新鬼臼毒素衍生物NK 611的药代动力学和药效学。AIO组PHASE-1和APOH的研究。,Cancer Chemotherapy and Pharmacology

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新鬼臼毒素衍生物NK 611的药代动力学和药效学。AIO组PHASE-1和APOH的研究。
Cancer Chemotherapy and Pharmacology ( IF 2.7 ) Pub Date : 1996-01-01 , DOI: 10.1007/s002800050474
K Mross ₁ , A Hüttmann , K Herbst , A R Hanauske , T Schilling , C Manegold , K Burk , D K Hossfeld

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NK 611是一种新的鬼臼毒素衍生物，其中二甲基氨基取代了依托泊苷糖部分的羟基。这导致了深刻的理化差异：NK 611的疏水性比依托泊苷低得多。临床前研究表明，NK 611在生物利用度及其抗癌活性方面具有优势。我在AIO框架内对癌症患者进行了I期临床研究。另外，还研究了其药代动力学和药效学。在30分钟的输注过程中，以60至140 mg / m2 [最大耐受剂量（MTD）120 mg / m2]的剂量将26例患者使用NK 611。从25名患者中收集血浆和尿液样本，并使用经过验证的高效液相色谱（HPLC）分析程序进行分析。用三室模型最好地描述了血浆样品中总NK 611的浓度与时间的关系曲线。总体中位药代动力学值如下（括号中给出范围）：平均停留时间（MRT）16.5（5.4-42.3）h，终末半衰期14.0（8.2-30.5）h，稳态分布体积（V （ss））11.4（7.9-18.1）l / m2和血浆清除率（Cl（p））15.1（3.6-36.4）ml min-1 m-2。用曲线下面积（AUC）表示的全身药物暴露总量在53.4至532.0微克ml-1 h之间变化。平均AUC（+/- SD）随着剂量从60 mg / m2的78.7 +/- 3.7微克ml-1 h增加到120 mg / m2的202.8 +/- 157.2微克ml-1 h。输注结束后48小时未改变药物的平均尿排泄（UE）分数在所输送总剂量的3.0％至25.8％之间变化。超滤液样品的分析显示蛋白质结合率约为99％。白细胞（WBC）和中性粒细胞（ANC）减少的百分比与剂量，AUC和AUC（free）相关。ANC减少的百分比与药代动力学参数（AUC）之间的最佳关系采用非线性Hill型形式。肾脏或肝脏功能的实验室参数与AUC不相关。在每个剂量水平内药代动力学参数的变化是深远的。这种药理行为的原因尚不清楚，应进一步研究。ANC减少的百分比与药代动力学参数（AUC）之间的最佳关系采用非线性Hill型形式。肾脏或肝脏功能的实验室参数与AUC不相关。在每个剂量水平内药代动力学参数的变化是深远的。这种药理行为的原因尚不清楚，应进一步研究。ANC减少的百分比与药代动力学参数（AUC）之间的最佳关系采用非线性Hill型形式。肾脏或肝脏功能的实验室参数与AUC不相关。在每个剂量水平内药代动力学参数的变化是深远的。这种药理行为的原因尚不清楚，应进一步研究。

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Pharmacokinetics and pharmacodynamics of the new podophyllotoxin derivative NK 611. A study by the AIO groups PHASE-I and APOH.

NK 611 is a new podophyllotoxin derivative in which a dimethyl amino group replaces a hydroxyl group at the sugar moiety of etoposide. This results in profound physico-chemical differences: NK 611 is much less hydrophobic than etoposide. Preclinical studies have shown that NK 611 is advantageous in terms of bioavailability and of the potency of its anticancer activity. A clinical phase I study was performed in cancer patients within the framework of the AIO. Additionally, its pharmacokinetics and pharmacodynamics were investigated. NK 611 was given to 26 patients at doses ranging from 60 to 140 mg/m2 [maximum tolerated dose (MTD) 120 mg/m2] in a 30-min infusion. Plasma and urine samples were collected from 25 patients and analyzed using a validated high-performance liquid chromatography (HPLC) assay procedure. The concentration versus time curve of total NK 611 in plasma samples was best described by a three-compartment model. The overall median pharmacokinetic values were as follows (ranges are given in parentheses): mean residence time (MRT) 16.5 (5.4-42.3)h, terminal half-life 14.0 (8.2-30.5)h, volume of distribution at steady state (V(ss)) 11.4 (7.9-18.1) l/m2 and plasma clearance (Cl(p)) 15.1 (3.6-36.4) ml min-1 m-2. The total systemic drug exposure, represented by the area under the curve (AUC), varied between 53.4 and 532.0 micrograms ml-1 h. The mean AUC (+/- SD) increased with the dose from 78.7 +/- 3.7 micrograms ml-1 h at 60 mg/m2 up to 202.8 +/- 157.2 micrograms ml-1 h at 120 mg/m2. The mean urinary excretion (UE) fraction of unchanged drug at 48 h after the end of the infusion varied between 3.0% and 25.8% of the total dose delivered. Analysis of ultrafiltrate samples showed a protein binding of approx.. 99%. The percentage reduction in white blood cells (WBC) and neutrophils (ANC) correlated with the dose, AUC, and AUC(free). The best relationship between the percentage of reduction in ANC and a pharmacokinetic parameter (AUC) took a nonlinear Hill-type form. The laboratory parameter for kidney or liver function did not correlate with the AUC. The variation of pharmacokinetic parameters within each dose level was profound. The reason for this pharmacological behavior remains unclear and should be investigated in further studies.

更新日期：2019-11-01

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