Kitchen B J, Balis F M, Poplack D G, O'Brien M, Craig C E, Adamson P C
Pediatric Branch, National Cancer Institute, Bethesda, Maryland 20892, USA.
Clin Cancer Res. 1997 May;3(5):713-7.
Although mercaptopurine is the thiopurine antimetabolite predominantly used in the treatment of childhood acute lymphoblastic leukemia (ALL), thioguanine (TG) is more potent than mercaptopurine in in vitro cytotoxicity studies in human leukemic cell lines and leukemic cells from patients with ALL. We conducted a pediatric Phase I trial of TG administered as a continuous i.v. infusion (CIV). A pharmacokinetically guided dose escalation was performed to define the dose rate of TG required to achieve a steady-state plasma concentration (Css) exceeding the target concentration of 1 microM, and then the maximum tolerated duration of infusion of TG at this dose rate was defined. Eighteen patients (median age, 18 years; range, 4-25 years) with refractory malignancies (16 solid tumors and 2 ALL) were enrolled in this study. The starting dose rate of 10 mg/m2/h administered for 24 h achieved an average Css of 0.9 microM (range, 0.7-1.2 microM). Therefore, the dose rate was escalated to 20 mg/m2/h, which achieved an average Css of 4.1 microM (range, 1. 0-8.3 microM). This disproportionate increase in the Css of TG suggested a capacity-limited (saturable) elimination process, and a pharmacokinetic model incorporating two compartments with capacity-limited elimination from the central compartment was developed to describe the disposition of TG. The TG clearances (derived from model parameters) at the 10- and 20-mg/m2/h dose rates were 987 and 608 ml/min/m2, respectively. Dose-limiting myelosuppression (absolute granulocyte count < 500/mm3 and platelet count < 25,000/mm3) was observed in two of three patients treated with a dose rate of 20 mg/m2/h administered for 36 h. Administration of CIV of TG at 20 mg/m2/h for 24 h was well tolerated in nine patients. Nonhematological toxicities included nonneutropenic infections and mild, reversible changes in hepatic function tests. The recommended dose rate and duration for CIV of TG is 20 mg/m2/h for 24 h.
尽管巯嘌呤是主要用于治疗儿童急性淋巴细胞白血病（ALL）的硫嘌呤抗代谢物，但在人白血病细胞系和ALL患者白血病细胞的体外细胞毒性研究中，硫鸟嘌呤（TG）比巯嘌呤更具活性。我们开展了一项TG持续静脉输注（CIV）的儿科I期试验。进行了药代动力学指导的剂量递增，以确定达到超过目标浓度1微摩尔的稳态血浆浓度（Css）所需的TG剂量率，然后确定在此剂量率下TG的最大耐受输注持续时间。18例难治性恶性肿瘤患者（年龄中位数18岁；范围4 - 25岁）（16例实体瘤和2例ALL）入组本研究。以10 mg/m²/h的起始剂量率输注24小时，平均Css为0.9微摩尔（范围0.7 - 1.2微摩尔）。因此，剂量率增至20 mg/m²/h，平均Css达到4.1微摩尔（范围1.0 - 8.3微摩尔）。TG的Css这种不成比例的增加提示存在容量限制（饱和）消除过程，并建立了一个包含两个房室且中央房室有容量限制消除的药代动力学模型来描述TG的处置。在10和20 mg/m²/h剂量率下，TG清除率（由模型参数得出）分别为987和608 ml/min/m²。在以20 mg/m²/h的剂量率输注36小时治疗的3例患者中，有2例观察到剂量限制性骨髓抑制（绝对粒细胞计数<500/mm³且血小板计数<25,000/mm³）。9例患者以20 mg/m²/h的剂量率进行24小时的TG CIV给药耐受性良好。非血液学毒性包括非中性粒细胞感染和肝功能检查中轻度、可逆的变化。TG CIV的推荐剂量率和持续时间为20 mg/m²/h，持续24小时。
