Abstracts

RATIONALE: Diazepam (DZP) is available in a rectal formulation (Diastat) for use by caregivers to stop emergent seizure conditions. However, many patients and caregivers are opposed to rectal administration. IM administration offers an acceptable alternative. However, older data suggest that the absorption of DZP is better rectally. The auto-injector system (Diaject) can inject DZP deep into muscule tissue with greater dispersion than conventional IM devices. The objectives of this study were to compare the pharmacokinetics, safety, and preference of DZP administered IM by the auto-injector system to DZP administered rectally under two different conditions.
METHODS: 24 subjects entered into an open-label, three-way, randomized, cross over study in which they received 10 mg of DZP rectally under [dsquote]ideal[dsquote] conditions in which the bowel had been cleansed (I), rectally under [dsquote]real life[dsquote] conditions (RL), and IM using the auto-injector (IM) The concentrations of 16 blood samples collected over 24 hours and assayed for DZP using a LCMS-MS procedure were used to determine AUC, Tmax, and Cmax of DZP for each method. The data were analyzed by ANOVA and Duncan[ssquote]s test.
RESULTS: The absorption from the IM administration was very consistent while there was significant variability in I and RL. The coefficient of variation at each time point, especially in the early sampling times, is much higher for I and RL than IM. Duncan[ssquote]s test showed that IM administration results in greater (p [lt] 0.05) absorption (AUC30minutes = 4695, CV 31.1%, AUC 24 hour = 165,085, CV 22.4%) than I (AUC30 minutes = 3806.7, CV 51.1%, AUC24 hours = 142,077, CV 36.l6%) or RL (AUC30 minutes = 3944.3, CV 43.9%, AUC 24 hours = 122,692, CV 41.9%). Cmax was 233.9 (I), 209.1 (RL), and 303.9 (IM). There was no significant sequence-treatment interaction. 8 subjects had 10 episodes of oozing after rectal administration. The volume was small and did not correlate with lower AUC or Cmax. The subjects tolerated all three doses well. 16/24 in I, 21/24 in RL, and 23/24 in IM had mild CNS side effects. Subjects reported discomfort with all routes of administration, however, 17/24 (71%) of the subjects preferred the IM route. The nurse administering the DZP rated the difficulty of administration as 0.58, 0.50, and 0.04 for I, RL, and IM. She preferred the IM route of administration.
CONCLUSIONS: DZP is rapidly and reliably absorbed when administered IM by the auto-injector system (Diaject). There are higher peaks and greater absorption with less variability with IM than with either I or RL. Both rectal routes had highly variable absorption. Cleansing the bowel did not result in better or less variable absorption. The higher number of CNS side effects seen with IM may be reflective of faster and greater absorption. The auto-injector system has the potential to be a very clinically useful method for administering DZP for the treatment of emergent seizure conditions.
[Supported by: Meridian Medical Technologies,Inc., Columbia, MD.]; (Disclosure: Salary - Warnarka & Mesa, Grant - Garnett, Stock - Warnarka & Mesa, Other - Warnarka & Mesa - bonus)