Pharmacokinetic modeling of the blood-stable camptothecin analog AR-67 in two different formulations.
Pharmacokinetic modeling of the blood-stable camptothecin analog AR-67 in two different formulations.
复制标题
两种不同制剂中血液稳定性喜树碱类似物 AR-67 的药代动力学模型。
DOI：
10.1002/bdd.2199
复制
发表时间：
2019
影响因子：
2.1
通讯作者：
Leggas,Markos
中科院分区：
文献类型：
--
作者：
Liu,Xiaoxi;Adane,Eyob;Tang,Fei;Leggas,Markos
AR-67是一种亲脂性喜树碱类似物，目前正在使用基于Cremophor EL的制剂进行临床研究。然而，由于Cremophor的临床使用存在潜在的毒性限制，因此提出了基于环糊精（SBE-β-CD）的替代制剂。在小鼠中进行药代动力学（PK）研究，并将基于SBE-β-CD的制剂与Cremophor EL制剂进行比较。在小鼠中静脉或经口给予含AR-67的Cremophor或SBE-β-CD制剂后进行PK研究。采用非房室模型分析确定血浆和组织药物分布。开发了非线性混合效应（群体）PK模型，以拟合口服和静脉给药数据并估计关键PK参数。在PK模型中将制剂的影响作为协变量进行探索。SBE-β-CD制剂中的AR-67具有与Cremophor EL制剂相似的血浆PK和生物分布。拟定的二室模型充分描述了两种制剂中AR-67的血浆PK。SBE-β-CD制剂中的AR-67在经口和静脉给药后均表现出剂量线性。我们的研究表明，SBE-β-CD是Cremophor EL的可行替代品，可作为配制AR-67的药用辅料。
AR‐67 is a lipophilic camptothecin analog currently under clinical investigation using a Cremophor EL based formulation. However, as potential toxicity limitations exist in the clinical use of Cremophor, an alternative cyclodextrin (SBE‐β‐CD) based formulation has been proposed. Pharmacokinetic (PK) studies were conducted in mice and the SBE‐β‐CD based formulation was compared with the Cremophor EL formulation. PK studies were conducted following intravenous or oral administration of AR‐67 in either Cremophor or SBE‐β‐CD formulation in mice. Noncompartmental analysis was used to determine the plasma and tissue drug distribution. A non‐linear mixed effects (population) PK model was developed to fit both the oral and intravenous data and to estimate key PK parameters. The effect of formulation was explored as a covariate in the PK model. AR‐67 in the SBE‐β‐CD formulation had similar plasma PK and biodistribution to that in the Cremophor EL formulation. The proposed two‐compartment model described the plasma PK of AR‐67 in both formulations adequately. AR‐67 in the SBE‐β‐CD formulation exhibited dose linearity following both oral and intravenous administration. Our studies indicate that SBE‐β‐CD is a viable alternative to Cremophor EL as a pharmaceutical excipient for formulating AR‐67.