Chen C L, Levine A, Rao A, O'Neill K, Messinger Y, Myers D E, Goldman F, Hurvitz C, Casper J T, Uckun F M
Parker Hughes Cancer Center, Hughes Institute, St. Paul, Minnesota 55113, USA.
J Clin Pharmacol. 1999 Dec;39(12):1248-55. doi: 10.1177/00912709922012051.
The authors examined the pharmacokinetics of the CD19 receptor-directed tyrosine kinase inhibitor B43-Genistein in 17 patients (4 children, 13 adults) with B-lineage lymphoid malignancies, including 12 patients with acute lymphoblastic leukemia (ALL) and 5 patients with non-Hodgkin's lymphoma (NHL). The immunoconjugate was administered intravenously as a 1-hour continuous infusion at a dose level of either 0.1 mg/kg (N = 12) or 0.18 mg/kg (N = 5), and the plasma concentration-time data were modeled by using the WinNonlin program to estimate the pharmacokinetic parameters. Pharmacokinetic analyses revealed a plasma half-life of 19 +/- 4 hours, mean residence time of 22 +/- 4 hours, and a systemic clearance of 18 +/- 2 mL/h/kg. The average (mean +/- SEM) values for the maximum plasma concentration Cmax, volume of distribution at steady state (Vss), and area under curve (AUC) were 1092 +/- 225 ng/ml, 291 +/- 37 mL/kg, and 9987 +/- 2021 micrograms x h/L, respectively. The AUC values were higher at the 0.18 mg/kg dose level than at the 0.1 mg/kg dose level (16,848 +/- 5118 micrograms x h/L vs. 7128 +/- 1156 micrograms x h/L, p = 0.009). Patients with ALL had a significantly larger volume of distribution at steady state (332 +/- 47 mL/kg vs. 191 +/- 12 mL/kg, p = 0.04), faster clearance (21 +/- 3 mL/h/kg vs. 11 +/- 2 mL/h/kg, p = 0.03), and lower dose-corrected AUC than patients with NHL (6010 +/- 836 micrograms x h/L vs. 12,044 +/- 2707 micrograms x h/L, p = 0.006). There was a trend toward faster clearance rates (23 +/- 4 mL/h/kg vs. 16 +/- 3 mL/h/kg, p = 0.1), shorter elimination half-lives (5.7 +/- 3.6 hours vs. 13 +/- 8.8 hours, p = 0.1), and shorter mean residence times (11 +/- 3 hours vs. 25 +/- 5 hours, p = 0.08) for non-Caucasian patients as compared to Caucasian patients. When compared to adult patients, pediatric patients showed a significantly larger volume of distribution at steady state (418 +/- 82 mL/kg vs. 252 +/- 34 mL/kg, p = 0.02) and a longer elimination half-lives (18.4 +/- 13.6 hours vs. 8.7 +/- 6.7 hours, p = 0.04). The pharmacokinetics of B43-Genistein was not affected by the gender of the patients or by bone marrow transplantation in past medical history. Overall, B43-Genistein showed favorable pharmacokinetics in this heavily pretreated leukemia/lymphoma patient population, which is reminiscent of its recently reported favorable pharmacokinetics in cynomolgus monkeys. To our knowledge, this is the first clinical pharmacokinetics study of a tyrosine kinase inhibitor containing immunoconjugate.
作者研究了CD19受体导向的酪氨酸激酶抑制剂B43-金雀异黄素在17例B系淋巴系统恶性肿瘤患者（4例儿童，13例成人）中的药代动力学，其中包括12例急性淋巴细胞白血病（ALL）患者和5例非霍奇金淋巴瘤（NHL）患者。免疫偶联物通过静脉内1小时持续输注给药，剂量水平为0.1mg/kg（N = 12）或0.18mg/kg（N = 5），并使用WinNonlin程序对血浆浓度-时间数据进行建模以估计药代动力学参数。药代动力学分析显示血浆半衰期为19±4小时，平均驻留时间为22±4小时，全身清除率为18±2mL/h/kg。最大血浆浓度Cmax、稳态分布容积（Vss）和曲线下面积（AUC）的平均值（均值±标准误）分别为1092±225ng/ml、291±37mL/kg和9987±2021μg·h/L。0.18mg/kg剂量水平的AUC值高于0.1mg/kg剂量水平（16,848±5118μg·h/L对7128±1156μg·h/L，p = 0.009）。ALL患者的稳态分布容积显著更大（332±47mL/kg对191±12mL/kg，p = 0.04），清除率更快（21±3mL/h/kg对11±2mL/h/kg，p = 0.03），且剂量校正后的AUC低于NHL患者（6010±836μg·h/L对12,044±2707μg·h/L，p = 0.006）。与白种人患者相比，非白种人患者有清除率更快（23±4mL/h/kg对16±3mL/h/kg，p = 0.1）、消除半衰期更短（5.7±3.6小时对13±8.8小时，p = 0.1）和平均驻留时间更短（11±3小时对25±5小时，p = 0.08）的趋势。与成年患者相比，儿科患者的稳态分布容积显著更大（418±82mL/kg对252±34mL/kg，p = 0.02），消除半衰期更长（18.4±13.6小时对8.7±6.7小时，p = 0.04）。B43-金雀异黄素的药代动力学不受患者性别或既往病史中骨髓移植的影响。总体而言，B43-金雀异黄素在这群经过大量预处理的白血病/淋巴瘤患者中显示出良好的药代动力学，这让人想起其最近在食蟹猴中报道的良好药代动力学。据我们所知，这是第一项关于含免疫偶联物的酪氨酸激酶抑制剂的临床药代动力学研究。
