A Placebo- and Midazolam-Controlled Phase I Single Ascending-Dose Study Evaluating the Safety, Pharmacokinetics, and Pharmacodynamics of Remimazolam (CNS 7056): Part II. Population Pharmacokinetic and Pharmacodynamic Modeling and Simulation
Abstract
Background A new benzodiazepine, remimazolam, which is rapidly metabolized by tissue esterases to an inactive metabolite, has been developed to permit a fast onset, a short, predictable duration of sedative action, and a more rapid recovery profile than currently available drugs. We report on modeling of the data and simulations of dosage regimens for future study. Methods A phase I, single-center, double-blind, placebo and active controlled, randomized, single-dose escalation study was conducted. Fifty-four healthy subjects in 9 groups received a single 1-minute IV infusion of remimazolam (0.01-0.3 mg/kg). There were 18 control subjects taking midazolam and 9 placebos. Population pharmacokinetic and pharmacodynamic modeling of the data was undertaken and the parameters obtained were used for Monte-Carlo simulations of alternative dosing regimens. Results A 4-compartment mammillary pharmacokinetic model of midazolam and a physiologically based recirculation model of remimazolam were fitted to the observed plasma levels. The recirculation model of remimazolam explained the observed high venous, compared with arterial, concentrations at later time points. The 2 models were used to simulate the arterial concentrations required for the pharmacodynamic models of sedation (Bispectral Index and Modified Observer's Assessment of Alertness/Sedation [MOAA/S]) and gave population mean pharmacodynamic parameters as follows: Bispectral Index-IC(50): 0.26, 0.07 μg/mL; γ: 1.6, 8.6; k(e0): 0…
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Remimazolam is hydroxylated by plasma tissue esterase to the inactive metabolite CNS 7054, which does not rely on kidney and liver metabolism.
“Remimazolam is hydroxylated by plasma tissue esterase to the inactive metabolite CNS 7054, which does not rely on kidney and liver metabolism (24,25).”
Long-term infusions or massive doses of remimazolam do not result in accumulation of the drug or its metabolite.
“Long-term infusions or administering massive doses do not result in the accumulation of the drug or its metabolite, making it superior to midazolam and propofol.”
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“[7], a decrease in the maximum BIS of 50% was achieved with a remima-”
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Remimazolam besilate, a benzodiazepine, has been approved for general anesthesia!!
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“One volunteer study, in which TBW of the volunteers ranged from 65–90 kg and remimazolam was administered as a 1-min bolus, reported that body weight was not a significant covariate [7].”
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“[66] In the case of midazolam, the context-sensitive half-time (the time required for blood concentrations to decrease by half after infusion termination) is predicted to increase dramatically with midazolam infusion length, reaching 60 min after a simulated 8-h infusion.[66] In contrast, the predicted context-sensiti…”
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“As an ultra-short-acting sedative/anesthetic drug, remimazolam is characterized by rapid onset, good water solubility, rapid clearance, inactive metabolites and specific antagonists (Wiltshire et al., 2012; Schüttler et al., 2020; Sheng et al., 2020), which may be an ideal anesthetic/ sedative for bronchoscopy.”
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Remimazolam: New Beginnings or Just a Me-Too?
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“Remimazolam seems to be a substantial improvement on midazolam with an apparently inactive metabolite and a context-sensitive half-time plot reminiscent of that for remifentanil.(2) What should we expect from a Phase 1 study? Regulators, such as the Food and Drug Administration, require the demonstration of safety and…”
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“The extent of sedative effects of remimazolam are dose-dependent, with a peak effect at 1–4 min after drug administration [70, 75].”
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“However, some adverse reactions, such as head-ache, drowsiness and hypoxia, QT interval prolongation, allergy, tachycardia, and hypertension, have been reported during research trials (25,39,40).”
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“Similar to remimazolam besylate in structure and pharmacological properties [9, 10], remimazolam tosilate (RT) is a new short-acting GABA (A) receptor agonist with a tosilate counterion.”
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“92 h [1], fewer adverse events, faster recovery, and quicker return to cognitive function when compared with propofol and midazolam [1–3].”
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“Remimazolam has multiple advantages, such as a slight circulatory suppressive effect and liver and kidney function-independent metabolism.(4) During the 2-years it has been on the market, remimazolam has prompted widespread concern and has emerged as an ideal sedative drug for populations at an advanced age or in a vu…”
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“can maintain a sedative effect with continuous administration [3].”
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“075 mg/kg, and the sedation depth and recovery time are dose-dependent.(18,19) Compared with midazolam, remimazolam provides more effective sedation with faster recovery, lower incidence of hypotension and shorter time to restoration of neuropsychiatric function.”
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“Remimazolam is rapidly metabolized in the liver 3 and has virtually no cumulative effects 2,4 .”
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“This novel anesthetic agent has a relatively short context-sensitive half-life of 7–8 minutes, even after a 2-hour infusion, and, as with midazolam, can be reversed with flumazenil.”
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“5 min) and significantly shorter than that of midazolam [7].”
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“16 Despite the wealth of PK and PD data in adults, to date, there is only study evaluating these parameters in pediatric-aged patients (see below).”
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“Wiltshire et al suggested that dosing of remimazolam by body weight maybe not better than fixed doses for no clinically relevant covariate effects observed.(13) It was proved to be safe and effective for moderate sedation with no-weight adjusted doses in gastrointestinal endoscopy.”
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“Similar results were confirmed by Wiltshire et al. , suggesting that remimazolam does not accumulate after constant infusion and can be used for the maintenance of general anesthesia in order to obtain a quick full-alert time [14].”
ResultJeong, H., Kim, H.-R., & Ahn, H. (2023) · Journal of Clinical Medicine · doi:10.3390/jcm12051763 · Cited by 13 · see citing works
Clinical Application and Research Progress of Remimazolam for Pediatric Patients
Bai, C., Xu, M., Guo, Y., Jin, Y.-W., & Zhao, X. (2024) · Drug Design, Development and Therapy · doi:10.2147/dddt.s453440 · Cited by 12 · see citing works
“13 In addition, Masui et al 8 found that the blood remimazolam concentration in adult women was higher than that in men during the initial and maintenance periods of administration, which may be related to higher CES activity in adult women.”
BackgroundBenefits of remimazolam as an anesthetic sedative for older patients: A review
Jin, N., & Xue, Z.-Q. (2024) · Heliyon · doi:10.1016/j.heliyon.2024.e25399 · Cited by 12 · see citing works
“This indicates that remimazolam has a more accurate maintenance dose than slower-acting medications [26].”
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Chen, Y.-T., Gong, C.-S., Liu, F., Jiao, Z., & Zheng, X.-C. (2024) · Pharmaceutics · doi:10.3390/pharmaceutics16091122 · Cited by 11
“This difference may be attributed to the type of sample collected (veins vs. arteries) [22].”
BackgroundResultInfluentialRemimazolam Use in Cardiac Anesthesia: A Narrative Review.
Muncan, B., & Bennett-Guerrero, E. (2024) · Journal of Cardiothoracic and Vascular Anesthesia · doi:10.1053/j.jvca.2024.07.045 · Cited by 11 · see citing works
Wu, X.-H., Zeng, L., Zhang, T.-Y., Wu, W., Tian, Y.-M., & Dong, S.-K. (2023) · Medicine · doi:10.1097/md.0000000000034731 · Cited by 11 · see citing works
“[22] Additional studies suggest that dosing by body weight may not offer an advantage over a fixed dose in patients with body weights in the 65 to 90 kg range.[25] Remazolam besylate, as a new ultrashort-acting benzodiazepine narcotic, combined with other drugs for painless gastroscopy has been less studied.”
BackgroundZhu, H.-C., Su, Z., Huai, X., Chen, C., Zhang, X., Zhou, J., & Su, D. (2022) · Trials · doi:10.1186/s13063-022-06935-0 · Cited by 11 · see citing works
“Compared with propofol, remimazolam has no injection pain and has a lower incidence of hypotension [14].”
BackgroundContext sensitive decrement times of remimazolam.
Schnider, T., & Minto, C. (2013) · Anesthesia and Analgesia · doi:10.1213/ane.0b013e3182942954 · Cited by 11 · see citing works
Recirculatory pharmacokinetic modeling: what goes around, comes around.
Krejcie, T., & Avram, M. (2012) · Anesthesia and Analgesia · doi:10.1213/ane.0b013e318240139b · Cited by 11
“In this issue of the journal, Wiltshire et al.(1) report the pharmacokinetics and pharmacodynamics of a promising new benzodiazepine, remimazolam (CNS 7056), that has a rapid onset of effect and a short duration of action.”
BackgroundMethodResultInfluentialTeaching an Old GABA Receptor New Tricks
Trudell, J. R., Bertaccini, E. J., & MacIver, M. B. (2012) · Anesthesia & Analgesia · doi:10.1213/ane.0b013e31824a0b3c · Cited by 12 · see citing works
Remimazolam: a comprehensive review
Aszkiełowicz, A., Kapłan, C., Kapica, P., & Marszałek, R. (2025) · Anaesthesiology Intensive Therapy · doi:10.5114/ait/210611 · Cited by 10 · see citing works
“The dose-dependent half-life following a 3-hour infusion of remimazolam was over five times shorter than that of midazolam (approximately 7.5 min vs. 40 min) and comparable to that of propofol (approximately 7.5 min) [9–11].”
InfluentialAssociation of remimazolam with delirium and cognitive function
Arias, J., Wegner, G. R. M., Wegner, B. F. M., Silva, L. S., Bezerra, F., & Filardi, R. G. M. (2024) · European Journal of Anaesthesiology · doi:10.1097/eja.0000000000002107 · Cited by 9 · see citing works
New medications and techniques in ambulatory anesthesia.
Melton, M., Nielsen, K. C., Tucker, M. S., Klein, S. M., & Gan, T. (2014) · Anesthesiology Clinics · doi:10.1016/j.anclin.2014.02.003 · Cited by 9
Tong, R.-J., Lv, Y.-Z., Shi, Y.-F., Lai, L., & Shen, Q.-H. (2025) · Aging Clinical and Experimental Research · doi:10.1007/s40520-025-03166-6 · Cited by 8 · see citing works
Remimazolam: a new string to the TIVA bow
Hirota, K. (2023) · Journal of Anesthesia · doi:10.1007/s00540-023-03186-4 · Cited by 8 · see citing works
“phase I pharmacokinetic trials demonstrated that the simulated context-sensitive half-time of remimazolam is 7–8 min after 2-h infusion; this is much shorter than midazolam [2].”
BackgroundSun, Y.-Y., Zhang, J., & Feng, S.-W. (2023) · Psychiatry Investigation · doi:10.30773/pi.2022.0323 · Cited by 8 · see citing works
Challenges of bringing a new sedative to market!
Sear, J. (2018) · Current Opinion in Anaesthesiology · doi:10.1097/aco.0000000000000614 · Cited by 8
Ilic, R. (2015) · International Anesthesiology Clinics · doi:10.1097/aia.0000000000000053 · Cited by 8
“The degree and duration of sedation with remimazolam are dose dependent, with an observed peak effect at 1 to 4 minutes after initiation of treatment.(42,43) With higher doses, remimazolam caused a deeper sedation, but an alert state was still achieved at a faster rate than with midazolam treatment.”
BackgroundLiu, T., Qin, L., Su, M., Wei, Y., Yu, H., Wei, H.-T., Xie, Y.-B., & Chen, J. (2025) · Scientific Reports · doi:10.1038/s41598-025-08403-6 · Cited by 7
“The possible reason 18,19 may be related to the influence of the combined anesthesia of benzodiazepine sedative drugs and propofol on the pharmacokinetics of propofol.”
Efficacy and safety of remimazolam tosilate in anesthesia for short otolaryngology surgery
Cheng, W., Cheng, Y., He, H., Zhou, D.-D., Wang, J., Zhang, Y., & Wang, Z. (2024) · BMC Anesthesiology · doi:10.1186/s12871-024-02790-5 · Cited by 7 · see citing works
“Sedation was induced by intravenous injection with 0.3 mg/kg [15, 16] remimazolam tosilate (Jiangsu Hen-grui Pharmaceutical Co. Ltd. in China) or 0.075 mg/kg [17] midazolam (Jiangsu Enhua Pharmaceutical in China) to the RM or MD groups, respectively.”
MethodInfluentialActions of remimazolam on inhibitory transmission of rat spinal dorsal horn neurons.
Hoshino, R., Ohashi, N., Uta, D., Ohashi, M., Deguchi, H., & Baba, H. (2024) · Journal of Pharmacological Sciences · doi:10.1016/j.jphs.2024.04.002 · Cited by 6
Oh, J., Park, S.-Y., Moon, J.-Y., Park, J.-H., & Joe, H. (2024) · Journal of Clinical Medicine · doi:10.3390/jcm13030670 · Cited by 6
“According to Wiltshire et al. [28], PD models using BIS monitoring revealed that men are twice as sensitive to remimazolam compared to women, which contradicts our results.”
Result
- Authors
- Wiltshire, H. R., Kilpatrick, G. J., Tilbrook, G. S., & Borkett, K. M.
- Affiliations
- Paion (United Kingdom) (GB)
- Corresponding author
- Wiltshire, Hugh R.
- ORCID
- Kilpatrick, Gavin J.
- Venue
- Anesthesia & Analgesia
- Published
- 2012-08
- Volume
- 115
- Issue
- 2
- Pages
- 284-296
- ISSN
- 0003-2999 (ISSN-L)
- OpenAlex
- W1977462728
- Cited by
- 215
- References
- 0
- Citations by year
- 2026: 16 · 2025: 37 · 2024: 38 · 2023: 30 · 2022: 28 · 2021: 11 · 2020: 14 · 2019: 3 · 2018: 5 · 2017: 8 · 2016: 4 · 2015: 5 · 2014: 5 · 2013: 3 · 2012: 6
- FWCI
- 8.11
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Anesthesia & Analgesia (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Anesthesiology and Pain Medicine › Anesthesia and Sedative Agents
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmaceutical studies and practices
- Keywords
- remimazolam, benzodiazepines, midazolam, pharmacokinetics, pharmacodynamics, sedation, bispectral index, population pharmacokinetic model, dose simulation, drug safety, healthy volunteers, single ascending dose, intravenous infusion
- MeSH terms
- Adult, Benzodiazepines, Computer Simulation, Consciousness, Dose-Response Relationship, Drug, Double-Blind Method, Female, Humans, Hypnotics and Sedatives, Infusions, Intravenous, Male, Maryland, Metabolic Clearance Rate, Midazolam, Middle Aged, Models, Biological, Monte Carlo Method, Placebos, Treatment Outcome, Young Adult, Consciousness Monitors
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