Abstract Details

Title Assessment of Pharmacokinetic Linearity and Relative Bioavailability of an Intranasal Diazepam Formulation Compared with Diazepam Rectal Gel in Healthy Adult Subjects

Topic Epilepsy

Presentation(s) P02 - (-)

Poster/Presentation
Number 214

Objective

Background BACKGROUND: Diazepam rectal gel (DRG) is the approved treatment for patients with acute repetitive seizures. Because treatment with rectal gel is inconvenient, a diazepam formulation administered as nasal spray (DZNS), is under development.

Design/Methods DESIGN/METHODS: A Phase 1, single-center, randomized, open-label, three-period crossover study was conducted. Twenty-four healthy subjects (18-50years) with no clinically relevant abnormalities were enrolled. Subjects fasted for 10hr pre-dosing and for 2hr post-dosing; water was permitted ad libitum. Plasma diazepam and metabolite concentrations were measured by serial sampling (19 samples per treatment-period). Safety parameters included vital signs, pulse oximetry, local irritation, alertness, drug-leakage and adverse events. Dose proportionality for DZNS doses was assessed by mean maximum plasma concentration (Cmax), mean area under the plasma concentration-time curve from time 0-infinity (AUC0-[infin]) and mean AUC from time 0-24h (AUC0-24).

Results RESULTS: The two DZNS formulations showed dose proportionality with median time to Cmax of 1h for both doses. Administration of single 20mg DZNS resulted in similar plasma concentrations of diazepam and desmethyldiazepam but with less variability than with 20mg DRG. Coefficient of variation for plasma diazepam levels with DRG ranged from 42%-106% over 24h compared with 27%-47% for DZNS during the same interval. Three subjects with DRG had low diazepam levels due to drug-leakage. Excluding these outliers, the geometric mean ratio (DZNS/DRG) and 90% CI for diazepam Cmax and AUC0-24 were 0.98 (0.85, 1.14) and 0.89 (0.80, 0.98), respectively. Both treatments were generally well tolerated with similar safety profiles; mild nasal/pharyngeal adverse events were more frequent with DZNS.

Conclusions CONCLUSIONS: The pharmacokinetics of the two formulations administered as nasal spray showed dose proportionality. Single dose 20mg DZNS demonstrated comparable bioavailability to that of 20mg DRG.

Authors/Disclosures
PRESENTER	No disclosure on file
	No disclosure on file
Bill Wargin	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file

��ɫ��

��ɫ��