Kearns C M, Blakley R L, Santana V M, Crom W R
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105.
Cancer Res. 1994 Mar 1;54(5):1235-9.
Cladribine is a synthetic purine nucleoside with demonstrated activity in hairy cell leukemia and acute myeloid leukemia. We have studied the pharmacokinetics of this drug in 25 pediatric patients with acute leukemia treated with cladribine as a single agent, 8.9 mg/m2/24 h, for 5 days by continuous i.v. infusion. Twelve patients were in relapse, and acute myeloid leukemia was newly diagnosed in 13 patients. Plasma, urine, and cerebrospinal fluid cladribine concentrations were determined by a radioimmunoassay with a limit of detection of 1 nM. An open two-compartment model was fit to the plasma concentration data. The mean (SD) clearance was 39.4 (12.4) liters/h/m2 and ranged from 14.4-55.4 liters/h/m2. When clearance was normalized to body weight (liters/h/kg) it was negatively correlated with age, with older patients having slower clearances per unit of body weight. However, when clearance was normalized to body surface area, no significant correlation with age was observed. The mean (SD) steady-state plasma concentration (predicted 120-h concentration) was 37.7 (17.3) nM and ranged from 23.2-84.5 nM. The terminal phase half-life in 22 patients ranged from 14.3-25.8 h, with a mean (SD) of 19.7 (3.4) h. The volume of distribution at steady state was highly variable, with a mean (SD) of 356.6 (225.2) liters/m2. None of these parameters was significantly different between patients in relapse and patients with newly diagnosed disease. Renal clearance was determined in 7 patients and ranged from 34.6-643.6 ml/min/m2, with a mean (SD) of 317.9 (208.7) ml/min/m2. Renal clearance as a percentage of total systemic clearance ranged from 11.0-85.1%, with a mean of 51.0%. In 11 patients, the mean (SD) cerebrospinal fluid concentration was 6.1 (3.97) nM, a mean of 18.2% of the steady-state plasma concentration. The CSF:plasma concentration ratio was significantly higher on day 5 (22.7% in 7 patients) than on day 4 (7.6% in 3 patients; P = 0.03). Additional studies are needed to further define the metabolic fate of cladribine. In this paper we provide the first comprehensive description of the pharmacokinetics of this drug in children and provide data which suggest that cladribine may be useful in the treatment of patients with meningeal leukemia or malignancies of the central nervous system.
克拉屈滨是一种合成嘌呤核苷，在毛细胞白血病和急性髓系白血病中具有已证实的活性。我们研究了该药在25例接受克拉屈滨单药治疗的急性白血病儿科患者中的药代动力学，剂量为8.9mg/m²/24小时，持续静脉输注5天。12例患者处于复发期，13例患者为新诊断的急性髓系白血病。采用检测限为1nM的放射免疫分析法测定血浆、尿液和脑脊液中的克拉屈滨浓度。对血浆浓度数据拟合开放二室模型。平均（标准差）清除率为39.4（12.4）升/小时/平方米，范围为14.4 - 55.4升/小时/平方米。当清除率按体重（升/小时/千克）进行标准化时，它与年龄呈负相关，年龄较大的患者每单位体重的清除率较慢。然而，当清除率按体表面积进行标准化时，未观察到与年龄有显著相关性。平均（标准差）稳态血浆浓度（预测的120小时浓度）为37.7（17.3）nM，范围为23.2 - 84.5nM。22例患者的终末相半衰期范围为14.3 - 25.8小时，平均（标准差）为19.7（3.4）小时。稳态分布容积高度可变，平均（标准差）为356.6（225.2）升/平方米。复发患者和新诊断疾病患者之间这些参数均无显著差异。在7例患者中测定了肾清除率，范围为34.6 - 643.6毫升/分钟/平方米，平均（标准差）为317.9（208.7）毫升/分钟/平方米。肾清除率占全身总清除率的百分比范围为11.0% - 85.1%，平均为51.0%。在11例患者中，平均（标准差）脑脊液浓度为6.1（3.97）nM，平均为稳态血浆浓度的18.2%。脑脊液与血浆浓度比值在第5天（7例患者中为22.7%）显著高于第4天（3例患者中为7.6%；P = 0.03）。需要进一步研究以进一步明确克拉屈滨的代谢转归。在本文中，我们首次全面描述了该药在儿童中的药代动力学，并提供了数据表明克拉屈滨可能对治疗脑膜白血病或中枢神经系统恶性肿瘤患者有用。
