Loos W J, Gelderblom H, Sparreboom A, Verweij J, de Jonge M J
Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek) and University Hospital Rotterdam, The Netherlands.
Clin Cancer Res. 2000 Jul;6(7):2685-9.
Anticancer drugs still are dosed based on the body-surface area (BSA) of the individual patient, although the BSA is not the main predictor of the clearance for the majority of drugs. The relevance of BSA-based dosing has not been evaluated for topotecan yet. A retrospective pharmacological analysis was performed of kinetic data from four clinical Phase I studies in which topotecan was administered p.o. as a single agent combined with data from a combination study of topotecan and cisplatin. A strong correlation (r = 0.91) was found between the area under the plasma concentration time curve of the lactone and carboxylate forms of topotecan by plotting 326 data sets obtained from 112 patients receiving oral topotecan at dose levels ranging from 0.15-2.70 mg/m2. The intrapatient variability, studied in 47 patients sampled for 3 or more days, for the apparent lactone clearance, ranged from 7.4-69% (mean, 24 +/- 13%; median, 20%). The interpatient variabilities in the lactone clearance, calculated with the data of all studied patients, expressed in liter/h/m2 and in liter/h were 38% and 42%, respectively. In view of the relatively high inter- and intrapatient variabilities in topotecan clearance, in contrast to a variability of only 12% in the BSA of the studied patients, no advantage of BSA-based dosing was found over fixed dose regimens.
尽管体表面积并非大多数药物清除率的主要预测指标，但抗癌药物的剂量仍根据个体患者的体表面积（BSA）来确定。目前尚未评估基于体表面积给药对于拓扑替康的相关性。对四项临床I期研究的动力学数据进行了回顾性药理学分析，这些研究中拓扑替康作为单一药物口服给药，并结合了拓扑替康与顺铂联合研究的数据。通过绘制从112名接受口服拓扑替康的患者获得的326个数据集，剂量范围为0.15 - 2.70mg/m²，发现拓扑替康内酯和羧酸盐形式的血浆浓度-时间曲线下面积之间存在强相关性（r = 0.91）。在47名被采样3天或更长时间的患者中研究的患者内变异性，对于表观内酯清除率，范围为7.4 - 69%（平均值，24±13%；中位数，20%）。根据所有研究患者的数据计算的内酯清除率的患者间变异性，以升/小时/平方米和升/小时表示，分别为38%和42%。鉴于拓扑替康清除率存在相对较高的患者间和患者内变异性，与所研究患者体表面积仅12%的变异性形成对比，未发现基于体表面积给药相对于固定剂量方案有任何优势。
