High-dose MTX110 (soluble panobinostat) safely administered into the fourth ventricle in a nonhuman primate model

View More View Less
  • 1 Departments of Pediatric Surgery and
  • 2 Neurosurgery,
  • 3 Center for Laboratory Animal Medicine and Care, and
  • 4 Departments of Pathology and Laboratory Medicine and
  • 5 Diagnostic and Interventional Imaging, McGovern Medical School, The University of Texas Health Science Center at Houston, Texas; and
  • 6 Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota
Restricted access

Purchase Now

USD  $45.00

JNS + Pediatrics - 1 year subscription bundle (Individuals Only)

USD  $505.00

JNS + Pediatrics + Spine - 1 year subscription bundle (Individuals Only)

USD  $600.00
Print or Print + Online

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.

ABBREVIATIONS HDACi = histone deacetylase inhibitor; IM = intramuscular; MTX110 = soluble panobinostat.

JNS + Pediatrics - 1 year subscription bundle (Individuals Only)

USD  $505.00

JNS + Pediatrics + Spine - 1 year subscription bundle (Individuals Only)

USD  $600.00

Contributor Notes

Correspondence David I. Sandberg: McGovern Medical School/University of Texas Health Science Center at Houston, Houston, TX. david.i.sandberg@uth.tmc.edu.

INCLUDE WHEN CITING Published online May 1, 2020; DOI: 10.3171/2020.2.PEDS19786.

Disclosures The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

  • 1

    Sandberg DI, Crandall KM, Koru-Sengul T, Pharmacokinetic analysis of etoposide distribution after administration directly into the fourth ventricle in a piglet model. J Neurooncol. 2010;97(1):2532.

    • Search Google Scholar
    • Export Citation
  • 2

    Sandberg DI, Crandall KM, Petito CK, Chemotherapy administration directly into the fourth ventricle in a new piglet model. J Neurosurg Pediatr. 2008;1(5):373380.

    • Search Google Scholar
    • Export Citation
  • 3

    Sandberg DI, Peet MM, Johnson MD, Chemotherapy administration directly into the fourth ventricle in a nonhuman primate model. J Neurosurg Pediatr. 2012;9(5):530541.

    • Search Google Scholar
    • Export Citation
  • 4

    Sandberg DI, Solano J, Petito CK, Safety and pharmacokinetic analysis of methotrexate administered directly into the fourth ventricle in a piglet model. J Neurooncol. 2010;100(3):397406.

    • Search Google Scholar
    • Export Citation
  • 5

    Sandberg DI, Kerr ML. Ventricular access device placement in the fourth ventricle to treat malignant fourth ventricle brain tumors: technical note. Childs Nerv Syst. 2016;32(4):703707.

    • Search Google Scholar
    • Export Citation
  • 6

    Sandberg DI, Crandall K, Petito CK, Distribution of etoposide in cerebrospinal fluid after infusions into the fourth ventricle in piglets. J Neurosurg Pediatr. 2008;1:A354.

    • Search Google Scholar
    • Export Citation
  • 7

    Sandberg DI, Rytting M, Zaky W, Methotrexate administration directly into the fourth ventricle in children with malignant fourth ventricular brain tumors: a pilot clinical trial. J Neurooncol. 2015;125(1):133141.

    • Search Google Scholar
    • Export Citation
  • 8

    Sandberg DI, Yu B, Patel R, Infusion of 5-azacytidine (5-AZA) into the fourth ventricle or resection cavity in children with recurrent posterior fossa ependymoma: a pilot clinical trial. J Neurooncol. 2019;141(2):449457.

    • Search Google Scholar
    • Export Citation
  • 9

    Pei Y, Liu KW, Wang J, HDAC and PI3K Antagonists cooperate to inhibit growth of MYC-driven medulloblastoma. Cancer Cell. 2016;29(3):311323.

    • Search Google Scholar
    • Export Citation
  • 10

    Singleton WGB, Bienemann AS, Woolley M, The distribution, clearance, and brainstem toxicity of panobinostat administered by convection-enhanced delivery. J Neurosurg Pediatr. 2018;22(3):288296.

    • Search Google Scholar
    • Export Citation
  • 11

    Van Veggel M, Westerman E, Hamberg P. Clinical pharmacokinetics and pharmacodynamics of panobinostat. Clin Pharmacokinet. 2018;57(1):2129.

    • Search Google Scholar
    • Export Citation
  • 12

    Savelieva M, Woo MM, Schran H, Population pharmacokinetics of intravenous and oral panobinostat in patients with hematologic and solid tumors. Eur J Clin Pharmacol. 2015;71(6):663672.

    • Search Google Scholar
    • Export Citation

Metrics

All Time Past Year Past 30 Days
Abstract Views 18 18 18
Full Text Views 1 1 1
PDF Downloads 1 1 1
EPUB Downloads 0 0 0