Transl Clin Pharmacol.  2017 Sep;25(3):117-124. 10.12793/tcp.2017.25.3.117.

Intracerebroventricular drug administration

• Atkinson A

• KMID: 2390930
• DOI: http://doi.org/10.12793/tcp.2017.25.3.117

Abstract

Among the various routes of drug administration, perhaps the least studied is intracerebroventricular (ICV) administration. This route has been shown to be particularly useful in administering to the central nervous system (CNS) drugs that do not cross the blood-brain barrier readily. As such, the ICV route is a valuable option for providing therapeutic CNS drug concentrations to treat patients with CNS infectious and neoplastic diseases. This route of drug administration also has the advantage of minimizing systemic toxicity.

Keyword

Intracerebroventricular drug administration; Cerebrospinal fluid physiology; Pharmacokinetics; Meningitis; CNS cancer

MeSH Terms

Blood-Brain Barrier
Central Nervous System
Humans
Meningitis
Pharmacokinetics

Figure

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  Figure 1 The Ommaya reservoir consists of a mushroom-shaped dome made of specially thickened silicone rubber that can accommodate multiple needle punctures. It is connected to a silicone rubber catheter that is inserted via a burr hole into a lateral cerebral ventricle. The dome is mounted subcutaneously and is a compressible pump. This pump facilitates extensive mixing of injected drugs within the CSF space and also permits withdrawing well-mixed ventricular CSF samples (This figure was released to the public domain by its author, Patrick L. Lynch. You may find the image at https://commons.wikimedia.org/wiki/File:Ommaya_01.png#file).

Reference

1. Ziai WC, Lewin JJ 3rd. Improving the role of intraventricular antimicrobial agents in the management of meningitis. Curr Opin Neurol. 2009; 22:277–282. PMID: 19434796.

2. Fleischhack G, Jaehde U, Bode U. Pharmacokinetics following intraventricular administration of chemotherapy in patients with neoplastic meningitis. Clin Pharmacokinet. 2005; 44:1–31.

3. Deer TR, Pope JE, Hayek SM, Lamer TJ, Veizi IE, Erdek M, et al. The polyanalgesic consensus conference (PACC): guidance for improving safety and mitigating risks. Neuromodulation. 2017; 20:155–176. PMID: 28042914.

4. Heetla HW, Staal MJ, Proost JH, van Laar T. Clinical relevance of pharmacological and physiological data in intrathecal baclofen therapy. Arch Phys Med Rehabil. 2014; 95:2199–2206. PMID: 24893275.

5. Raffa RB, Pergolizzi JV Jr. Intracerebroventricular opioids for intractable pain. Br J Clin Pharmacol. 2012; 74:34–41. PMID: 22295988.

6. Hajdu SI. A note from history: discovery of the cerebrospinal fluid. Ann Clin Lab Sci. 2003; 33:334–336. PMID: 12956452.

7. Cushing H. Cameron Lectures: Lecture 1. - The third circulation and its channels. Lancet. 1925; 209:851–857.

8. Sakka L, Coll G, Chazai J. Anatomy and physiology of cerebrospinal fluid. Eur Ann Otorhinolaryngol Head Neck Dis. 2011; 128:309–316. PMID: 22100360.

9. Lei Y, Han H, Yuan F, Javeed A, Zhao Y. The brain interstitial system: Anatomy, modeling, in vivo measurement, and applications. Prog Neurobiol. 2016; pii: S0301-0082(15)30069-1. DOI: 10.1016/j.pneurobio.2015.12.007.

10. Abbott NJ. Evidence for bulk flow of brain interstitial fluid: significance for physiology and pathology. Neurochem Int. 2004; 45:545–552. PMID: 15186921.

11. Jessen NA, Munk ASF, Lundgaard I, Nedergaard M. The glymphatic system - a beginners guide. Neurochem Res. 2015; 40:2583–2599. PMID: 25947369.

12. Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA, et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and clearance of interstitial solutes, including amyloid β. Sci Transl Med. 2012; 4:147ra111. DOI: 10.1126/scitranslmed.3003748.

13. Benarroch EE. Choroid plexus-CSF system: Recent developments and clinical correlations. Neurology. 2016; 86:286–296. PMID: 26683646.

14. Farrell CL, Yang J, Pardridge WM. GLUT-1 glucose transporter is present within apical and basolateral membranes of brain epithelial interfaces and in microvascular endothelial with and without tight junctions. J Histochem Cytochem. 1992; 40:193–199. PMID: 1552163.

15. Ghersi-Egea JF, Strazielle N. Brain drug delivery, drug metabolism, and multidrug resistance at the choroid plexus. Microsc Res Tech. 2001; 52:83–88. PMID: 11135451.

16. Ghersi-Egea JF, Leninger-Muller B, Suleman G, Siest G, Minn A. Localization of drug-metabolizing enzyme activities to the blood-brain interfaces and circumventricular organs. J Neurochem. 1994; 62:1089–1096. PMID: 8113796.

17. Silva-Alvarez C, Carrasco M, Balmaceda-Aquilera C, Pastor P, Garcia M, Reinicke K, et al. Ependymal cell differentiation and GLUT-1 expression is a synchronous process in the ventricular wall. Neurochem Res. 2005; 30:1227–1236. PMID: 16341584.

18. Goodwin GM, Shelley HJ. The sugar content of the cerebrospinal fluid and its relation to the blood sugar. Arch Intern Med. 1925; 34:242–258.

19. Atkinson AJ Jr, Weiss M F. Kinetics of blood-cerebrospinal fluid glucose transfer in the normal dog. Am J Physiol. 1969; 216:1120–1126. PMID: 5819586.

20. Atkinson AJ Jr. The cerebrospinal fluid glucose concentration: steady state and kinetic studies in patients with cryptococcal meningitis. Am Rev Respir Dis. 1969; 99:59–66. PMID: 5762113.

21. Bleyer WA, Poplack DG, Simon RM. “Concentration x time” methotrexate via a subcutaneous reservoir: a less toxic regimen for intraventricular chemotherapy of central nervous system neoplasms. Blood. 1978; 51:835–842. PMID: 638249.

22. Tunkel AR, Hartman BJ, Kaplan SL, Kaufman BA, Roos KL, Scheid WM, et al. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis. 2004; 39:1267–1284. PMID: 15494903.

23. Brown EM, Edwards RJ, Pople IK. Conservative management of patients with cerebrospinal fluid shunt infections. Neurosurgery. 2006; 58:657–665. PMID: 16575329.

24. Mason WP, Yeh SDJ, DeAngelis LM. ¹¹¹indium-diethylenetriamin pentaacetic acid cerebrospinal fluid flow studies predict distribution of intrathecally administered chemotherapy and outcome n patients with leptomeningeal metastases. Neurology. 1998; 50:438–444. PMID: 9484369.

25. Butler WT, Alling DW, Spickard A, Utz JP. Diagnostic and prognostic value of clinical and laboratory findings in cryptococcal meningitis. N Engl J Med. 1964; 270:59–67. PMID: 14063470.

26. Spickard A, Butler WT, Andriole V, Utz JP. The improved prognosis of cryptococcal meningitis with amphotericin B therapy. Ann Intern Med. 1963; 58:66–83. PMID: 13990086.

27. Ommaya AK. Subcutaneous reservoir and pump for sterile access to ventricular cerebrospinal fluid. Lancet. 1963; 2:983–984. PMID: 14059058.

28. Atkinson AJ Jr, Bindschadler DD. Pharmacokinetics of intrathecally administered amphotericin B. Am Rev Respir Dis. 1969; 99:917–924. PMID: 5819291.

29. Polsky B, Depman MR, Gold JW, Galicich JH, Armstrong D. Intraventricular therapy of cryptococcal meningitis via a subcutaneous reservoir. Am J Med. 1986; 81:24–28. PMID: 3728551.

30. Saag M, Graybill RJ, Larsen RA, Pappas PG, Perfect JR, Powderly WG, et al. Practice guidelines for the management of cryptococcal disease. Clin Infect Dis. 2000; 30:710–718. PMID: 10770733.

31. Ng K, Mabasa VH, Chow I, Ensom MH. Systematic review of efficacy, pharmacokinetics, and administration of intraventricular vancomycin in adults. Neurocrit Care. 2014; 20:158–171. PMID: 23090839.

32. Pau AK, Smego RA Jr, Fisher MA. Intraventricular vancomycin: observations of tolerance and pharmacokinetics in two infants with ventricular shunt infections. Pediatr Infect Dis. 1986; 5:93–96. PMID: 3945581.

33. Yasuda T, Tomita T, McLone DG, Donovan M. Measurement of cerebrospinal fluid output through external ventricular drainage in one hundred infants and children: correlation with cerebrospinal fluid production. Pediatr Neurosurg. 2002; 36:22–28. PMID: 11818742.

34. Otilia E. Studies on the cerebrospinal fluid in premature infants. Acta Pediatr. 1948; 35(Suppl S72):7–100.

35. Reesor C, Chow AW, Kureishi A, Jewesson PJ. Kinetics of intraventricular vancomycin in infections of cerebrospinal fluid shunts. J Infect Dis. 1988; 158:1142–1143. PMID: 3183426.

36. Hirsch BE, Amodio M, Einzig AI, Halevy R, Soeiro R. Installation of vancomycin into a cerebrospinal fluid reservoir to clear infections: pharmacokinetic considerations. J Infect Dis. 1991; 163:197–200. PMID: 1984469.

37. Luer MS, Hatton J. Vancomycin administration into the cerebrospinal fluid: a review. Ann Pharmacother. 1993; 27:912–921. PMID: 8364278.

38. Rahal JJ Jr. Treatment of gram-negative bacillary meningitis in adults. Ann Intern Med. 1972; 77:295–302. PMID: 4345082.

39. Kaiser AB, McGee ZA. Aminoglycoside therapy of gram-negative bacillary meningitis. N Engl J Med. 1975; 293:1215–1220. PMID: 1102982.

40. Moore RD, Leitman PS, Smith CR. Clinical response to aminoglycoside therapy: importance of the ratio of peak concentration to minimal inhibitory concentration. J Infect Dis. 1987; 155:93–99. PMID: 3540140.

41. Zimm S, Collins JM, Miser J, Chatterji D, Poplack DG. Cytosine arabinoside cerebrospinal fluid kinetics. Clin Pharmacol Ther. 1984; 35:826–830. PMID: 6587957.

42. Bonadio WA. The cerebrospinal fluid: physiologic aspects and alterations associated with bacterial meningitis. Pediatr Infect Dis J. 1992; 11:423–431. PMID: 1608676.

43. Hamada A, Kawaguchi T, Nakano M. Clinical pharmacokinetics of cytarabine formulations. Clin Pharmacokinet. 2002; 41:705–718. PMID: 12162758.

44. Padgett BL, Walker DL. Prevalence of antibodies in human sera against JC virus, an isolate from a case of progressive multifocal leukoencephalopathy. J Infect Dis. 1973; 127:467–470. PMID: 4571704.

45. Pavlovic D, Patera AC, Nyberg F, Gerber M, Liu M. Progressive Multifocal Leukoencephalopathy Consortium. Progressive multifocal leukoencephalopathy: current treatment options and future perspectives. Ther Adv Neurol Disord. 2015; 8:255–273. PMID: 26600871.

46. Hall CD, Dafni U, Simpson D, Clifford D, Wetherill PE, Cohen B, et al. Failure of cytarabine in progressive multifocal leukoencephalopathy associated with human immunodeficiency virus infection. N Engl J Med. 1998; 338:1345–1351. PMID: 9571254.

47. Hou J, Major EO. The efficacy of nucleoside analogs against JC virus multiplication in a persistently infected human fetal brain cell line. J Neurovirol. 1998; 4:451–456. PMID: 9718138.

48. Rueda Domínguez A, Hidalgo DO, Garrido RV, Sanchez ET. Liposomal cytarabine (DepoCyte®) for the treatment of neoplastic meningitis. Clin Transl Oncol. 2005; 7:232–238. PMID: 16131445.

49. Bode U, Macgrath IT, Bleyer WA, Poplack DG, Glaubiger DL. Active transport of methotrexate from cerebrospinal fluid in humans. Cancer Res. 1980; 40:19802184–2187.

50. Rubin R, Owens E, Rall D. Transport of methotrexate by the choroid plexus. Cancer Res. 1968; 28:689–694. PMID: 5649058.

51. Moser AM, Adamson PC, Gillespie AJ, Poplack DG, Balis FM. Intraventricular concentration times time (C x T) methotrexate and cytarabine for patients with recurrent meningeal leukemia and lymphoma. Cancer. 1999; 85:511–516. PMID: 10023723.

52. Pels H, Schmidt-Wolf IG, Glasmacher A, Schulz H, Engert A, Diehl V, et al. Primary central nervous system lymphoma: results of a pilot and Phase II study of systemic and intraventricular chemotherapy with deferred radiotherapy. J Clin Oncol. 2003; 21:4489–4495. PMID: 14597744.

53. Wolff SN, Grosh WW, Prater K, Hande KR. In vitro pharmacodynamic evaluation of VP-16-213 and implications for chemotherapy. Cancer Chemother Pharmacol. 1987; 19:246–249. PMID: 3581418.

54. Henwood JM, Brogden RN. Etoposide: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in combination chemotherapy of cancer. Drugs. 1990; 39:438–490. PMID: 2184009.

55. Fleischhack G, Reif S, Hasan C, Jaehde U, Hettmer S, Bode U. Feasibility of intraventricular administration of etoposide in patients with metastatic brain tumors. Br J Cancer. 2001; 84:1453–1459. PMID: 11384092.

56. Chamberlain MC, Tsao-Wei DD, Groshen S. Phase II trial of intracerebrospinal fluid etoposide in the treatment of neoplastic meningitis. Cancer. 2006; 106:2021–2027. PMID: 16583432.

57. Cohen-Pfeffer JL, Gururangan S, Lester T, Lim DA, Shaywitz AJ, Westphal M, et al. Intracerebroventricular delivery as a safe, long-term route of drug administration. Pediatr Neurol. 2017; 67:23–35. PMID: 28089765.

58. Weigel R, Senn P, Weis J, Krauss . Severe complications after intrathecal methotrexate (MTX) for treatment of primary central nervous system lymphoma (PCNL). Clin Neurol Neurosurg. 2004; 106:82–87. PMID: 15003295.

59. Widemann BC, Balis FM, Shalabi A, Boron M, O'Brien M, Cole DE, et al. Treatment of accidental intrathecal methotrexate overdose with intrathecal caboxypeptidase G2. J Natl Cancer Inst. 2004; 96:1557–1559. PMID: 15494606.

60. Wilson TJ, Stetler WR Jr, Al-Holou W, Sullivan SE. Comparison of the accuracy of ventricular catheter placement using free hand placement, ultrasonic guidance, and sterotactic neuronavigation. J Neurosurg. 2013; 119:66–70. PMID: 23330995.

61. Xu LW, Sussman ES, Li G. Frameless, electromagnetic image-guided ventriculostomy for ventriculoperitoneal shunt and Ommaya reservoir placement. Clin Neurol Neurosurg. 2016; 147:46–52. PMID: 27290637.

62. Cook AM, Mieure KD, Owen RD, Pesaturo AB, Harton J. Intracerebroventricular administration of drugs. Pharmacotherapy. 2009; 29:832–845. PMID: 19558257.

63. Groves MD, Glantz MJ, Chamberlain MC, Baumgartner KE, Conrad CA, Hsu S, et al. A multicenter Phase II trial of intrathecal topotecan in patients with meningeal malignancies. Neuro Oncol. 2008; 10:208–215. PMID: 18316473.

64. Partap S, Murphy PA, Vogel H, Barnes PD, Edwards MSB, Fisher PG. Liposomal cytarabine for central nervous system embryonal tumors in children and young adults. J Neurooncol. 2011; 103:561–566. PMID: 20859651.

65. Boogerd W, van der Sande JJ, Moffie D. Acute fever and delayed leukoencephalopathy following low dose intraventricular methotrexate. J Neurol Neurosurg Psychiatry. 1988; 51:1277–1283. PMID: 3225584.

66. Zairi F, Le Rhun E, Bertrand N, Boulanger T, Taillibert S, Aboukais R, et al. Complications related to the use of an intraventricular access device for the treatment of leptomeningeal metastases from solid tumors: a single centre experience in 112 patients. J Neurooncol. 2015; 124:317–323. PMID: 26070555.

67. Mead PA, Safdieh JE, Nizza P, Tuma S, Sepkowitz KA. Ommaya reservoir infections: a 16-year retrospective analysis. J Infect. 2014; 68:225–230. PMID: 24321561.