Development of intravenous topiramate for neuroprotection and seizure control in neonates.

Abstract

Hypoxic-ischemic brain injury in newborns is a significant medical problem with a high mortality rate, grave neurological sequelae including impaired cognition, neonatal seizures, and serious treatment-related adverse effects that can cause further brain injury. A safer, more effective treatment for neonatal seizures combined with the potential for neuroprotection would represent a significant advancement in the care of babies with hypoxic-ischemic brain injury. Intravenous topiramate holds the promise of controlling seizures and providing neuroprotection in newborn babies, but its safety and dosing must first be established in adults and, possibly, older infants and children. When designing a new treatment option for neonatal seizures it is important to understand the developmental differences in the pathophysiology of seizures in the immature brain compared to the adult brain. Developmental age-specific mechanisms exist that alter the generation of seizures, the effect of seizures on the brain, and the effectiveness and impact of antiseizure therapy. Differences in the expression and activity of excitatory and inhibitory pathways in the developing brain may explain why many of the traditional antiepileptic drugs used to treat neonatal seizures are ineffective. The research presented in my dissertation is focused on defining the safety and pharmacokinetics of intravenous topiramate. Topiramate is an antiepileptic drug used in adults and children to treat epilepsy. Recent research has shown topiramate is highly effective in controlling seizures and is neuroprotective in newborn laboratory animals in models of status epilepticus and cerebral ischemia. The proven safety and effectiveness of topiramate for seizures in older children and adults together with substantial laboratory evidence showing benefit in models of hypoxic-ischemic encephalopathy strongly suggest that topiramate would be useful in the treatment of neonatal seizures and in addition might provide neuroprotection resulting from hypoxic-ischemic insult. The studies included in this thesis include an animal study, a Phase I study in patients with epilepsy and migraines, and a healthy volunteer pharmacokinetic and safety study. The goal of the animal study was to determine plasma topiramate concentrations in rat pups given doses previously shown to result in neuroprotective effects. In that study, the neuroprotective dose produced concentrations slightly above the proposed therapeutic range (5 to 20 µg/mL), while the non-neuroprotective dose produced concentrations approximately twice as high as the therapeutic range for topiramate when used to treat epilepsy. Results from this study now provide target concentrations for future neuroprotection studies. Results for the two human studies included in this thesis provide previously unreported information about topiramate. In adults, topiramate plasma concentrations attained by intravenous infusion were very similar to oral administration. The determination that the oral absorption is approximately 100% indicates patients can be given the same dose when switched from intravenous to oral, or vice versa. The studies also revealed an extended elimination half-life of topiramate indicating it can be given once or twice daily in some patients while maintaining targeted plasma concentrations. Intravenous infusion of doses of 25 mg to 100 mg over 10 to 15 minutes appears to be safe. No serious adverse events were reported by subjects following intravenous or oral administration of topiramate. Subjects reported no local discomfort due to administration of the intravenous formulation. Reported side effects were generally mild and resolved by 4 hours regardless of route of medication. Topiramate is known to have cognitive and neurological adverse events. Onset of cognitive adverse events and ataxia occurred early post-infusion, demonstrating the intravenous infusion may have quick penetration into the brain. For the treatment of neonatal seizures, in which a fast onset of action is required, rapid penetration into the brain is beneficial. Ideally, a rapid reduction of the duration and frequency of seizures should minimize the long-term neurodevelopmental adverse outcomes that occur after neonatal seizures.

These studies provide pharmacokinetic and safety data needed to begin studies in younger patients. Results from these studies will inform the design of subsequent studies, including controlled clinical trials intended to determine the efficacy and safety of intravenous topiramate for neuroprotection and seizure control in neonates.