Objective: We aimed to 1) develop physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) models of a novel midazolam rectal gel in healthy adults, 2) assess the contribution of different physiologically relevant factors in rectal absorption, and 3) to provide supports for future clinical studies of midazolam rectal gel.
Methods: We developed the rectal PBPK model after built the intravenous and the oral PBPK model. Then, the physiological progress of rectal route was described in terms of the drug release, the rectal absorption and the particle first-pass elimination. Next, the validated PBPK model was combined with the sigmoid Emax PD model. This PBPK/PD model was used to identify the dose range and the critical parameters to ensure safety sedation.
Results: Based on the simulations, the recommended maximum dose for adults' sedation was 15 mg. And the retention time of midazolam rectal gel should be longer than 3 h to reach over 80% pharmacokinetics and pharmacodynamics effects.
Conclusion: We successfully developed a PBPK/PD model for the midazolam rectal gel, which accurately described the PK/PD behavior in healthy adults and indicated the transit time of rectum was the most sensitive parameter for absorption. This PBPK/PD model would be expected to support the future clinical studies and pediatric application.
Keywords: Midazolam Gel; PBPK; PBPK/PD; Rectal Dosing; Transit Time.
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