Schellens J H, Creemers G J, Beijnen J H, Rosing H, de Boer-Dennert M, McDonald M, Davies B, Verweij J
Department of Medical Oncology, Rotterdam Cancer Institute, The Netherlands.
Br J Cancer. 1996 May;73(10):1268-71. doi: 10.1038/bjc.1996.243.
The results of preclinical and clinical studies indicate enhanced antineoplastic activity of topotecan (SKF 104864-A) when administered as a chronic treatment. We determined the apparent bioavailability and pharmacokinetics of topotecan administered orally to 12 patients with solid tumours in a two-part crossover study. The oral dose of 1.5 mg m-2 was administered as a drinking solution of 200 ml on day 1. The i.v. dose of 1.5 mg m-2 was administered as a 30 min continuous infusion on day 2. The bioavailability was calculated as the ratio of the oral to i.v. area under the curve (AUC) calculated up to the last measured time point. The oral drinking solution was well tolerated. The bioavailability revealed moderate inter-patient variation and was 30% +/- 7.7% (range 21-45%). The time to maximum plasma concentration after oral administration (Tmax) was 0.78 h (median; range 0.33-2.5). Total i.v. plasma clearance of topotecan was 824 +/- 154 ml min-1 (range 535-1068 ml min(-1)). The AUC ratio of topotecan and the lactone ring-opened hydrolysis product (hydroxy acid) was of the same order after oral (0.34-1.13) and i.v. (0.47-0.98) administration. The bioavailability of topotecan after oral administration illustrates significant systemic exposure to the drug which may enable chronic oral treatment.
临床前和临床研究结果表明，拓扑替康（SKF 104864-A）进行长期治疗时抗肿瘤活性增强。在一项分为两部分的交叉研究中，我们测定了12例实体瘤患者口服拓扑替康后的表观生物利用度和药代动力学。第1天，以200 ml饮用溶液的形式给予1.5 mg/m²的口服剂量。第2天，以30分钟持续输注的形式给予1.5 mg/m²的静脉注射剂量。生物利用度计算为口服给药与静脉注射给药至最后一个测量时间点的曲线下面积（AUC）之比。口服饮用溶液耐受性良好。生物利用度显示患者间存在中度差异，为30%±7.7%（范围21%-45%）。口服给药后达到最大血浆浓度的时间（Tmax）为0.78小时（中位数；范围0.33 - 2.5小时）。拓扑替康的静脉血浆总清除率为824±154 ml/min（范围535 - 1068 ml/min）。口服（0.34 - 1.13）和静脉注射（0.47 - 0.98）给药后，拓扑替康与内酯环开环水解产物（羟基酸）的AUC比值处于同一水平。口服拓扑替康后的生物利用度表明该药物有显著的全身暴露，这可能使慢性口服治疗成为可能。
