijnen Jos H, Voest Emile E, Schellens Jan H M
机构信息
Division of Experimental Therapy, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
出版信息
Br J Clin Pharmacol. 2015 Aug;80(2):253-66. doi: 10.1111/bcp.12606. Epub 2015 May 20.
AIMS
The aim of the study was to determine the effect of renal impairment and prior platinum-based chemotherapy on the toxicity and pharmacokinetics of oral topotecan and to identify recommended doses for patients with renal impairment or prior platinum-based (PB) chemotherapy.
METHODS
A multicentre phase I toxicity and pharmacokinetic study of oral topotecan was conducted in patients with advanced solid tumours. Patients were grouped by normal renal function with limited or prior PB chemotherapy or impaired renal function (mild [creatinine clearance (CLcr) = 50-79 ml min(-1) ], moderate [CLcr = 30-49 ml min(-1) ], severe [CLcr <30 ml min(-1) ]).
RESULTS
Fifty-nine patients were evaluable. Topotecan lactone and total topotecan area under the concentration-time curve (AUC) was significantly increased in patients with moderate and severe renal impairment (109% and 174%, respectively, topotecan lactone and 148% and 298%, respectively, total topotecan). Asian patients (23 in total) had higher AUCs than non-Asian patients with the same degree of renal impairment. Thirteen dose-limiting toxicities (DLTs) were observed, which were mostly haematological. The maximum tolerated dose (MTD) was 2.3 mg m(-2) day(-1) , given on days 1 to 5 in a 21 day cycle, for patients with prior PB chemotherapy or mild renal impairment, and 1.2 mg m(-2) day(-1) for patients with moderate renal impairment (suggested dose 1.9 mg m(-2) day(-1) for non-Asians). Due to incomplete enrolment of patients with severe renal impairment, the MTD was determined as ≥ 0.6 mg m(-2) day(-1) in this cohort.
CONCLUSIONS
Oral topotecan dose adjustments are not required in patients with prior PB chemotherapy or mildly impaired renal function, but reduced doses are required for patients with moderate or severe renal impairment.
目的
本研究旨在确定肾功能损害和既往铂类化疗对口服拓扑替康毒性和药代动力学的影响，并确定肾功能损害或既往接受铂类（PB）化疗患者的推荐剂量。
方法
对晚期实体瘤患者进行了一项口服拓扑替康的多中心I期毒性和药代动力学研究。患者按肾功能正常且既往接受有限或PB化疗或肾功能损害（轻度[肌酐清除率（CLcr）=50 - 79 ml·min⁻¹]、中度[CLcr = 30 - 49 ml·min⁻¹]、重度[CLcr < 30 ml·min⁻¹]）进行分组。
结果
59例患者可评估。中度和重度肾功能损害患者的拓扑替康内酯和总拓扑替康浓度 - 时间曲线下面积（AUC）显著增加（拓扑替康内酯分别增加109%和174%，总拓扑替康分别增加148%和298%）。亚洲患者（共23例）在相同程度肾功能损害下的AUC高于非亚洲患者。观察到13例剂量限制性毒性（DLT），大多为血液学毒性。既往接受PB化疗或轻度肾功能损害患者的最大耐受剂量（MTD）为2.3 mg·m⁻²·d⁻¹，在21天周期的第1至5天给药；中度肾功能损害患者的MTD为1.2 mg·m⁻²·d⁻¹（非亚洲患者建议剂量为1.9 mg·m⁻²·d⁻¹）。由于重度肾功能损害患者入组不完全，该队列的MTD确定为≥0.6 mg·m⁻²·d⁻¹。
结论
既往接受PB化疗或轻度肾功能损害的患者无需调整口服拓扑替康剂量，但中度或重度肾功能损害的患者需要降低剂量。
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