Low cerebrospinal fluid-to-plasma ratios of orally administered lenalidomide mediated by its low cell membrane permeability in patients with hematologic malignancies
Low cerebrospinal fluid-to-plasma ratios of orally administered lenalidomide mediated by its low cell membrane permeability in patients with hematologic malignancies
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DOI：
10.1007/s00277-022-04893-w
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发表时间：
2022-06-22
影响因子：
3.5
通讯作者：
Yamazaki，Hiroshi
中科院分区：
文献类型：
--
作者：
Ogiya，Daisuke;Murayama，Norie;Yamazaki，Hiroshi
来那度胺是通过去除一个酮基（加上一个氨基）形成的沙利度胺的合成类似物;它具有有益于治疗血液恶性肿瘤的抗肿瘤活性。然而，据报道，与沙利度胺相比，来那度胺在动物模型中的脑分布较低。本研究的目的是评估血浆和脑脊液中来那度胺浓度的恶性血液肿瘤患者。尽管来那度胺的体外胃肠道渗透性较低，但在口服20 mg来那度胺后1.5 h，使用液相色谱/质谱法在3例日本患者的血浆中检测到来那度胺。临床观察到的来那度胺脑脊液/血浆比值较低（1.3-2.4%）。在猴血脑屏障模型和人胎盘细胞系统中观察到的来那度胺的内流渗透性值比沙利度胺和另一种第二代药物泊马度胺沿着阳性渗透性对照咖啡因低一个数量级。由于体外试验证明来那度胺的细胞屏障渗透性较低，因此来那度胺的临床相关药代动力学特征导致恶性血液病患者从血浆进入脑脊液的渗透性较低。来那度胺最终建议通过患者的全身暴露来证明其有利的免疫调节作用。
Lenalidomide is a synthetic analog of thalidomide formed by the removal of one keto group (plus the addition of an amino group); it has anti-tumor activities beneficial for the treatment of hematologic malignancies. However, lenalidomide distribution to brain in animal models is reportedly low compared with that of thalidomide. The aim of this study was to evaluate plasma and cerebrospinal fluid concentrations of lenalidomide in three patients with malignant hematologic malignancies. Lenalidomide was detected in plasma from the three Japanese patients 1.5 h following oral administration of 20 mg lenalidomide using liquid chromatography/mass spectrometry, despite the in vitro gastrointestinal permeability of lenalidomide being low. Clinically observed cerebrospinal fluid-to-plasma ratios of lenalidomide were low (1.3–2.4%). Observed influx permeability values for lenalidomide in monkey blood–brain barrier model and human placental cell systems were one order of magnitude lower than those of thalidomide and another second-generation drug, pomalidomide along with a positive permeability control, caffeine. Because of the low cell-barrier permeability of lenalidomide demonstrated in in vitro assays, clinically relevant pharmacokinetic profiles of lenalidomide resulted in low penetrability from plasma into cerebrospinal fluid in patients with hematologic malignancies. Lenalidomide is conclusively suggested to expert its favorable immunomodulatory effects via systemic exposures in the patients.