OBJECTIVE 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. METHODS 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. RESULTS 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). CONCLUSIONS 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.
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MRI scans demonstrated catheter placement within the fourth ventricle. In 2 of 4 animals, the catheter passed through the fourth ventricle and ended slightly more rostral than intended. This was due to the technical difficulties of keeping the catheter in a perfect position in the small fourth ventricle of a primate. In clinical trials to date performed in humans, in whom the fourth ventricle is larger, all prior catheter placements have been accurate, with catheter tips terminating within the fourth ventricle.7,8 Of note, in the current experiments, all catheters were found on postmortem exams to have entered the fourth ventricle, with no catheter holes visualized distal to the obex. Since the catheters have multiple holes coursing along their distal portion, we can conclude that all 4 primates received MTX110 into the fourth ventricle and that 2 of them additionally received MTX110 in the cerebral aqueduct and/or third ventricle. No animals had any evidence of ischemia or other damage to the brain after fourth-ventricle MTX110 infusions. The safety of MTX110 infusions into the fourth ventricle was also supported by postmortem histological evaluations. All brains and other evaluated organs looked grossly normal, and histological evaluation demonstrated only minor postoperative changes with no damage to the brain or any other organs.
This work was supported by the Dr. Marnie Rose Foundation (David I. Sandberg, MD) and by a generous donation from Mr. Dick Bassett (David I. Sandberg, MD). We also gratefully acknowledge funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD099543; Rachael W. Siranni, PhD, and David I. Sandberg, MD).
- Brain tumor
- Fourth ventricle
PubMed: MeSH publication types
- Journal Article