Original Paper

The plasma pharmacokinetics and cerebral spinal fluid penetration of intravenous topiramate in newborn pigs†

  1. Jeffrey L. Galinkin1,2,‡,
  2. C. Dean Kurth1,§,
  3. Heng Shi2,§,
  4. Margaret A. Priestley1,
  5. Andreas W. Loepke1,§,
  6. Peter C. Adamson2,*

Article first published online: 7 JUL 2004

DOI: 10.1002/bdd.408

Issue

Biopharmaceutics & Drug Disposition

Biopharmaceutics & Drug Disposition

Volume 25, Issue 6, pages 265–271, September 2004

Additional Information

How to Cite

Galinkin, J. L., Kurth, C. D., Shi, H., Priestley, M. A., Loepke, A. W. and Adamson, P. C. (2004), The plasma pharmacokinetics and cerebral spinal fluid penetration of intravenous topiramate in newborn pigs. Biopharmaceutics & Drug Disposition, 25: 265–271. doi: 10.1002/bdd.408

Author Information

  1. 1

    Department of Anesthesiology and Critical Care Medicine, The Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, USA

  2. 2

    Division of Clinical Pharmacology and Therapeutics, The Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, USA

  1. ‡

    Department of Anesthesia and Pediatrics, Cincinnati Children's Hospital, University of Cincinnati School of Medicine, Cincinnati, OH, USA

  2. §

    The Children's Hospital, Department of Anesthesia, University of Colorado Health Science Center, Denver, CO, USA

*The Children's Hospital of Philadelphia, 3615 Civic Center Blvd., ARC 916, Philadelphia, PA 19104-4399, USA

  1. †

    This work was presented at the meetings of the International Society for Anaesthetic Pharmacologists at Orlando, FL (October 11, 2002) and the American Society for Clinical Pharmacology and Therapeutics (April 9, 2003).

Publication History

  1. Issue published online: 7 JUL 2004
  2. Article first published online: 7 JUL 2004
  3. Manuscript Accepted: 8 APR 2004
  4. Manuscript Revised: 7 APR 2004
  5. Manuscript Received: 20 JAN 2004

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Keywords:

  • hypoxia;
  • neonatal;
  • neuroprotectant

Abstract

Introduction—Pre-clinical studies suggest that the anticonvulsant topiramate confers neurologic protection against ischemia. An intravenous formulation of topiramate has been developed for administration during conditions such as hypoxia-ischemia when enteral absorption may be unpredictable. The plasma pharmacokinetics, cerebrospinal fluid (CSF) penetration and pharmacodynamics of intravenous topiramate were studied in an established piglet model of hypoxia-ischemia.

Methods—The plasma pharmacokinetics of topiramate were studied in a group of chronically instrumented conscious piglets (n = 8), and in a group of piglets following an episode of hypoxia-ischemia (n = 8). These groups were divided into equal dose cohorts in which two doses of intravenously administered topiramate, 5 and 40 mg/kg, were studied. The animals' heart rate, arterial pressure and EEG were monitored. Plasma for topiramate concentration was sampled for up to 26 h. A single CSF topiramate concentration was determined 1 h following drug administration. Topiramate was quantified using a specific LC/MS assay.

Results—The animals tolerated intravenous topiramate well, with no significant changes in physiologic and neurologic parameters. Plasma topiramate concentrations following an intravenous dose were best described by a bi-exponential equation, with a mean clearance of 39±18 ml/h/kg, and a terminal half-life of 14.3 (range 7.5–48.1) h. A dose of 5 mg/kg was sufficient to maintain plasma drug concentrations greater than 10 µM for 24 h. CSF topiramate concentration at 1 h was 12±1 µM and 109±26 µM at the 5 and 40 mg/kg doses, respectively.

Conclusion—Topiramate administered intravenously was well tolerated. Slow clearance of the drug allowed for maintenance of potential neuroprotective concentrations following a single dose of drug for 24 h. High drug penetration into the CSF is an ideal pharmacologic characteristic of any potential neuroprotective agent. The pharmacokinetic profile of intravenously administered topiramate, including its penetration into the CSF, appears to achieve this goal. Copyright © 2004 John Wiley & Sons, Ltd.

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