SpringerLink
Log in

Pharmacokinetic analysis of etoposide distribution after administration directly into the fourth ventricle in a piglet model

  • Laboratory Investigation - Human/Animal Tissue
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

We hypothesize that infusion of chemotherapeutic agents directly into the fourth ventricle potentially may play a role in treating malignant posterior fossa brain tumors. Accordingly, we used a piglet model developed in our laboratory to test the safety of etoposide infusions into the fourth ventricle and to study the pharmacokinetics associated with these infusions. In 5 piglets, closed-tip silicone catheters were inserted into the fourth ventricle and lumbar cistern. Five consecutive daily infusions of etoposide (0.5 mg) were administered via the fourth ventricle catheter. Serum and CSF from both catheters were sampled for measurement of etoposide level by reversed-phase high performance liquid chromatography (HPLC). For CSF samples, area under the concentration-time curve (AUC) was calculated. Piglets underwent daily neurological examinations, a 4.7 Tesla MRI scan, and then were sacrificed for post-mortem brain examination. No neurological deficits or signs of meningitis were caused by intraventricular chemotherapy infusions. MRI scans showed catheter placement within the fourth ventricle but no signal changes in the brain stem or cerebellum. In all piglets, the mean fourth ventricular CSF peak etoposide level exceeded the mean peak lumbar etoposide levels by greater than 10-fold. Statistically significant differences between fourth ventricle and lumbar AUC were noted at peaks (ΔAUC = 3384196 ng h/ml with 95%CI: 1758625, 5009767, P = 0.0044) and at all collection time points (ΔAUC = 1422977 ng h/ml with 95%CI: 732188, 2113766, P = 0.0046) but not at troughs (ΔAUC = −29546 ng h/ml (95%CI: −147526, 88434.2, P = 0.5251). Serum etoposide was absent at two and four hours after intraventricular infusions in all animals. Pathological analysis demonstrated meningitis, choroid plexitis, and ependymitis in the fourth and occasionally lateral ventricles. Etoposide can be infused directly into the fourth ventricle without clinical or radiographic evidence of damage. Autopsy examination revealed ventriculitis and meningitis which did not have a clinical correlate. Etoposide does not distribute evenly throughout CSF spaces after administration into the fourth ventricle, and higher peak CSF levels are observed in the fourth ventricle than in the lumbar cistern.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Sandberg DI et al (2008) Chemotherapy administration directly into the fourth ventricle in a new piglet model. J Neurosurg Pediatrics 1(5):373–380

    Article  Google Scholar 

  2. Reddy AT, Packer RJ (1999) Medulloblastoma. Curr Opin Neurol 12(6):681–685

    Article  CAS  PubMed  Google Scholar 

  3. Rutka JT (1997) Medulloblastoma. Clin Neurosurg 44:571–585

    CAS  PubMed  Google Scholar 

  4. Choux M et al (1982) Medulloblastoma. Neurochirurgie 28(Suppl 1):1–229

    Google Scholar 

  5. Silverman CL, Simpson JR (1982) Cerebellar medulloblastoma: the importance of posterior fossa dose to survival and patterns of failure. Int J Radiat Oncol Biol Phys 8(11):1869–1876

    CAS  PubMed  Google Scholar 

  6. Suit HD, Westgate SJ (1986) Impact of improved local control on survival. Int J Radiat Oncol Biol Phys 12(4):453–458

    CAS  PubMed  Google Scholar 

  7. Rutkowski S et al (2005) Treatment of early childhood medulloblastoma by postoperative chemotherapy alone. N Engl J Med 352(10):978–986

    Article  CAS  PubMed  Google Scholar 

  8. Slavc I et al (2003) Feasibility of long-term intraventricular therapy with mafosfamide (n = 26) and etoposide (n = 11): experience in 26 children with disseminated malignant brain tumors. J Neurooncol 64(3):239–247

    Article  PubMed  Google Scholar 

  9. Slavc I et al (1998) Intrathecal mafosfamide therapy for pediatric brain tumors with meningeal dissemination. J Neurooncol 38(2–3):213–218

    Article  CAS  PubMed  Google Scholar 

  10. Fleischhack G et al (2001) Feasibility of intraventricular administration of etoposide in patients with metastatic brain tumours. Br J Cancer 84(11):1453–1459

    Article  CAS  PubMed  Google Scholar 

  11. Sandberg DI et al (2000) Ommaya reservoirs for the treatment of leptomeningeal metastases. Neurosurgery 47(1):49–54; discussion 54–5

    Article  CAS  PubMed  Google Scholar 

  12. Jacobs A, Clifford P, Kay HE (1981) The Ommaya reservoir in chemotherapy for malignant disease in the CNS. Clin Oncol 7(2):123–129

    CAS  PubMed  Google Scholar 

  13. Obbens EA et al (1985) Ommaya reservoirs in 387 cancer patients: a 15-year experience. Neurology 35(9):1274–1278

    CAS  PubMed  Google Scholar 

  14. Shapiro WR et al (1977) Treatment of meningeal neoplasms. Cancer Treat Rep 61(4):733–743

    CAS  PubMed  Google Scholar 

  15. Rubinstein LJ et al (1975) Disseminated necrotizing leukoencephalopathy: a complication of treated central nervous system leukemia and lymphoma. Cancer 35(2):291–305

    Article  CAS  PubMed  Google Scholar 

  16. Macdonald DR (1991) Neurologic complications of chemotherapy. Neurol Clin 9(4):955–967

    CAS  PubMed  Google Scholar 

  17. Chamberlain MC, Kormanik PA, Barba D (1997) Complications associated with intraventricular chemotherapy in patients with leptomeningeal metastases. J Neurosurg 87(5):694–699

    Article  CAS  PubMed  Google Scholar 

  18. Bleyer WA et al (1978) The Ommaya reservoir: newly recognized complications and recommendations for insertion and use. Cancer 41(6):2431–2437

    Article  CAS  PubMed  Google Scholar 

  19. Reif S et al (2001) Bioequivalence investigation of high-dose etoposide and etoposide phosphate in lymphoma patients. Cancer Chemother Pharmacol 48(2):134–140

    Article  CAS  PubMed  Google Scholar 

  20. Gajjar A et al (1999) Chemotherapy of medulloblastoma. Childs Nerv Syst 15(10):554–562

    Article  CAS  PubMed  Google Scholar 

  21. Sirisangtragul C et al (2003) Cerebrospinal fluid pharmacokinetics after different dosage regimens of intraventricular etoposide. Int J Clin Pharmacol Ther 41(12):606–607

    CAS  PubMed  Google Scholar 

  22. Henwood JM, Brogden RN (1990) Etoposide. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in combination chemotherapy of cancer. Drugs 39(3):438–490

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the Miami Children’s Hospital Foundation and the Women’s Cancer Association of the University of Miami. Lumbar catheters used in these experiments were obtained through a grant from Medtronic. We thank Ms. Mariana Nunez for her assistance with preparation of pathological specimens.

Author information

Authors and Affiliations

  1. Department of Neurological Surgery, University of Miami Miller School of Medicine and Miami Children’s Hospital, 3215 S.W. 62nd Avenue, Ambulatory Care Building Suite 3109, Miami, FL, 33155, USA

    David I. Sandberg & Kenneth M. Crandall

  2. Department of Epidemiology and Public Health, University of Miami Miller School of Medicine, Clinical Research Building, Room 1042, 1120 N.W. 14th Street, Miami, FL, 33136, USA

    Tulay Koru-Sengul

  3. Division of Biostatistics and Bioinformatics, University of Miami Miller School of Medicine Sylvester Comprehensive Cancer Center, Clinical Research Building, 1120 N.W. 14th Street, Miami, FL, 33136, USA

    Tulay Koru-Sengul

  4. Department of Radiology, University of Miami Miller School of Medicine, 1115 N.W. 14th St, Miami, FL, 33136, USA

    Kyle R. Padgett

  5. Departments of Chemistry and Biochemistry, Florida International University, 11200 S.W. 8th St, Miami, FL, 33199, USA

    John Landrum & Darwin Babino

  6. Department of Pathology, University of Miami Miller School of Medicine, 1611 N.W. 12th Avenue, Miami, FL, 33136, USA

    Carol K. Petito

  7. Department of Pediatrics, University of Miami Miller School of Medicine, 1601 N.W. 12th Avenue, Miami, FL, 33136, USA

    Juan Solano, Manuel Gonzalez-Brito & John W. Kuluz

Authors
  1. David I. Sandberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kenneth M. Crandall
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tulay Koru-Sengul
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kyle R. Padgett
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. John Landrum
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Darwin Babino
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Carol K. Petito
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Juan Solano
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Manuel Gonzalez-Brito
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. John W. Kuluz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David I. Sandberg.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sandberg, D.I., Crandall, K.M., Koru-Sengul, T. et al. Pharmacokinetic analysis of etoposide distribution after administration directly into the fourth ventricle in a piglet model. J Neurooncol 97, 25–32 (2010). https://doi.org/10.1007/s11060-009-9998-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11060-009-9998-x

Keywords

Search

Navigation