Collins J M, Zaharko D S, Dedrick R L, Chabner B A
Cancer Treat Rep. 1986 Jan;70(1):73-80.
Concepts elucidated from preclinical pharmacology studies have made a substantial impact on the clinical use of anticancer drugs. However, the majority of animal pharmacology results have not been available until after drugs have entered clinical trials. Since clinical pharmacokinetic measurements are already part of many phase I trials, human data could be directly compared with mouse data if mouse pharmacology studies were completed before clinical trials were initiated. Once the starting dose in a phase I clinical trial has been evaluated, subsequent doses are escalated until the maximum tolerated dose is reached. The rate of escalation is empirically defined by a modified Fibonacci series. This universal escalation scheme is applied to all drugs, with no modifications based upon pharmacology or other factors. If the starting dose is far removed from the maximum tolerated dose, a large number of dose escalations are required. Consequently, most patients receive subtherapeutic doses, and the amount of resources allocated to each drug increases. We are exploring potential strategies for controlling the rate of dose escalation based upon pharmacokinetic determinations in mouse and man. Retrospective analyses indicate that 20%-50% savings in the total number of dose escalations are possible.
临床前药理学研究阐明的概念对抗癌药物的临床应用产生了重大影响。然而，大多数动物药理学结果直到药物进入临床试验后才可得。由于临床药代动力学测量已经是许多I期试验的一部分，如果在启动临床试验之前完成小鼠药理学研究，人类数据就可以直接与小鼠数据进行比较。一旦评估了I期临床试验的起始剂量，后续剂量就会逐步增加，直到达到最大耐受剂量。递增速率根据改良的斐波那契数列凭经验确定。这种通用的递增方案适用于所有药物，不根据药理学或其他因素进行修改。如果起始剂量与最大耐受剂量相差甚远，则需要大量的剂量递增。因此，大多数患者接受的是亚治疗剂量，并且分配给每种药物的资源量会增加。我们正在探索基于小鼠和人类药代动力学测定来控制剂量递增速率的潜在策略。回顾性分析表明，剂量递增总数有可能节省20% - 50%。
