Janssen Julie M, Dorlo T P C, Niewerth D, Wilhelm A J, Zwaan C M, Beijnen J H, Attarbaschi A, Baruchel A, Fagioli F, Klingebiel T, De Moerloose B, Palumbo G, von Stackelberg A, Kaspers G J L, Huitema A D R
Department of Pharmacy and Pharmacology, Netherlands Cancer Institute-Antoni van Leeuwenhoek, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
Department of Pediatric Oncology/Hematology, VU University Medical Center, Amsterdam, The Netherlands.
Clin Pharmacokinet. 2020 Feb;59(2):207-216. doi: 10.1007/s40262-019-00803-y.
The pharmacokinetics (PK) of the 20S proteasome inhibitor bortezomib are characterized by a large volume of distribution and a rapid decline in plasma concentrations within the first hour after administration. An increase in exposure was observed in the second week of treatment, which has previously been explained by extensive binding of bortezomib to proteasome in erythrocytes and peripheral tissues. We characterized the nonlinear population PK and pharmacodynamics (PD) of bortezomib in children with acute lymphoblastic leukemia.
Overall, 323 samples from 28 patients were available from a pediatric clinical study investigating bortezomib at an intravenous dose of 1.3 mg/m twice weekly (Dutch Trial Registry number 1881/ITCC021). A semi-physiological PK model for bortezomib was first developed; the PK were linked to the decrease in 20S proteasome activity in the final PK/PD model.
The plasma PK data were adequately described using a two-compartment model with linear elimination. Increased concentrations were observed in week 2 compared with week 1, which was described using a Langmuir binding model. The decrease in 20S proteasome activity was best described by a direct effect model with a sigmoidal maximal inhibitory effect, representing the relationship between plasma concentrations and effect. The maximal inhibitory effect was 0.696 pmol AMC/s/mg protein (95% confidence interval 0.664-0.728) after administration.
The semi-physiological model adequately described the nonlinear PK and PD of bortezomib in plasma. This model can be used to further optimize dosing of bortezomib.
20S蛋白酶体抑制剂硼替佐米的药代动力学（PK）特征为分布容积大，给药后第一小时内血浆浓度迅速下降。在治疗的第二周观察到暴露增加，此前这被解释为硼替佐米与红细胞和外周组织中的蛋白酶体广泛结合。我们对急性淋巴细胞白血病患儿中硼替佐米的非线性群体PK和药效学（PD）进行了表征。
总体而言，来自一项儿科临床研究的28例患者的323份样本可用，该研究调查了静脉注射剂量为1.3mg/m²、每周两次的硼替佐米（荷兰试验注册编号1881/ITCC021）。首先建立了硼替佐米的半生理PK模型；在最终的PK/PD模型中，PK与20S蛋白酶体活性的降低相关联。
使用具有线性消除的二室模型充分描述了血浆PK数据。与第1周相比，第2周观察到浓度升高，这用Langmuir结合模型进行了描述。20S蛋白酶体活性的降低最好用具有S形最大抑制作用的直接效应模型来描述，该模型代表血浆浓度与效应之间的关系。给药后最大抑制作用为0.696pmol AMC/s/mg蛋白质（95%置信区间0.664 - 0.728）。
半生理模型充分描述了硼替佐米在血浆中的非线性PK和PD。该模型可用于进一步优化硼替佐米的给药方案。
