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A population pharmacokinetic model of remimazolam for general anesthesia and consideration of remimazolam dose in clinical practice

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Abstract

Background

Remimazolam besylate is a novel short-acting benzodiazepine. An appropriate pharmacokinetic model of remimazolam is desirable in anesthesia practice. The aim of the study was to develop a pharmacokinetic model using plasma samples from patients anesthetized with remimazolam. Influence of patient characteristics, context-sensitive decrement-times, and dose regimens were also examined.

Methods

Data were obtained from four trials on patients, and seven trials on healthy volunteers. The characteristics of 416 male and 246 female subjects were as follows: age, 18–93 years; body weight, 34–149 kg; and American Society of Anesthesiologists physical status (ASA-PS), I-IV. 2231 arterial and 3200 venous samples were used for the final model. The equilibration rate constant between arterial plasma and effect-site was estimated using the concept of time to peak effect. The final model was used to generate context-sensitive decrement times and dose regimens for general anesthesia.

Results

A three-compartment model plus virtual venous compartment with allometric scaling of adjusted body weight (ABW), age, sex, and ASA-PS as covariates were selected as the final model. Elimination clearance was lower in males, and in subjects with higher ABW and ASA-PS scores. Approximately 10% or 20% higher dose rate was necessary in females than in males or ASA-PS I/II than III/IV patient. The context-sensitive half-time for effect-site concentration in a 55-year-old, 70-kg, 170-cm male or female ASA-PS I/II patient after > 6-h infusion was 16.7 or 15.9 min.

Conclusion

Remimazolam pharmacokinetic model for general anesthesia was successfully developed. ABW, ASA-PS, and sex has a considerable impact on the remimazolam concentration.

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Acknowledgements

We thank Akito Ishikawa and Rieko Ichihara (Data Science Department, Mundipharma K.K., Tokyo, Japan), who cross-checked the spread sheet containing the data for pharmacokinetic analysis.

We received a professional English editing service from Cactus Communications. K.K., Tokyo, Japan.

Funding

This study was mainly funded by a research grant from Mundipharma K.K., Tokyo, Japan, and was partially funded by the Department of Anesthesiology, Showa University School of Medicine, Japan.

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Authors and Affiliations

  1. Department of Anesthesiology, Yokohama City University School of Medicine, Fukuura 3-9, Yokohama, Kanazawa-ku, 236-0004, Japan

    Kenichi Masui

  2. Department of Anesthesiology, Showa University School of Medicine, Tokyo, Japan

    Kenichi Masui

  3. PAION Deutschland GmbH, Aachen, Germany

    Thomas Stöhr & Marija Pesic

  4. Medical Excellence Department, Mundipharma K.K, Tokyo, Japan

    Tomohiro Tonai

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  1. Kenichi Masui
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Contributions

Kenichi Masui: This author contributed to the study design, data analysis and interpretation, and manuscript preparation. Marija Pesic, Thomas Stöhr and Tomohiro Tonai: These authors contributed to data preparation and interpretation as well as manuscript preparation.

Corresponding author

Correspondence to Kenichi Masui.

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Conflict of interest

Kenichi Masui was a consultant/advisor for Mundipharma K.K., Tokyo, Japan, and has been awarded a research grant for this study and has received payment for delivering domestic lectures from Mundipharma. Additionally, he is an Editor of Journal of Anesthesia, and an Editorial Board of JA Clinical Reports. Thomas Stöhr and Marija Pesic are employees of PAION Deutschland GmbH, Aachen, Germany. PAION is the developer of remimazolam besylate. Tomohiro Tonai is an employee of Mundipharma K.K., Tokyo, Japan. Mundipharma have an exclusive license and rights for development and commercialization of remimazolam in Japan.

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Masui, K., Stöhr, T., Pesic, M. et al. A population pharmacokinetic model of remimazolam for general anesthesia and consideration of remimazolam dose in clinical practice. J Anesth 36, 493–505 (2022). https://doi.org/10.1007/s00540-022-03079-y

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  • DOI: https://doi.org/10.1007/s00540-022-03079-y

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