Graham M A, Newell D R, Foster B J, Gumbrell L A, Jenns K E, Calvert A H
Drug Development Section, Royal Marsden Hospital, Sutton, Surrey, England.
Cancer Res. 1992 Feb 1;52(3):603-9.
The pharmacokinetics of the anthrapyrazole CI-941 has been investigated in conjunction with the Phase I evaluation of the drug with the intent of applying a pharmacokinetically guided dose escalation strategy. A starting dose of 5 mg/m2 was chosen, based on one-tenth the 10% lethal dose in mice. Due to the steep dose lethality relationship and nonlinear pharmacokinetics in mice, a target area under the CI-941 plasma concentration x time curve (AUC) of 110 microM x min (i.e., 40% of the mouse 10% lethal dose AUC) was chosen. This AUC was achieved in mice at 40 mg/m2. A total of 37 patients received 74 courses of CI-941 (5 to 55 mg/m2), with 26 patients consenting to pharmacokinetic monitoring. CI-941 was rapidly cleared from plasma, and a triexponential open model could be fitted to the data (t1/2 alpha = 7.6 +/- 2 min, t1/2 beta = 65 +/- 27 min, t1/2 zeta = 21 +/- 9 h). CI-941 was subjected to only limited urinary elimination, accounting for 5.2 +/- 2.8% of the administered dose. Wide interpatient variability in plasma CI-941 clearance at the starting dose and subsequent doses precluded the implementation of a pharmacokinetically guided dose escalation scheme, and the dose was escalated in 5-mg/m2 increments until the maximally tolerated dose was achieved. A number of investigations were performed to study potential reasons for variability in CI-941 clearance. However, CI-941 plasma protein binding (95 +/- 1%) and measures of pretreatment renal (51Cr-EDTA clearance), hepatic (plasma alanine transaminase and alkaline phosphatase levels), or cardiac function (left ventricular ejection fractions) did not relate strongly to CI-941 clearance. In patients treated at 40 mg/m2, the AUC values (156 to 415 microM x min) approximated or exceeded the target AUC. Fifty mg/m2 was the Phase II recommended dose. Further prospective studies are warranted to assess the utility of pharmacokinetically guided dose escalation strategies and to determine whether or not the variability encountered in clearance is unique to CI-941.
蒽吡唑CI - 941的药代动力学已结合该药物的I期评估进行了研究，目的是应用药代动力学指导的剂量递增策略。基于小鼠10%致死剂量的十分之一，选择了5mg/m²的起始剂量。由于小鼠中剂量与致死率关系陡峭且药代动力学呈非线性，因此选择了CI - 941血浆浓度-时间曲线下面积（AUC）为110μM·min（即小鼠10%致死剂量AUC的40%）的目标值。在小鼠中给予40mg/m²剂量时可达到该AUC。共有37例患者接受了74个疗程的CI - 941治疗（剂量为5至55mg/m²），其中26例患者同意进行药代动力学监测。CI - 941从血浆中快速清除，数据可拟合为三指数开放模型（t1/2α = 7.6±2分钟，t1/2β = 65±27分钟，t1/2ζ = 21±9小时）。CI - 941仅经有限的尿液排泄，占给药剂量的5.2±2.8%。起始剂量及后续剂量时患者间CI - 941血浆清除率存在很大差异，这使得无法实施药代动力学指导的剂量递增方案，因此剂量以5mg/m²的增量递增，直至达到最大耐受剂量。进行了多项研究以探讨CI - 941清除率变异性的潜在原因。然而，CI - 941的血浆蛋白结合率（95±1%）以及治疗前肾脏（51Cr - EDTA清除率）、肝脏（血浆丙氨酸转氨酶和碱性磷酸酶水平）或心脏功能（左心室射血分数）的指标与CI - 941清除率并无密切关系。在接受40mg/m²治疗的患者中，AUC值（156至415μM·min）接近或超过目标AUC。50mg/m²是II期推荐剂量。有必要进行进一步的前瞻性研究，以评估药代动力学指导的剂量递增策略的实用性，并确定清除率中遇到的变异性是否为CI - 941所特有。
