Application of pharmacokinetically guided dose escalation with respect to cell cycle phase specificity.
Application of pharmacokinetically guided dose escalation with respect to cell cycle phase specificity.
复制标题
就细胞周期时相特异性而言，应用药代动力学指导的剂量递增。
DOI：
10.1093/jnci/86.13.989
复制
发表时间：
1994
期刊：
影响因子：
--
通讯作者：
Y. Sugiyama
中科院分区：
文献类型：
--
作者：
E. Fuse;S. Kobayashi;M. Inaba;H. Suzuki;Y. Sugiyama
背景
1986年，提出了药代动力学指导剂量递增（PGDE）的概念，以根据动物数据预测抗肿瘤药物在人体中的最大耐受剂量（MTD）。我们以前已经表明，抗肿瘤药物可以分为两种类型，这取决于它们的细胞毒性机制：1型药物，这是细胞周期阶段非特异性药物，即，血浆中药物浓度对时间（AUC）依赖性药物的曲线下面积;以及2型药物，其为细胞周期阶段特异性药剂，即，那些依赖于时间的。
目的
对于1型和2型药物，检查了10%小鼠给药致死剂量（LD 10）下的AUC等于人体MTD下的AUC这一假设的有效性，这是PGDE所基于的前提。
方法
回顾性分析了文献中的发现，包括柯林斯及其同事的发现。将AUC的人/小鼠比彼此进行比较，并与人/小鼠剂量比进行比较，基于毫克/平方米体表面积，目前用于抗肿瘤药物临床试验的测量。对于6种1型药物，还比较了总药物AUC（AUC）和未结合药物AUC（AUCu）的人/小鼠比值，这被认为是药理学和毒理学效应的决定因素。
结果
对于1型药物（r = .898），小鼠LD 10时的log AUC与人MTD时的log AUC之间存在极好的相关性，但对于2型药物（r = .677）则不相关。对于1型药物，未结合药物（r = 0.961）的LD 10时小鼠AUC和MTD时人AUC之间的相关性优于总药物（r = 0.892）。
结论
PGDE可用于1型药物;然而，在使用该方法时应考虑种属之间蛋白结合的差异。
BACKGROUND
In 1986, the concept of pharmacokinetically guided dose escalation (PGDE) was proposed to predict the maximum tolerated dose (MTD) of an antitumor drug in humans from animal data. We have previously shown that antitumor drugs can be classified into two types, depending on their cytotoxic mechanisms: type 1 drugs, which are cell cycle phase-nonspecific agents, i.e., area under the curve for drug concentration in the plasma versus time (AUC)-dependent drugs; and type 2 drugs, which are cell cycle phase-specific agents, i.e., those that are time dependent.
PURPOSE
The validity of the assumption that the AUC at the dose lethal for 10% of mice administered drug (LD10) is equal to the AUC at MTD for humans, the premise on which PGDE is based, was examined for type 1 and 2 drugs.
METHODS
Findings in the literature, including those of Collins and co-workers, were retrospectively analyzed. The human/mouse ratios for the AUC were compared with each other and with the human/mouse dose ratios, based on milligram per meter square of body surface area, the measurement currently used in clinical trials of antitumor drugs. For six of the type 1 drugs, the human/mouse ratio for the AUC of total drug (AUC) and that of unbound drug (AUCu), which has been considered a determinant of pharmacologic and toxicologic effects, were also compared.
RESULTS
There was an excellent correlation between log AUC at LD10 for mice and log AUC at MTD for humans for type 1 drugs (r = .898), but not for type 2 drugs (r = .677). For type 1 drugs, the correlation between mouse AUC at LD10 and human AUC at MTD was better for unbound drug (r = .961) than for total drug (r = .892).
CONCLUSIONS
PGDE is useful for type 1 drugs; differences in protein binding between species should, however, be considered when using this method.