麻豆传媒

BALTIMORE -- Diazepam nasal spray (Valtoco; NRL-1), an investigational rescue medicine for epilepsy patients with seizure clusters or acute repetitive seizures, had high bioavailability and was tolerated well, researchers reported .

Intranasal administration led to good diazepam exposure in patients on stable regimens of antiepileptic drugs who needed help controlling bouts of increased seizure activity, reported R. Edward Hogan, MD, of Washington University in St. Louis, at the American Epilepsy Society annual meeting.

The pharmacokinetic profile of intranasal diazepam was generally comparable to rectal administration but with less interpatient variability, he added.

"Intranasal delivery is attractive because it's relatively easy, especially in an outpatient setting," Hogan told 麻豆传媒. "The acute treatment form of diazepam that's available right now is rectally administered [Diastat], which is not an ideal solution."

From 25% to 50% of all epilepsy patients experience seizure clusters that are different than their baseline seizure pattern, noted Prakash Kotagal, MD, of the Cleveland Clinic Epilepsy Center, who wasn't involved with the research.

"Seizure clusters may progress to status epilepticus and are associated with increased risk of morbidity and mortality and greatly impact quality of life," he told 麻豆传媒. "Prompt treatment of seizure clusters is therefore imperative."

Rectal administration of rescue medications is inconvenient, difficult, and not usually preferred by adults and older children, Kotagal noted. "Oral, buccal, or sublingual administration of benzodiazepines takes significantly longer to begin working," he added. "Availability of intranasal benzodiazepines represents a significant step forward in making effective rescue medication for seizure clusters available for those in whom rectal administration is impractical."

In their study, Hogan and colleagues looked at how well intranasal diazepam was absorbed. "This preparation is given through the nose in a vitamin E solution with an agent called Intravail that works as a surfactant," he said. "That helps it adhere to the nasal passage wall and also opens up tight junctions that allow the medicine to get through the nasal mucosa and be absorbed more effectively." Intravail technology also is used in the (Tosymra) approved for migraine earlier this year.

The researchers studied epilepsy patients during both ictal/peri-ictal (seizure) and inter-ictal (non-seizure) periods. Patients received open-label intranasal diazepam with at least 14 days washout between periods; either ictal/peri-ictal or inter-ictal administration could be first. In both periods, a single dose of 5, 10, 15, or 20 mg -- depending on patient's weight -- was given. A second dose was allowed if seizures persisted.

In total, 57 patients received one or more doses and were included in the safety population, which was 54% female and 81% white. Both children and adults were studied; ages ranged from 6 to 59 and were an average of 28. Pharmacokinetic data were available from 49 patients through the 6-hour sampling period.

"At the end of the day, what we found was that dose concentrations in both situations -- both the ictal/peri-ictal and inter-ictal periods -- were very similar," Hogan said.

Overall, median time to maximum plasma concentration was about 2 hours. Maximum plasma concentration and exposure over the first 6 hours were similar under both ictal/peri-ictal and inter-ictal conditions. Interpatient variability ranged from 53.6% to 59.3%, consistent with previous reports that showed the intranasal drug had less variability than rectal diazepam, Hogan said.

"Overall, this was a pretty well tolerated medication," he added. "We saw nothing we wouldn't expect to see with diazepam." Seventeen patients (29.8%) reported treatment-emergent adverse events, most commonly dysgeusia (5.3%), nasal discomfort (3.5%), nasopharyngitis (3.5%), and seizures (3.5%). One patient experienced two serious adverse events -- recurrent seizures and static encephalopathy -- which were deemed not to be related to the treatment. There were no post-dose reports of suicide ideation.

Earlier this year, the FDA approved midazolam nasal spray (Nayzilam) as the for seizure clusters. Diazepam nasal spray is currently before the FDA; if it wins approval, it will be the third drug that works as rescue medicine for epilepsy patients to use during seizures on the market.

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