Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA.
J Clin Pharmacol. 2011 May;51(5):679-86. doi: 10.1177/0091270010372519. Epub 2010 Jun 4.
Clofarabine, a newer purine analog with reduced central nervous system toxicity, may prove advantageous in hematopoietic cell transplantation in patients for whom neurotoxicity is a natural part of disease progression. This study evaluated clofarabine pharmacokinetics in adult and pediatric patients undergoing hematopoietic cell transplantation for the treatment of high-risk, inherited metabolic disorders. Clofarabine (40 mg/m(2)/d) was administered intravenously on days -7 to -3. Kinetic sampling occurred with doses 1 and 5, along with a single level collected on day of transplant (day(0)). Sixteen patients were studied with a median (range) age and body surface area (BSA) of 7.5 years (0.5-43) and 0.94 m(2) (0.31-2.3), respectively. Clofarabine area under the concentration-time curve from time 0 to infinity was 931 ng·h/mL (685-1876), maximum concentration was 226 ng/mL (162-600), and minimum concentration was 3.2 ng/mL (1.7-5.6). Clofarabine clearance was 1.6 L/h/kg (0.7-2.4) and weakly correlated with weight (r(2) = 0.33) and BSA (r(2) = 0.26). No difference in plasma concentrations was found between dose 1 and dose 5 (all P > .05). All concentrations were below the limit of quantification (1 ng/mL) on day(0) in patients with normal renal function. Variability in clofarabine clearance was approximately 3-fold and was not adequately explained by covariates describing renal function and body size. In patients with adequate renal function, no drug accumulation occurs with consecutive daily dosing.
氯法拉滨是一种新型嘌呤类似物，其中枢神经系统毒性降低，在因疾病进展而导致神经毒性成为自然现象的造血细胞移植患者中，可能具有优势。本研究评估了氯法拉滨在接受造血细胞移植以治疗高危遗传性代谢疾病的成人和儿科患者中的药代动力学。氯法拉滨（40mg/m2/d）于-7 至-3 天静脉给药。在剂量 1 和 5 时进行了动力学采样，并在移植当天（第 0 天）采集了单个样本。16 名患者进行了研究，中位（范围）年龄和体表面积（BSA）分别为 7.5 岁（0.5-43）和 0.94m2（0.31-2.3）。氯法拉滨 0 至无穷大时间的浓度-时间曲线下面积为 931ng·h/mL（685-1876），最大浓度为 226ng/mL（162-600），最小浓度为 3.2ng/mL（1.7-5.6）。氯法拉滨清除率为 1.6L/h/kg（0.7-2.4），与体重（r2=0.33）和 BSA（r2=0.26）呈弱相关。剂量 1 和剂量 5 之间的血浆浓度无差异（均 P＞0.05）。在肾功能正常的患者中，所有浓度在第 0 天均低于定量下限（1ng/mL）。氯法拉滨清除率的变异性约为 3 倍，不能用描述肾功能和体型的协变量充分解释。在肾功能充足的患者中，连续每日给药不会发生药物蓄积。
