This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Strong, J. M. Articles by Poplack, D. G. Search for Related Content PubMed PubMed Citation Articles by Strong, J. M. Articles by Poplack, D. G.

Pharmacokinetics of Intraventricular and Intravenous N,N',N''-Triethylenethiophosphoramide (Thiotepa) in Rhesus Monkeys and Humans

Laboratory of Biological Chemistry, Clinical Pharmacology Branch, and Pediatrics Branch, Division of Cancer Treatment, National Cancer Institute, Bethesda, Maryland 20892

The cerebrospinal fluid (CSF) and plasma pharmacokinetics of N,N',N''-triethylenethiophosphoramide (thiotepa), an alkylating agent used for treatment of carcinomatous meningitis, were determined in rhesus monkeys in order to assess the relative advantage of intraventricular versus systemic administration of the drug. Following an i.v. thiotepa dose of 0.9 mg/kg (11 mg/sq m), peak plasma levels of parent drug reached approximately 1 µg/ml. Thiotepa was rapidly equilibrated with lumbar and ventricular CSF. Systemic, lumbar, and ventricular exposure to the drug, measured as area under the curve (AUC), were similar in all cases. After a 1-mg intraventricular dose of thiotepa, peak ventricular levels were greater than 100 µg/ml. However, peak levels in the lumbar CSF at 1 h after intraventricular administration were less than 10 µg/ml. The AUC for ventricular CSF was nearly 100-fold greater for the intraventricular route than for the i.v. route; however, the AUC for lumbar CSF following intraventricular delivery was only 5% of the AUC for ventricular CSF. N,N',N''-Triethylenephosphoramide, an active metabolite of thiotepa observed in all fluids, appeared to have a much slower total body clearance than thiotepa. Comparison of the data obtained from monkey experiments with data from a patient with meningeal disease supports the use of the monkey as a model for intraventricular pharmacokinetics. The data presented indicate that there is no relative advantage to intraventricular administration of thiotepa at the doses currently used in clinical trials.

¹ To whom requests for reprints should be addressed, at Laboratory of Biological Chemistry, National Cancer Institute, Building 37, Room 5D-02, Bethesda, MD 20892.

Received 4/16/86. Revised 7/15/86. Accepted 8/13/86.

This article has been cited by other articles:

				M. L de Lemos, S. Monfared, T. Denyssevych, L. Hamata, S. Jennings, B. Thiessen, S. Smith, and D. Waterhouse Evaluation of osmolality and pH of various concentrations of methotrexate, cytarabine, and thiotepa prepared in normal saline, sterile water for injection, and lactated Ringer's solution for intrathecal administration Journal of Oncology Pharmacy Practice, March 1, 2009; 15(1): 45 - 52. [Abstract] [PDF]

				L. L. Muldoon, C. Soussain, K. Jahnke, C. Johanson, T. Siegal, Q. R. Smith, W. A. Hall, K. Hynynen, P. D. Senter, D. M. Peereboom, et al. Chemotherapy Delivery Issues in Central Nervous System Malignancy: A Reality Check J. Clin. Oncol., June 1, 2007; 25(16): 2295 - 2305. [Abstract] [Full Text] [PDF]

				S. Modak, S. Gardner, I. J. Dunkel, C. Balmaceda, M. K. Rosenblum, D. C. Miller, S. Halpern, and J. L. Finlay Thiotepa-Based High-Dose Chemotherapy With Autologous Stem-Cell Rescue in Patients With Recurrent or Progressive CNS Germ Cell Tumors J. Clin. Oncol., May 15, 2004; 22(10): 1934 - 1943. [Abstract] [Full Text] [PDF]

				M. J. Glantz, K. A. Jaeckle, M. C. Chamberlain, S. Phuphanich, L. Recht, L. J. Swinnen, B. Maria, S. LaFollette, G. B. Schumann, B. F. Cole, et al. A Randomized Controlled Trial Comparing Intrathecal Sustained-release Cytarabine (DepoCyt) to Intrathecal Methotrexate in Patients with Neoplastic Meningitis from Solid Tumors Clin. Cancer Res., November 1, 1999; 5(11): 3394 - 3402. [Abstract] [Full Text] [PDF]

				M. C. Chamberlain Pediatric Leptomeningeal Metastases: Outcome Following Combined Therapy J Child Neurol, January 1, 1997; 12(1): 53 - 59. [Abstract] [PDF]

				S. L. Berg and D. G. Poplack Treatment of Meningeal Malignancy Oncologist, February 1, 1996; 1(1): 56 - 61. [Abstract] [Full Text] [PDF]

				M. C. Chamberlain Topical Review: A Review of Leptomeningeal Metastases in Pediatrics J Child Neurol, May 1, 1995; 10(3): 191 - 199. [Abstract] [PDF]

				T. C. Shea, K. H. Antman, J. P. Eder, A. Elias, W. P. Peters, S. Schryber, W. D. Henner, D. A. Schoenfeld, L. E. Schnipper, and E. Frei III Malignant Melanoma: Treatment With High-Dose Combination Alkylating Agent Chemotherapy and Autologous Bone Marrow Support Arch Dermatol, June 1, 1988; 124(6): 878 - 884. [Abstract] [PDF]