title: The plasma pharmacokinetics and cerebral spinal fluid penetration of intravenous topiramate in newborn pigs.
abstract: BACKGROUND
  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 micro M for 24 h. CSF topiramate concentration at 1 h was 12+/-1 micro M and 109+/-26 micro M at the 5 and 40 mg/kg doses, respectively.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, The Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Galinkin
authors.forename: C Dean
authors.initials: CD
authors.lastname: Kurth
authors.forename: Heng
authors.initials: H
authors.lastname: Shi
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Priestley
authors.forename: Andreas W
authors.initials: AW
authors.lastname: Loepke
authors.forename: Peter C
authors.initials: PC
authors.lastname: Adamson
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000927:Anticonvulsants / Q000009:adverse effects / Q000097:blood / Q000134:cerebrospinal fluid; D001794:Blood Pressure / Q000187:drug effects; D002853:Chromatography, Liquid; D004562:Electrocardiography; D005260:Female; D005632:Fructose / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood* / Q000134:cerebrospinal fluid*; D006207:Half-Life; D006339:Heart Rate / Q000187:drug effects; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism; D007275:Injections, Intravenous; D008297:Male; D013058:Mass Spectrometry; D018696:Neuroprotective Agents / Q000009:adverse effects / Q000097:blood* / Q000134:cerebrospinal fluid*; D013552:Swine; D013997:Time Factors; D000077236:Topiramate
chemical_list: D000927:Anticonvulsants; D018696:Neuroprotective Agents; D000077236:Topiramate; D005632:Fructose