Capizzi R L
Jefferson Medical College, Philadelphia, PA 19107, USA.
Invest New Drugs. 1996;14(3):249-56. doi: 10.1007/BF00194527.
In the bench to bedside development of drugs to treat patients with cancer, the common guide to dose and schedule selection is toxicity to normal organs patterned after the preclinical profile of the drug. An understanding of the cellular pharmacology of the drug and specifically the cellular targets linked to the drug's effect is of substantial value in assisting the clinical investigator in selecting the proper dose and schedule of drug administration. The clinical development of ara-C for the treatment of acute myeloid leukemia (AML) provides a useful paradigm for the study of this process. An understanding of the cellular pharmacology, cytokinetics and pharmacokinetics of ara-C in leukemic mice showed substantial schedule-dependency. Exposure to high doses for a short duration (C x t) resulted in a palliative therapeutic outcome. In marked contrast, exposure to lower doses for a protracted period (c x T) was curative. Clinical use of ara-C in patients with AML patterned after the murine experience, c x T approach, has been of limited benefit in terms of long-term disease-free survival. Studies with human leukemia blasts from patients have shown that for the majority of patients, the initial rate-limiting step is membrane transport, the characteristics of which are substantially affected by extracellular drug concentration (dose). This pharmacologic impediment is eliminated with the blood levels attained during the infusion of gram doses (1-3 gm/m2) of the drug (high-dose ara-C, HiDaC) for shorter periods of time, a C x t approach. Clinical confirmation of these pharmacologic observations is evident in the therapeutic efficacy of HiDaC in patients with relapsed or SDaC-refractory acute leukemia. This is further emphasized by the significantly improved leukemia-free survival of patients with AML treated with HiDaC intensification during remission compared to those patients treated with milligram doses typical of SDaC protocols. Thus, the identification and monitoring of important parameters of drug action in tumors during the course of a clinical trial can be of substantial assistance in optimizing drug dose and schedule so as to attain the best therapeutic index.
在从实验室到临床的抗癌药物研发过程中，选择剂量和给药方案的常见指导原则是依据药物临床前研究中对正常器官的毒性表现。了解药物的细胞药理学，特别是与药物作用相关的细胞靶点，对于协助临床研究人员选择合适的药物给药剂量和方案具有重要价值。阿糖胞苷（ara-C）用于治疗急性髓系白血病（AML）的临床研发为研究这一过程提供了一个有用的范例。对白血病变种小鼠体内阿糖胞苷的细胞药理学、细胞动力学和药代动力学的了解表明，其疗效显著依赖于给药方案。短时间暴露于高剂量（C×t）会产生姑息性治疗效果。与之形成鲜明对比的是，长时间暴露于低剂量（c×T）则具有治愈效果。按照小鼠实验经验采用c×T方法在AML患者中临床应用阿糖胞苷，就长期无病生存而言，获益有限。对患者的人类白血病原始细胞进行的研究表明，对于大多数患者来说，初始限速步骤是膜转运，而膜转运的特性会受到细胞外药物浓度（剂量）的显著影响。在较短时间内输注克剂量（1 - 3 gm/m²）的药物（高剂量阿糖胞苷，HiDaC）所达到的血药浓度可消除这种药理学障碍，这是一种C×t方法。这些药理学观察结果在HiDaC对复发或对标准剂量阿糖胞苷（SDaC）难治的急性白血病患者的治疗效果中得到了临床证实。与采用SDaC方案典型的毫克剂量治疗的患者相比，HiDaC强化治疗缓解期AML患者的无白血病生存期显著改善，这进一步凸显了上述结论。因此，在临床试验过程中识别和监测肿瘤中药物作用的重要参数，对于优化药物剂量和给药方案以获得最佳治疗指数可能会有很大帮助。
