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Bioavailability of Intranasal vs. Rectal Diazepam

10.10.2018 | Alexandra Jerome
Valium bioavailability chart
Bioavailability of Intranasal vs. Rectal Diazepam

Three intranasal treatments (Nas-A 10 mg, Nas-B 10 mg and Nas-B 13.4 mg) were compared to a 10 mg dose of the rectal gel. Twelve healthy volunteers were enrolled into an active-control, double-blind, four-period, crossover pharmacokinetic and tolerability study. Blood samples for plasma DZP concentration–time characterization were collected pre-dose and at regular intervals to 240 h post-dose. A single dose of each formulation was administered followed by at least a 14 day washout period. Tolerability and sedation were assessed using visual analog scales.

Present address: EnVivo Pharmaceutical, Watertown, MAS, United States.

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We have previously reported that intranasal diazepam (DZP) administration is feasible, with maximum plasma concentrations ( C max ) and time to maximum concentration ( T max ) that are comparable to rectal DZP; but tolerability was poor. In the present study, the tolerability and pharmacokinetics of two investigational nasal formulations were compared with DZP rectal gel. There remains an unmet medical need in the out-of-hospital management of seizure emergencies because older children and adults often refuse treatment with diazepam rectal gel due to social objections.

Mean DZP C max (±SD) was 181.8 ± 84.16, 151.3 ± 108.1 and 180.7 ± 82.1 ng/mL for Nas-A 10 mg, Nas-B 10 and Nas-B 13.4 mg respectively; in comparison the C max for the rectal gel was 160.9 ± 109.4 ng/mL. Median T max was 0.75 h for all treatments.

Both intranasal formulations were well tolerated and exhibited relatively rapid, but variable, absorption with bioavailability of 70–90% relative to DZP rectal gel. We conclude that intranasal DZP offers a viable alternative to rectal administration, but enhancement of formulations is needed to improve the extent and consistency of absorption. This study shows that the development of a well-tolerated nasal formulation is possible and that the rate and extent of absorption approximates that of DZP rectal gel.

Present address: Medivation, Inc., San Francisco, CA, United States.

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