Clinical Pharmacology, Oncology, Global Product Development, Pfizer Inc, 10555 Science Center Drive, San Diego, CA, 92121, USA.
Pfizer Global Product Development Oncology, 300 Technology Square, Suite 302, Cambridge, MA, 02139-3520, USA.
Clin Pharmacokinet. 2019 Feb;58(2):271-282. doi: 10.1007/s40262-018-0694-x.
To date, the population pharmacokinetics (popPK) of gemtuzumab ozogamicin (GO), a CD33-directed antibody-drug conjugate consisting of hP67.6 antibody linked to N-acetyl gamma calicheamicin used in the treatment of acute myeloid leukemia (AML), has not been characterized in pediatric patients. This report describes the popPK of GO following intravenous administration in 29 pediatric patients aged ≤ 17 years with relapsed or refractory AML who were enrolled in the 0903A1-102-US phase I/II study.
The pharmacokinetics (PK) of GO, as represented by total hP67.6 antibody, were described by a two-compartment model with two clearance components: a linear clearance (CL) and time-dependent clearance that includes a decay coefficient. The PK of unconjugated calicheamicin (UC; payload) were described by a two-compartment model with CL and an input rate of formation based on antibody rate of elimination. Allometric scaling was included in both models, with baseline body weight as a fixed effect on CL and central volume.
PK parameters for hP67.6 and UC were not significantly affected by any of the available demographic factors and safety laboratory values tested as covariates (except baseline body weight). Simulations to compare GO dosing regimens (6, 7.5, and 9 mg/m on days 1 and 15 versus, 3 mg/m fractionated dosing on days 1, 4, and 7) were performed, showing that total antibody and UC trough concentrations were maintained at higher concentrations during treatment following the more frequent dosing than following the original regimen.
0903A1-102-US.
迄今为止，gemtuzumab ozogamicin（GO）的群体药代动力学（popPK）尚未在儿科患者中进行描述，GO 是一种由 hP67.6 抗体与 N-乙酰基γ-calicheamicin 连接而成的靶向 CD33 的抗体药物偶联物，用于治疗急性髓细胞白血病（AML）。本报告描述了在接受过治疗的复发或难治性 AML 儿科患者（≤17 岁）中，静脉注射 GO 后的 popPK。这些患者参加了 0903A1-102-US 的 I/II 期研究。
GO 的药代动力学（PK），表现为总 hP67.6 抗体，通过一个具有两个清除分量的两室模型来描述：一个线性清除（CL）和包含衰减系数的时间依赖性清除。未缀合 calicheamicin（UC；有效载荷）的 PK 通过一个两室模型来描述，其 CL 和形成输入率基于抗体的消除率。两种模型都包含体表面积比例缩放，以基线体重作为 CL 和中央容积的固定效应。
hP67.6 和 UC 的 PK 参数不受任何可用的人口统计学因素和安全性实验室值的影响，这些值作为协变量进行了测试（除了基线体重）。进行了模拟比较 GO 给药方案（第 1 和 15 天给予 6、7.5 和 9mg/m2，与第 1、4 和 7 天给予 3mg/m2 分剂量），结果表明，与原始方案相比，在更频繁的给药后，总抗体和 UC 谷浓度在治疗期间保持在更高的浓度。
0903A1-102-US。
