Fuse E, Kobayashi S, Inaba M, Suzuki H, Sugiyama Y
Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., Shizuoka, Japan.
J Natl Cancer Inst. 1994 Jul 6;86(13):989-96. doi: 10.1093/jnci/86.13.989.
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.
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.
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.
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).
PGDE is useful for type 1 drugs; differences in protein binding between species should, however, be considered when using this method.
1986年，药代动力学指导剂量递增（PGDE）的概念被提出，旨在根据动物数据预测人类抗肿瘤药物的最大耐受剂量（MTD）。我们之前已经表明，抗肿瘤药物可根据其细胞毒性机制分为两类：1型药物，即细胞周期非特异性药物，也就是血浆中药物浓度-时间曲线下面积（AUC）依赖性药物；2型药物，即细胞周期特异性药物，也就是时间依赖性药物。
研究PGDE所基于的假设，即给予药物后导致10%小鼠死亡的剂量（LD10）下的AUC等于人类MTD下的AUC，对于1型和2型药物是否成立。
对包括柯林斯及其同事的研究结果在内的文献进行回顾性分析。根据每平方米体表面积的毫克数（这是目前抗肿瘤药物临床试验中使用的测量方法），比较了AUC的人/鼠比值，以及人/鼠剂量比值。对于6种1型药物，还比较了总药物AUC（AUC）和游离药物AUC（AUCu）的人/鼠比值，游离药物AUC被认为是药理和毒理作用的决定因素。
对于1型药物，小鼠LD10时的log AUC与人类MTD时的log AUC之间存在极好的相关性（r = 0.898），但对于2型药物则不然（r = 0.677）。对于1型药物，游离药物在小鼠LD10时的AUC与人类MTD时的AUC之间的相关性（r = 0.961）优于总药物（r = 0.892）。
PGDE对1型药物有用；然而，在使用该方法时应考虑物种间蛋白质结合的差异。
