Sugiyama Y, Kobayashi T, Inaba M
Faculty of Pharmaceutical Sciences, University of Tokyo, Japan.
Gan To Kagaku Ryoho. 1987 Dec;14(12):3183-98.
After examining the in vitro cell-kill kinetics of various anticancer drugs by using cultured human cell lines, Shimoyama et al. classified the drugs into two groups according to the types of action: 1) type-I drugs (cytocidal and concentration-dependent action) such as alkylating agents and anticancer antibiotics; 2) type-II drugs (cytostatic and time-dependent action) such as antimetabolites, Vinca alkaloids and L-asparaginase. In the present paper, we will present a rational basis for such a classification by using cell-kill pharmacodynamic models, and consider the optimal dosage regimen depending on the type of drugs by combining the cell-kill kinetic and pharmacokinetic models. In these models, classification of the drugs depends on whether the cell population is kinetically homogenous or not. It is assumed that cell population is homogenous for type-I drugs and there exist both drug sensitive and insensitive cell populations for type-II drugs. The concentration (or dose)-time-cell survival curves in both in vitro and in vivo, which are simulated based on the kinetic models, are consistent with the experimental data found in the literature. Further analysis on the optimal dose regimen according to these kinetic models clarified that the type-I drugs showed a similar cell-kill effect irrespective of the mode of administration as long as the area under the plasma unbound concentration curves (AUCp, free) is kept constant, while the type-II drugs are more effective by multiple dosing or infusion regimen than single administration of a large dose of drugs. In other words, the extents of AUCp, free and the residence time in the plasma (above certain concentrations of drugs) are determinants of the in vivo cell-kill effects of type-I drugs and type-II drugs, respectively. If the pharmacokinetics of newly developed anticancer drugs in human are predicted from the animal data according to the so-called "animal scale-up" technique and combined with the in vitro cell-kill kinetic data by the use of proposed kinetic models, one may obtain not only the optimal dosage regimen but also good screening systems for truly active drugs for the treatment of human cancer.
在使用培养的人类细胞系研究了各种抗癌药物的体外细胞杀伤动力学后，岛山等人根据作用类型将这些药物分为两组：1）I型药物（细胞杀伤且浓度依赖性作用），如烷化剂和抗癌抗生素；2）II型药物（细胞生长抑制且时间依赖性作用），如抗代谢物、长春花生物碱和L-天冬酰胺酶。在本文中，我们将通过使用细胞杀伤药效学模型为这种分类提供合理依据，并结合细胞杀伤动力学和药代动力学模型，根据药物类型考虑最佳给药方案。在这些模型中，药物的分类取决于细胞群体在动力学上是否同质。假设I型药物的细胞群体是同质的，而II型药物存在药物敏感和不敏感的细胞群体。基于动力学模型模拟的体外和体内浓度（或剂量）-时间-细胞存活曲线与文献中的实验数据一致。根据这些动力学模型对最佳剂量方案的进一步分析表明，只要血浆未结合浓度曲线下面积（AUCp，游离）保持恒定，I型药物无论给药方式如何都表现出相似的细胞杀伤效果，而II型药物通过多次给药或输注方案比单次大剂量给药更有效。换句话说，AUCp，游离的程度和血浆中（高于一定药物浓度）的停留时间分别是I型药物和II型药物体内细胞杀伤效果的决定因素。如果根据所谓的“动物放大”技术从动物数据预测新开发的抗癌药物在人体内的药代动力学，并通过使用所提出的动力学模型将其与体外细胞杀伤动力学数据相结合，人们不仅可以获得最佳给药方案，还可以获得用于治疗人类癌症的真正活性药物的良好筛选系统。
