This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services 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 Sung, C. Articles by Dedrick, R. L. Search for Related Content PubMed PubMed Citation Articles by Sung, C. Articles by Dedrick, R. L.

A Pharmacokinetic Model of Topotecan Clearance from Plasma and Cerebrospinal Fluid

Biomedical Engineering & Instrumentation Program, National Center for Research Resources, NIH; [C. S., R. L. D.]; Department of Pediatrics, Walter Reed Army Medical Center [S. M. B.]; and Pediatric Branch, National Cancer Institute, NIH [D. E. C., F. M. B.], Bethesda, Maryland 20892

We present a physiological pharmacokinetic model that describes the plasma and cerebrospinal fluid (CSF) concentrations of topotecan [(S)-9-dimethylaminomethyl-10-hydroxycamptothecin hydrochloride, SK&F 104864-A, NSC 609699] following i.v. and intraventricular administrations in monkeys. The model consists of three physical spaces: the CSF, the plasma, and a body compartment. The model incorporates such processes as reversible conversion of topotecan lactone to an inactive hydroxy acid form, microvascular exchange between CSF and plasma, bulk CSF flow, exchange between plasma and body compartments, and elimination of drug from the plasma compartment. Several parameters in the model were obtained from published literature on the physiology of the monkey. The model was then fit to the plasma and CSF data to deduce the other parameters. Calculated clearances of topotecan lactone and total drug from the CSF after intraventricular injection were 3.9 and 2.2 ml/h, respectively. Clearances of topotecan lactone and total drug from the plasma following a 10-min infusion were 26.3 liters/h/m² and 17.8 liters/h/m², respectively. The calculated ratios of the area under the concentration curve in the CSF following i.v. infusion to the area under the concentration curve in plasma were 0.11 and 0.19 for topotecan and total drug, respectively, indicating significant CSF penetration. The volume of distribution was 0.77 liters/kg, which represents distribution in a volume approximating total body water. The forward and reverse rate constants for the lactone-to-hydroxy acid conversion were 1.0 and 0.29 h^-1, respectively. Comparison of the clearances (normalized to body surface area) with values reported for mice and humans shows reasonable similarity across species. This pharmacokinetic model may help guide future development and refinement of clinical protocols, especially in the treatment of diseases of the central nervous system.

¹ To whom requests for reprints should be addressed, at NIH, Building 13, Room 3N17, Bethesda, MD 20892.

Received 11/ 8/93. Accepted 8/ 5/94.

This article has been cited by other articles:

				E. T. Wong and A. Berkenblit The Role of Topotecan in the Treatment of Brain Metastases Oncologist, February 1, 2004; 9(1): 68 - 79. [Abstract] [Full Text] [PDF]

				S. M. Blaney, R. Heideman, S. Berg, P. Adamson, A. Gillespie, J. R. Geyer, R. Packer, K. Matthay, K. Jaeckle, D. Cole, et al. Phase I Clinical Trial of Intrathecal Topotecan in Patients With Neoplastic Meningitis J. Clin. Oncol., January 1, 2003; 21(1): 143 - 147. [Abstract] [Full Text] [PDF]

				M. J. Egorin, E. G. Zuhowski, C. M. McCully, S. M. Blaney, J. Z. Kerr, S. L. Berg, and F. M. Balis Pharmacokinetics of Intrathecal Gemcitabine in Nonhuman Primates Clin. Cancer Res., July 1, 2002; 8(7): 2437 - 2442. [Abstract] [Full Text] [PDF]

				N. G. Avgeropoulos and T. T. Batchelor New Treatment Strategies for Malignant Gliomas Oncologist, June 1, 1999; 4(3): 209 - 224. [Abstract] [Full Text]

				S. Winter and M. Weller Potentiation of CD95L-Induced Apoptosis of Human Malignant Glioma Cells by Topotecan Involves Inhibition of RNA Synthesis but Not Changes in CD95 or CD95L Protein Expression J. Pharmacol. Exp. Ther., September 1, 1998; 286(3): 1374 - 1382. [Abstract] [Full Text]