Gianni L, Viganò L, Surbone A, Ballinari D, Casali P, Tarella C, Collins J M, Bonadonna G
Laboratory of Clinical Pharmacology, Istituto Nazionale Tumori, Milan, Italy.
J Natl Cancer Inst. 1990 Mar 21;82(6):469-77. doi: 10.1093/jnci/82.6.469.
In a prospective phase I trial involving 35 patients with metastatic carcinoma, we tested a pharmacokinetic strategy for guiding dose escalation of the anthracycline 4'-iodo-4'-deoxydoxorubicin (I-DOX), a new analogue reported to be more potent and less toxic than doxorubicin. This strategy is potentially a safe and more rapid way of determining the maximum tolerated dose (MTD) of anticancer agents. Retrospective studies have shown that the total plasma drug exposure after a dose lethal to 10% of mice (LD10) is approximately equivalent to the total exposure produced in humans by the MTD. Thus, we intended to aim dose escalation in humans to achieve the area under the curve for I-DOX plasma concentration x time (AUC) equivalent to that produced in mice by an LD10. However, differences in I-DOX pharmacokinetics and metabolism in BDF1 mice and humans at the initial dose prevented immediate application of this strategy. Therefore, we escalated the dose by the modified Fibonacci scheme while investigating the pharmacology of I-DOX and its major plasma metabolite 4'-iodo-4'-deoxy-13-dihydrodoxorubicin (I-DOXOL). Plasma pharmacokinetics was characterized by rapid elimination and extensive metabolism of I-DOX to I-DOXOL. The ratio of I-DOXOL to I-DOX plasma AUC was 12.8 +/- 7.3 SD. The plasma pharmacokinetics of I-DOX and I-DOXOL were linear in the range of tested doses (2-90 mg/m2). The LD10 in mice was 6.8 mg/kg for I-DOXOL and 6 mg/kg for I-DOX, and the concentration of drug that inhibited by 50% (IC50) the growth of human granulocyte-macrophage colony-forming units (CFU-GM) was 80 nM for I-DOXOL and 50 nM for I-DOX. From these findings, we concluded that the toxic effects of I-DOX and I-DOXOL are equivalent and reset the pharmacokinetic target of escalation to the sum of I-DOX and I-DOXOL AUCs at I-DOX LD10. Then we safely applied pharmacokinetically guided escalation to determine the MTD (80 mg/m2). The plasma AUC of I-DOX and I-DOXOL at the human MTD is 71% of the AUC at mouse LD10. The only dose-limiting toxic effect was severe granulocytopenia.
在一项涉及35例转移性癌患者的前瞻性I期试验中，我们测试了一种药代动力学策略，以指导蒽环类药物4'-碘-4'-脱氧阿霉素（I-DOX）的剂量递增，I-DOX是一种新的类似物，据报道其效力比阿霉素更强且毒性更低。该策略可能是一种安全且更快地确定抗癌药物最大耐受剂量（MTD）的方法。回顾性研究表明，对10%的小鼠致死剂量（LD10）后的血浆药物总暴露量大约相当于人类MTD产生的总暴露量。因此，我们打算在人体中进行剂量递增，以使I-DOX血浆浓度-时间曲线下面积（AUC）达到相当于小鼠LD10产生的AUC。然而，在初始剂量时，I-DOX在BDF1小鼠和人类中的药代动力学及代谢差异阻碍了该策略的直接应用。因此，我们采用改良的斐波那契方案递增剂量，同时研究I-DOX及其主要血浆代谢物4'-碘-4'-脱氧-13-二氢阿霉素（I-DOXOL）的药理学特性。血浆药代动力学的特征是I-DOX快速消除并广泛代谢为I-DOXOL。I-DOXOL与I-DOX血浆AUC的比值为12.8±7.3标准差。在测试剂量范围（2 - 90 mg/m²）内，I-DOX和I-DOXOL的血浆药代动力学呈线性。I-DOXOL在小鼠中的LD10为6.8 mg/kg，I-DOX为6 mg/kg，抑制人粒细胞-巨噬细胞集落形成单位（CFU-GM）生长50%（IC50）的药物浓度，I-DOXOL为80 nM，I-DOX为50 nM。基于这些发现，我们得出结论，I-DOX和I-DOXOL的毒性作用相当，并将递增的药代动力学目标重新设定为I-DOX LD10时I-DOX和I-DOXOL AUC的总和。然后，我们安全地应用药代动力学指导的递增来确定MTD（80 mg/m²）。人体MTD时I-DOX和I-DOXOL的血浆AUC是小鼠LD10时AUC的71%。唯一的剂量限制性毒性作用是严重粒细胞减少。
