School of Pharmacy and Medical Sciences, University of South Australia, North Terrace, Adelaide, 5001, Australia.
Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
Cancer Chemother Pharmacol. 2019 Nov;84(5):1073-1087. doi: 10.1007/s00280-019-03941-z. Epub 2019 Sep 6.
Lenalidomide is used widely in B-cell malignancies for its immunomodulatory activity. It is primarily eliminated via the kidneys, with a significant proportion of renal elimination attributed to active processes. Lenalidomide is a weak substrate of P-glycoprotein (P-gp), though it is unclear whether P-gp is solely responsible for lenalidomide transport. This study aimed to determine whether the current knowledge of lenalidomide was sufficient to describe the pharmacokinetics of lenalidomide in multiple tissues.
A physiologically based pharmacokinetic model was developed using the Open Systems Pharmacology Suite to explore the pharmacokinetics of lenalidomide in a variety of tissues. Data were available for mice dosed intravenously at 0.5, 1.5, 5, and 10 mg/kg, with concentrations measured in plasma, brain, heart, kidney, liver, lung, muscle, and spleen. P-gp expression and activity were sourced from the literature.
The model predictions in plasma, liver, and lung were representative of the observed data (median prediction error 13%, - 10%, and 30%, respectively, with 90% confidence intervals including zero), while other tissue predictions showed sufficient similarity to the observed data. Contrary to the data, model predictions for the brain showed no drug reaching brain tissue when P-gp was expressed at the blood-brain barrier. The data were better described by basolateral transporters at the intracellular wall. Local sensitivity analysis showed that transporter activity was the most sensitive parameter in these models for exposure.
As P-gp transport at the blood-brain barrier did not explain the observed brain concentrations alone, there may be other transporters involved in lenalidomide disposition.
来那度胺具有免疫调节活性，广泛用于 B 细胞恶性肿瘤。它主要通过肾脏消除，其中相当一部分的肾消除归因于主动过程。来那度胺是 P 糖蛋白（P-gp）的弱底物，尽管尚不清楚 P-gp 是否是来那度胺转运的唯一原因。本研究旨在确定目前对来那度胺的了解是否足以描述来那度胺在多种组织中的药代动力学。
使用开放式系统药理学套件开发了一种基于生理学的药代动力学模型，以探索来那度胺在各种组织中的药代动力学。数据可用于静脉内给予 0.5、1.5、5 和 10 mg/kg 的小鼠，在血浆、大脑、心脏、肾脏、肝脏、肺、肌肉和脾脏中测量浓度。P-gp 表达和活性来自文献。
模型在血浆、肝脏和肺中的预测与观察数据具有代表性（中位数预测误差分别为 13%、-10%和 30%，90%置信区间包括零），而其他组织的预测与观察数据具有足够的相似性。与数据相反，当 P-gp 在血脑屏障处表达时，模型对大脑的预测表明没有药物到达脑组织。细胞内壁的基底外侧转运体更好地描述了数据。局部敏感性分析表明，在这些模型中，转运体活性是暴露的最敏感参数。
由于 P-gp 在血脑屏障处的转运不能单独解释观察到的大脑浓度，因此可能有其他转运体参与来那度胺的处置。
