Pharmacokinetics and safety of VALTOCO (NRL‐1; diazepam nasal spray) in patients with epilepsy during seizure (ictal/peri‐ictal) and nonseizure (interictal) conditions: A phase 1, open‐label study

Abstract

Objective: To assess pharmacokinetics and safety of diazepam nasal spray (NRL-1; VALTOCO®) in pediatric and adult patients with epilepsy in seizure and nonseizure states. Methods: A single dose of diazepam nasal spray (5, 10, 15, or 20 mg based on weight) was administered during each of two conditions (ictal/peri-ictal and interictal condition) to patients 6-65 years old with partial or generalized epilepsy with motor seizures or seizures with clear alteration of awareness; a second dose was permitted if needed for persistent seizures. Dosing could be interictal or ictal/peri-ictal first, with a washout of ≥14 days. Blood samples for pharmacokinetic analysis were taken at prespecified time points. Treatment-emergent adverse events (TEAEs), sedation, nasal irritation, nasal mucosal pain, and olfactory changes were assessed. Results: Of 57 patients in the study (mean age = 28.1 years [range = 6-59], 54.4% female, 80.7% white), 49 were included in the primary pharmacokinetic analyses. Diazepam pharmacokinetic profiles were similar under both conditions, with approximately 2-hour median time to mean (SD) maximum plasma concentrations of 164 (88) and 189 (110) ng/mL for ictal/peri-ictal and interictal conditions, respectively; drug exposure during the first 6 hours postdosing was 532 (313) and 615 (368) h•ng/ mL, respectively. Seventeen patients (29.8%) reported TEAEs, of whom eight (14%)had treatment-related TEAEs, with those reported in ≥2 patients being dysgeusia (n = 3, 5.3%) and nasal discomfort (n = 2, 3.5%). One patient had serious TEAEs (recurrent seizures, metabolic encephalopathy), which were deemed unrelated to study treatment. No changes in respiratory rate were observed, nor were there clinically relevant changes in sedation, olfaction, nasal irritation, or acute nasal mucosal pain.

VALTOCO® (Diazepam Nasal Spray) for the Acute Treatment of Intermittent Stereotypic Episodes of Frequent Seizure Activity

“…The intranasal administration of Valtoco ® is more desirable by patients and has less variability than the rectal gel [ 8 ]. Diazepam nasal spray safety was consistent with the profile of diazepam [ 47 ].…”

“…The significance of the NCBI’s trial was that “Diazepam nasal spray shows predicable pharmacokinetics and represents a potential novel therapeutic approach to control bouts of increased seizure activity (cluster seizures, acute repetitive seizures).” It was shown to be acceptably safe, with less variability than the rectal diazepam route, and showed no damage to nasal mucosa [ 46 ]. The types of epileptic condition had no significant effect on the pharmacokinetics of Valtoco ® [ 47 ]. Valtoco ® is specifically marketed for the treatment of cluster seizures.…”

“…The absolute bioavailability of Valtoco ® relative to intravenous diazepam was 97%. The mean elimination half-life of diazepam following administration of a 10 mg dose of Valtoco ® was found to be about 49.2 h. In a pharmacokinetic study in patients with epilepsy, pharmacokinetic parameters were similar between seizure versus non-seizure states” [ 47 ]. The drug binds to plasma proteins.…”

“…The sedation was transient and was not dose-dependent. This study highlighted the efficacy and safety of intranasal diazepam in children and adolescents, who have been rarely included in many other studies for this drug [ 47 ]. See Table 2 .…”

The Nose Knows: Intranasal Midazolam To Treat Acute Seizures During Inpatient Epilepsy Monitoring

“…Additionally, a commercial form of IN diazepam using a new Intravail technology to enhance nasal drug absorption was approved for patients aged ≥6 years in 2020. 8 , 9 These 2 new products will be valuable options for patients during seizure clusters. The present study 3 is important because the inpatient location not only permitted corroboration of the effectiveness of in-MDZ reported in earlier studies but also provided accurate data both on the duration of effectiveness and on the length of post-dose sedation.…”