Lester McCully Cynthia, Rodgers Louis T, Cruz Rafael, Thomas Marvin L, Peer Cody J, Figg William D, Warren Katherine E
Pediatric Neuro-Oncology Section, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
Clinical Pharmacology Program, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
Neurooncol Adv. 2020 Jan-Dec;2(1):vdaa005. doi: 10.1093/noajnl/vdaa005. Epub 2020 Jan 1.
Epigenetic modifiers are being investigated for a number of CNS malignancies as tumor-associated mutations such as isocitrate dehydrogenase mutations (IDH1/IDH2) and H3K27M mutations, which result in aberrant signaling, are identified. We evaluated the CNS exposure of the DNA methyltransferase inhibitor, 5-azacytidine (5-AZA), in preclinical nonhuman primate (NHP) models to inform its clinical development for CNS tumors.
5-AZA and 5-AZA+Inulin pharmacokinetics (PK) were evaluated in NHPs ( = 10) following systemic (intravenous [IV]) and intrathecal (intraventricular [IT-V], intralumbar [IT-L], and cisternal [IT-C]) administration. Plasma, cerebrospinal fluid (CSF), cortical extracellular fluid (ECF), and tissues were collected. 5-AZA levels were quantified via ultra-high-performance liquid chromatography with tandem mass spectrometric detection assay and inulin via ELISA. PK parameters were calculated using noncompartmental methods.
After IV administration, minimal plasma exposure (area under the curve [AUC] range: 2.4-3.2 hµM) and negligible CSF exposure were noted. CSF exposure was notably higher after IT-V administration (AUC 1234.6-5368.4 hµM) compared to IT-L administration (AUC 7.5-19.3 h*µM). CSF clearance after IT administration exceeded the mean inulin CSF flow rate of 0.018 ± 0.003 ml/min as determined by inulin IT-V administration. 5-AZA IT-V administration with inulin increased the 5-AZA CSF duration of exposure by 2.2-fold. IT-C administration yielded no quantifiable 5-AZA ECF concentrations but resulted in quantifiable tissue levels.
IT administration of 5-AZA is necessary to achieve adequate CNS exposure. IT administration results in pronounced and prolonged 5-AZA CSF exposure above the reported IC range for IDH-mutated glioma cell lines. Inulin administered with 5-AZA increased the duration of exposure for 5-AZA.
随着肿瘤相关突变（如异柠檬酸脱氢酶突变（IDH1/IDH2）和H3K27M突变）的发现，这些突变会导致信号异常，表观遗传修饰剂正被用于多种中枢神经系统恶性肿瘤的研究。我们在临床前非人类灵长类动物（NHP）模型中评估了DNA甲基转移酶抑制剂5-氮杂胞苷（5-AZA）的中枢神经系统暴露情况，以为其用于中枢神经系统肿瘤的临床开发提供依据。
在10只NHP中，通过全身（静脉注射[IV]）和鞘内（脑室内[IT-V]、腰段[IT-L]和脑池内[IT-C]）给药评估5-AZA和5-AZA+菊粉的药代动力学（PK）。收集血浆、脑脊液（CSF）、皮质细胞外液（ECF）和组织。通过超高效液相色谱-串联质谱检测法对5-AZA水平进行定量，通过酶联免疫吸附测定法对菊粉进行定量。使用非房室方法计算PK参数。
静脉给药后，血浆暴露量极低（曲线下面积[AUC]范围：2.4 - 3.2 hµM），脑脊液暴露量可忽略不计。与IT-L给药（AUC 7.5 - 19.3 hµM）相比，IT-V给药后脑脊液暴露量明显更高（AUC 1234.6 - 5368.4 h*µM）。鞘内给药后脑脊液清除率超过了通过IT-V注射菊粉测定的菊粉脑脊液平均流速0.018 ± 0.003 ml/min。5-AZA与菊粉联合IT-V给药使5-AZA在脑脊液中的暴露持续时间增加了2.2倍。IT-C给药未产生可定量的5-AZA ECF浓度，但导致了可定量的组织水平。
5-AZA进行鞘内给药对于实现足够的中枢神经系统暴露是必要的。鞘内给药导致5-AZA在脑脊液中的暴露显著且持久，高于报道的IDH突变胶质瘤细胞系的IC范围。与5-AZA联合给药的菊粉增加了5-AZA的暴露持续时间。
