de Jong J, Geijssen G J, Munniksma C N, Vermorken J B, van der Vijgh W J
Department of Oncology, Free University Hospital, Amsterdam, The Netherlands.
J Clin Oncol. 1992 Dec;10(12):1897-906. doi: 10.1200/JCO.1992.10.12.1897.
N-l-leucyldoxorubicin (Leu-Dox) was developed as a prodrug of doxorubicin (Dox) to circumvent the cardiotoxicity associated with repeated administration of Dox. Our purpose was to assess the pharmacokinetics of Leu-Dox, Dox, doxorubicinol (Dol) and four other metabolites for pharmacokinetically guided dose-escalation and to verify the prodrug character of Leu-Dox.
Blood and urine of 14 patients were sampled during the phase I clinical trial and analyzed by high-performance liquid chromatography. Dose levels of Leu-Dox ranged from 18 mg/m2 to 225 mg/m2, the maximum-tolerated dose (MTD). Hematologic parameters were monitored regularly in each patient.
Leu-Dox was rapidly distributed (half-life at alpha phase [t1/2 alpha] = 2.5 +/- 0.6 minutes) followed by a biphasic elimination (half-life at beta phase [t1/2 beta] = 17.4 +/- 7.3 minutes; half-life at gamma phase [t1/2 gamma] = 1.5 +/- 0.5 hours), as measured over the first 12 hours after administration. In three patients, in whom Leu-Dox was found in the plasma for up to 48 hours after injection, a final elimination half-life (t1/2,elim) of 16 hours was observed. The t1/2,elim of Leu-Dox was short (0.6 to 16.5 hours) compared with the t1/2,elim of Dox (38 +/- 11 hours). The mean residence time and apparent volume of distribution were 23 +/- 5 minutes and 19 +/- 6 L/m2, respectively. Only 1.5% to 5% of the dose was excreted in the urine over 48 hours, with Dox as major constituent. Dox was rapidly formed, reaching its maximum concentration within 10 minutes after the end of Leu-Dox infusion. Areas under the plasma concentration versus time curve (AUC infinity, mean +/- SD, n = 16) of Leu-Dox, Dox, and Dol were 115 +/- 27 mumol.min/L, 41 +/- 12 mumol.min/L, and 33 +/- 14 mumol.min/L after a dose of 60 mg/m2 Leu-Dox (= 86 mumol/m2). After the same molar dose of Dox (50 mg/m2 = 86 mumol/m2), the AUC infinity of Dox was 179 mumol.min/L, indicating that Leu-Dox was converted into Dox for 23% in the plasma compartment. The AUCs infinity of Leu-Dox, Dox, and Dol increased linearly with the dose. Negligible AUCs were observed for the other four metabolites. The AUCs infinity of Leu-Dox and Dox at the MTD (517 and 145 mumol.min/L, respectively) were lower than those in mice at the LD10 (1,930 and 798 mumol.min/L, respectively), which means that the MTD could not be predicted from the preclinical pharmacokinetics in mice. Hematologic toxicity, especially the WBC count, appeared to correlate much better with the AUC of Dox (r = .91) than with the AUC of Leu-Dox (r = .74), thus confirming the prodrug character of Leu-Dox.
Dox is rapidly formed from Leu-Dox, and seems causative in the observed myelotoxicity. The MTD could not be predicted from the AUC at the LD10 in mice.
N-亮氨酰阿霉素（Leu-Dox）作为阿霉素（Dox）的前体药物而被研发出来，以规避与反复给予Dox相关的心脏毒性。我们的目的是评估Leu-Dox、Dox、阿霉素醇（Dol）及其他四种代谢物的药代动力学，以便进行药代动力学指导的剂量递增，并验证Leu-Dox的前体药物特性。
在I期临床试验期间采集了14例患者的血液和尿液样本，并通过高效液相色谱法进行分析。Leu-Dox的剂量水平范围为18mg/m²至225mg/m²，即最大耐受剂量（MTD）。对每位患者的血液学参数进行定期监测。
Leu-Dox分布迅速（α相半衰期[t1/2α]=2.5±0.6分钟），随后呈双相消除（β相半衰期[t1/2β]=17.4±7.3分钟；γ相半衰期[t1/2γ]=1.5±0.5小时），这是在给药后的前12小时内测得的。在3例患者中，注射后长达48小时血浆中仍可检测到Leu-Dox，其最终消除半衰期（t1/2,elim）为16小时。与Dox的t1/2,elim（38±11小时）相比，Leu-Dox的t1/2,elim较短（0.6至16.5小时）。平均驻留时间和表观分布容积分别为23±5分钟和19±6L/m²。在48小时内，仅1.5%至5%的剂量以Dox作为主要成分经尿液排泄。Dox迅速形成，在Leu-Dox输注结束后10分钟内达到其最高浓度。给予60mg/m²Leu-Dox（=86µmol/m²）剂量后，Leu-Dox、Dox和Dol的血浆浓度-时间曲线下面积（AUC∞，平均值±标准差，n = 16）分别为115±27µmol·min/L、41±12µmol·min/L和33±14µmol·min/L。给予相同摩尔剂量的Dox（50mg/m² = 86µmol/m²）后，则Dox的AUC∞为179µmol·min/L，这表明Leu-Dox在血浆中23%转化为Dox。Leu-Dox、Dox和Dol的AUC∞随剂量呈线性增加。其他四种代谢物的AUC∞可忽略不计。MTD（分别为517和145µmol·min/L）时Leu-Dox和Dox的AUC∞低于小鼠LD10时的AUC∞（分别为1930和798µmol·min/L），这意味着无法从小鼠临床前药代动力学预测MTD。血液学毒性，尤其是白细胞计数与Dox的AUC（r = 0.91）的相关性似乎比与Leu-Dox的AUC（r = 0.74）的相关性更好，从而证实了Leu-Dox的前体药物特性。
Dox由Leu-Dox迅速形成，似乎是观察到的骨髓毒性的原因。无法从小鼠LD10时的AUC预测MTD。
