Development of Intravenous Topiramate for Neuroprotection and Seizure Control in Neonates

................................................................................................................................................ iii TABLE OF CONTENTS .............................................................................................................................vi LIST OF TABLES .......................................................................................................................................ix LIST OF FIGURES ...................................................................................................................................... x CHAPTER 1: INTRODUCTION ................................................................................................................ 1 1.1 NEONATAL SEIZURES ....................................................................................................................... 2 1.1.1 Definition ...................................................................................................................................... 2 1.1.2 Incidence ....................................................................................................................................... 3 1.1.3 Clinical course .............................................................................................................................. 4 1.1.4 Prognosis ....................................................................................................................................... 5 1.1.5 Pathophysiology............................................................................................................................ 6 1.1.6 Current treatment of neonatal seizures .......................................................................................... 9 1.1.7 New treatment options for neonatal seizures .............................................................................. 12 1.1.8 Therapeutic hypothermia ........................................................................................................... 14 1.2 TOPIRAMATE .................................................................................................................................... 16 1.2.1 Physical-chemical properties ...................................................................................................... 16 1.2.2 Pharmacology ............................................................................................................................. 17 1.2.3 Pharmacokinetics ........................................................................................................................ 18 1.2.4 Indications ................................................................................................................................... 22 1.2.5 Neuroprotection .......................................................................................................................... 22 1.2.6 Topiramate use in infants & neonates ......................................................................................... 29 1.3 STABLE-LABELED ISOTOPES ......................................................................................................... 31 1.4 INTRAVENOUS TOPIRAMATE FORMULATION ............................................................................ 33 1.4.1 Cyclodextrin formulation ............................................................................................................ 34 1.4.2 Synthesis of stable-labeled topiramate ........................................................................................ 34 1.4.3 Solubility ..................................................................................................................................... 35 1.4.4 Stability ....................................................................................................................................... 36 1.5 ANALYTICAL METHODS .................................................................................................................. 37 1.5.1 Assay........................................................................................................................................... 37 1.6 ORPHAN DRUG DEVELOPMENT ................................................................................................... 39 1.7 MY ROLE IN PROJECTS ................................................................................................................... 42 CHAPTER 2: DETERMINATION OF NEUROPROTECTIVE TOPIRAMATE CONCENTRATIONS IN NEONATAL RAT PUPS ................................................................................ 45 2.1 BACKGROUND ................................................................................................................................. 46 2.2 STUDY AIMS ...................................................................................................................................... 47 2.3 STUDY METHODS ............................................................................................................................ 48 vii 2.4 RESULTS ............................................................................................................................................ 50 2.5 DISCUSSION AND CONCLUSIONS ................................................................................................. 53 CHAPTER 3: A PHASE 1 STUDY OF INTRAVENOUS TOPIRAMATE SAFETY AND PHARMACOKINETICS IN PATIENTS WITH EPILEPSY AND MIGRAINES ............................... 56 3.