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Safety, Pharmacokinetics, and Pharmacodynamics of Midazolam Gel After Rectal Administration in Healthy Chinese Subjects

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Abstract

Background and Objectives

Midazolam rectal gel is a novel rectal formulation that may be a promising and potential alternative to oral administration for pediatric sedation. The objective of this study was to evaluate the safety, pharmacokinetics, pharmacodynamics, and absolute bioavailability of midazolam rectal gel in healthy Chinese subjects.

Methods

An open-label, single-dose, randomized, two-period, two-treatment, crossover clinical study was conducted in 22 healthy subjects (16 males and six females), each receiving 2.5 mg intravenous midazolam in one period and 5 mg midazolam rectal gel in another period (the dosages here were calculated as active midazolam). Safety, pharmacokinetic, and pharmacodynamic assessments were conducted throughout the study.

Results

All of the subjects completed both treatment periods. The formulation of rectal gel was well tolerated, with no serious adverse events occurring. After a single rectal dose of 5 mg midazolam rectal gel, it was absorbed rapidly with a median value of time to peak concentration (Tmax) of 1.00 h, and mean values of the peak concentration (Cmax) and area under the concentration–time curve (AUC0–t) of 37.2 ng/mL and 137 h·ng/mL, respectively. The absolute bioavailability of rectal gel was 59.7%. The rectal gel exhibited a relatively delayed onset but a more stable sedative effect and a longer duration when compared with intravenous midazolam.

Conclusion

Midazolam rectal gel may be a feasible alternative with a high level of acceptance in pediatric sedation and enhanced bioavailability compared to an oral formulation. The modeling results may help to disclose out the exposure-response relationship of midazolam rectal gel and support the design of an escalating-doses study and pediatric extrapolation study.

Clinical trial registration

The study was registered at http://www.chinadrugtrials.org.cn (No. CTR20192350).

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Acknowledgements

The authors would like to thank the healthy subjects involved in the study and their families.

Author information

Author notes

  1. Sufeng Zhou and Jinying Zhu are co-first authors.

Authors and Affiliations

  1. Phase I Clinical Trial Unit, The First Affiliated Hospital with Nanjing Medical University, #300 Guangzhou Road, Nanjing, 210029, Jiangsu, China

    Sufeng Zhou, Jinying Zhu, Lijun Xie, Yuqing Zhao, Sijia Ding, Lu Wang, Juan Chen, Bei Zhu, Chen Zhou & Feng Shao

  2. Department of Clinical Pharmacology, Pharmacy College, Nanjing Medical University, Nanjing, 211166, China

    Jinying Zhu & Feng Shao

  3. Department of Anesthesiology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, 210029, China

    Xiaodi Sun

  4. Department of Pharmaceutics, Institute of Pharmacology and Toxicology of Academy of Military Medical Sciences, Beijing, 100850, China

    Aiping Zheng

  5. Xinjiang Tefeng Pharmaceutical Company, Ltd., Urumqi, 830054, China

    Yajuan Li

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  1. Sufeng Zhou
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Corresponding authors

Correspondence to Chen Zhou or Feng Shao.

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Conflicts of interest

Sufeng Zhou, Jinying Zhu, Xiaodi Sun, Lijun Xie, Yuqing Zhao, Sijia Ding, Lu Wang, Juan Chen, Bei Zhu, Chen Zhou, and Feng Shao are employees of the First Affiliated Hospital with Nanjing Medical University. Aiping Zheng is an employee of the Institute of Pharmacology and Toxicology of Academy of Military Medical Sciences. Yajuan Li is an employee of Xinjiang Tefeng Pharmaceutical Company, Ltd. The authors report no other conflicts of interest.

Funding

This study was funded by Xinjiang Tefeng Pharmaceutical Company, Ltd.

Availability of data and material

The data are not available in a repository, but reasonable requests can be directed to Feng Shao at jsphshaofeng@hotmail.com.

Ethical approval

This study was conducted according to Good Clinical Practice (GCP) following the tenets of the Declaration of Helsinki. The study was registered at chinadrugtrials.org.cn (CTR20192350). The protocol and informed consent form were approved by the Ethics Committee of the First Affiliated Hospital with Nanjing Medical University (Nanjing, China).

Informed consent

All subjects provided written informed consent before any study-related procedures were conducted.

Consent for publication

Not applicable.

Code availability

Not applicable

Author contributions

Conceptualization: FS, CZ, SZ. Methodology, material preparation and data collection: SZ, XS, LX, SD, LW, JC, BZ, AZ. Data analysis: JZ. Writing-original draft preparation: JZ. Writing-review and editing: SZ, JZ. Resources: YL. Supervision: FS. All authors approved the final version of the manuscript.

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Zhou, S., Zhu, J., Sun, X. et al. Safety, Pharmacokinetics, and Pharmacodynamics of Midazolam Gel After Rectal Administration in Healthy Chinese Subjects. Clin Drug Investig 43, 421–433 (2023). https://doi.org/10.1007/s40261-023-01276-5

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