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

Autor: Zhou S; Phase I Clinical Trial Unit, The First Affiliated Hospital with Nanjing Medical University, #300 Guangzhou Road, Nanjing, 210029, Jiangsu, China., Zhu J; Phase I Clinical Trial Unit, The First Affiliated Hospital with Nanjing Medical University, #300 Guangzhou Road, Nanjing, 210029, Jiangsu, China.; Department of Clinical Pharmacology, Pharmacy College, Nanjing Medical University, Nanjing, 211166, China., Sun X; Department of Anesthesiology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, 210029, China., Xie L; Phase I Clinical Trial Unit, The First Affiliated Hospital with Nanjing Medical University, #300 Guangzhou Road, Nanjing, 210029, Jiangsu, China., Zhao Y; Phase I Clinical Trial Unit, The First Affiliated Hospital with Nanjing Medical University, #300 Guangzhou Road, Nanjing, 210029, Jiangsu, China., Ding S; Phase I Clinical Trial Unit, The First Affiliated Hospital with Nanjing Medical University, #300 Guangzhou Road, Nanjing, 210029, Jiangsu, China., Wang L; Phase I Clinical Trial Unit, The First Affiliated Hospital with Nanjing Medical University, #300 Guangzhou Road, Nanjing, 210029, Jiangsu, China., Chen J; Phase I Clinical Trial Unit, The First Affiliated Hospital with Nanjing Medical University, #300 Guangzhou Road, Nanjing, 210029, Jiangsu, China., Zhu B; Phase I Clinical Trial Unit, The First Affiliated Hospital with Nanjing Medical University, #300 Guangzhou Road, Nanjing, 210029, Jiangsu, China., Zheng A; Department of Pharmaceutics, Institute of Pharmacology and Toxicology of Academy of Military Medical Sciences, Beijing, 100850, China., Li Y; Xinjiang Tefeng Pharmaceutical Company, Ltd., Urumqi, 830054, China., Zhou C; Phase I Clinical Trial Unit, The First Affiliated Hospital with Nanjing Medical University, #300 Guangzhou Road, Nanjing, 210029, Jiangsu, China. jsphkjzc@163.com., Shao F; Phase I Clinical Trial Unit, The First Affiliated Hospital with Nanjing Medical University, #300 Guangzhou Road, Nanjing, 210029, Jiangsu, China. jsphshaofeng@hotmail.com.; Department of Clinical Pharmacology, Pharmacy College, Nanjing Medical University, Nanjing, 211166, China. jsphshaofeng@hotmail.com.
Jazyk: angličtina
Zdroj: Clinical drug investigation [Clin Drug Investig] 2023 Jun; Vol. 43 (6), pp. 421-433. Date of Electronic Publication: 2023 Jun 04.
DOI: 10.1007/s40261-023-01276-5
Abstrakt: 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 (T max ) of 1.00 h, and mean values of the peak concentration (C max ) and area under the concentration-time curve (AUC 0-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).
(© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)
Databáze: MEDLINE
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