High-dose MTX110 (soluble panobinostat) safely administered into the fourth ventricle in a nonhuman primate model.
High-dose MTX110 (soluble panobinostat) safely administered into the fourth ventricle in a nonhuman primate model.
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DOI：
10.3171/2020.2.peds19786
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发表时间：
2020-08-01
期刊：
影响因子：
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通讯作者：
Sirianni RW
中科院分区：
文献类型：
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作者：
Sandberg DI;Kharas N;Yu B;Janssen CF;Trimble A;Ballester LY;Patel R;Mohammad AS;Elmquist WF;Sirianni RW
化疗药物直接注入第四脑室可能在治疗恶性第四脑室肿瘤中发挥作用。本研究测试了MTX 110（可溶性帕比司他; Midatech Pharma）短期和长期给药至非人灵长类动物第四脑室的安全性和药代动力学。四只恒河猴接受后颅窝颅骨切除术和第四脑室导管插入术。在组I（n = 2）中，导管外化，同时放置腰椎引流导管，以评估短期输注后的CSF分布。MTX 110（0.5 ml 300 μM帕比司他溶液）每日输注至第四脑室，连续5天。测量连续CSF和血清帕比司他水平。在第二组（n = 2），第四脑室导管连接到皮下放置的端口，随后长期输注。在8周内给予4个周期的MTX 110，每个周期包括5次每日输注（0.5 ml 300 μM帕比司他溶液）。对动物进行详细的神经学评价、MRI扫描和死后组织学分析。脑室内MTX 110输注后未发生神经功能缺损。MRI扫描显示，所有4只动物的导管放置在第四脑室内，1只动物延伸至大脑导水管，1只动物延伸至第三脑室。所有动物的脑干、小脑或大脑其他部位均无MRI信号变化。在组织学上，所有动物均保留了正常的脑细胞结构，仅出现局灶性轻度术后变化。在两组的所有样品中，在输注后2小时和4小时收集的血清样品中均未检测到帕比司他。在组I中，第四脑室CSF中的平均峰值帕比司他水平（6242 ng/ml）显著高于腰椎CSF中的平均峰值帕比司他水平（9 ng/ml; p < 0.0001）。在组II中，平均峰值CSF帕比司他水平（11，042 ng/ml）显著高于平均谷CSF帕比司他水平（33 ng/ml; p < 0.0001）。MTX 110可以以超治疗剂量安全地输注到非人灵长类动物的第四脑室内。输注后CSF帕比司他水平在第四脑室中立即达到峰值，然后在24小时内迅速下降。在输注后4小时内，从腰池测量的CSF中可检测到低水平的帕比司他。这些结果将为复发性髓母细胞瘤患者的初步临床试验提供背景数据。
Chemotherapy infusions directly into the fourth ventricle may play a role in treating malignant fourth-ventricular tumors. This study tested the safety and pharmacokinetics of short-term and long-term administration of MTX110 (soluble panobinostat; Midatech Pharma) into the fourth ventricle of nonhuman primates. Four rhesus macaque monkeys underwent posterior fossa craniectomy and catheter insertion into the fourth ventricle. In group I (n = 2), catheters were externalized and lumbar drain catheters were placed simultaneously to assess CSF distribution after short-term infusions. MTX110 (0.5 ml of 300 μM panobinostat solution) was infused into the fourth ventricle daily for 5 consecutive days. Serial CSF and serum panobinostat levels were measured. In group II (n = 2), fourth-ventricle catheters were connected to a subcutaneously placed port for subsequent long-term infusions. Four cycles of MTX110, each consisting of 5 daily infusions (0.5 ml of 300 μM panobinostat solution), were administered over 8 weeks. Animals underwent detailed neurological evaluations, MRI scans, and postmortem histological analyses. No neurological deficits occurred after intraventricular MTX110 infusions. MRI scans showed catheter placement within the fourth ventricle in all 4 animals, with extension to the cerebral aqueduct in 1 animal and into the third ventricle in 1 animal. There were no MRI signal changes in the brainstem, cerebellum, or elsewhere in the brains of any of the animals. Histologically, normal brain cytoarchitecture was preserved with only focal mild postsurgical changes in all animals. Panobinostat was undetectable in serum samples collected 2 and 4 hours after infusions in all samples in both groups. In group I, the mean peak panobinostat level in the fourth-ventricle CSF (6242 ng/ml) was significantly higher than that in the lumbar CSF (9 ng/ml; p < 0.0001). In group II, the mean peak CSF panobinostat level (11,042 ng/ml) was significantly higher than the mean trough CSF panobinostat level (33 ng/ml; p < 0.0001). MTX110 can be safely infused into the fourth ventricle in nonhuman primates at supratherapeutic doses. Postinfusion CSF panobinostat levels peak immediately in the fourth ventricle and then rapidly decrease over 24 hours. Panobinostat is detectable at low levels in CSF measured from the lumbar cistern up to 4 hours after infusions. These results will provide background data for a pilot clinical trial in patients with recurrent medulloblastoma.