Impact of CES1 Genotype on Remimazolam

Study Overview
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Brief Summary
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Remimazolam is primarily metabolized via CES1, and other drugs that are commonly metabolized by CES1 are known to have their pharmacokinetics and clinical effects affected by genetic polymorphisms in CES1. The goal of this observational study is to investigate the impact of the CES1 genotype on the pharmacokinetics, safety, and efficacy of remimazolam in patients undergoing elective surgery.

Official Title
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A Clinical Study to Explore the Effect of Carboxylesterase 1 (CES1) Genotype on Pharmacokinetics, Safety, and Efficacy of Remimazolam

Conditions
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Adult, Middle Aged, Elective Surgical Procedures

Intervention / Treatment
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* Drug: Remimazolam besylate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: American Society of Anesthesiologists (ASA) physical status 1 or 2 Age 19-64 years Elective surgery Exclusion Criteria: Concomitant regional anesthesia Uncontrolled hypertension (systolic blood pressure >180 mmHg) Uncontrolled diabetes mellitus (HbA1c >9.0%) Aspartate transaminase (AST), Alanine transferase (ALT), Total bilirubin > more than 2 times the normal upper limit Estimated glomerular filtration rate <60 ml/min/1.73m2 Moderate to severe chronic pulmonary obstructive disease or respiratory failure Emergency Hepatectomy, Liver transplantation Cardiopulmonary bypass use Craniotomy due to head trauma, unstable intracranial pressure, or brain disease Use of benzodiazepine medications (if tolerance is present) Anxiety, alcohol/drug dependence, or addiction to tricyclic antidepressants Reported hypersensitivity and adverse reactions to benzodiazepines, flumazenil, and other agents used during anesthesia Lactose-related genetic disorders Myasthenia gravis or myasthenia gravis syndrome Newly diagnosed myocardial infarction/clinically significant coronary artery disease, cerebral ischemic attack/stroke within 6 months, or significant untreated coronary artery disease Implanted rate-responsive cardiac pacemaker with a bioelectrical impedance sensor. Intrinsic brain disorders or other conditions that make it difficult to determine the depth of anesthesia through EEG measurements (e.g., epilepsy) History of severe allergies Cognitive impairment that prevents comprehension of the instructions and consent form of this study, in case of sedation Expected intraoperative blood loss of 1000 ml or more Judged by the investigator to be unsuitable for participation in this study due to other reasons

Ages Eligible for Study
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Minimum Age: 19 Years
Maximum Age: 64 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| CES1 without or without single nucleotide polymorphism (SNP)<br>We will determine the CES1 genotype of participants through a laboratory test. Several different types of SNPs can be identified, and analyses can be further stratified by CES1 SNP type. | Drug: Remimazolam besylate<br>* This is an observational study, meaning that no interventions are actually administered to the participants. However, blood and urine samples will be collected for research purposes. Participants will receive remimazolam besylate for at least 2 hours during anesthesia and surgery. Blood will be drawn to determine the concentration of remimazolam in the blood at the following time points: (1) before remimazolam administration, (2) after remimazolam administration has lasted at least 2 hours without a change in concentration, (3) immediately before discontinuation of remimazolam if there has been a change in concentration since the second blood draw, (4) within 5 minutes of discontinuation, (5) within 15-60 minutes of discontinuation, and (6) 90 minutes after discontinuation. Urine will also be collected after the end of anesthesia to check for metabolites of remimazolam.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-adjusted steady-state concentration of remimazolam | Determine the dose-adjusted steady-state concentration of remimazolam using Liquid Chromatography-Mass Spectrometry/Mass Spectrometry (LC-MS/MS) | Immediately before the initiation of remimazolam administration   120 minutes after the cessation of remimazolam | 
| Maintenance dose of remimazolam for maintaining general anesthesia | Hourly maintenance dose of remimazolam for maintaining general anesthesia | Immediately before the initiation of remimazolam administration   120 minutes after the cessation of remimazolam | 
| Total dose of remimazolam used to induce general anesthesia | Determine the total dose of remimazolam to achieve loss of consciousness (LOC). Modified Observer's Alertness/Sedation Scale (MOAA/S) <2 indicates LOC. The MOAA/S scale assesses a patient's level of alertness and response to stimulation, and is scored on a 6-point scale (6: awake and alert, 1: deeply asleep and unresponsive to any stimulus). | Initiation of remimazolam administration   5 minutes after start of remimazolam | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to LOC after remimazolam administration during anesthesia induction | Determine the time to achieve LOC after remimazolam dosing. | Initiation of remimazolam administration   5 minutes after start of remimazolam | 
| Time to bispectral index(BIS) < 60 after remimazolam administration during anesthesia induction | Determine the time to achieve BIS <60 after remimazolam dosing | Initiation of remimazolam administration   10 minutes after start of remimazolam | 
| Changes in BIS during induction and maintenance of anesthesia | Measure BIS during anesthesia | Initiation of remimazolam administration   30 minutes after cessation of remimazolam | 
| Percentage maintained BIS >60 during general anesthesia | Calculate Time maintained BIS >60 / Time remimazolam administered | Initiation of remimazolam administration   Cessation of remimazolam(up to 10 hours after start of remimazolam administration) | 
| Changes in BIS during anesthesia induction and maintenance | Assess BIS values during general anesthesia | Initiation of remimazolam administration   30 minutes after cessation of remimazolam | 
| Postanesthesia care unit (PACU) length of stay | Determine how long participants stay in the PACU before being transferred to a general ward | PACU admission   PACU discharge (within 3 hours after PACU admission) | 
| Emergence delirium | Richmond Agitation Sedation Scale (RASS) ≥1 indicates emergence delirium (RASS score ranges from -5 to +4, with negative numbers indicating varying degrees of sedation or lethargy, and positive numbers indicating varying degrees of agitation or restlessness) | Immediately after extubation   3 hours after PACU admission | 
| Resedation | Richmond Agitation Sedation Scale (RASS) ≤-2 indicates resedation | Immediately after extubation   3 hours after PACU admission | 
| Precipitation | Visually determine whether remimazolam administration causes precipitation in the fluid line through which the agent is administered | Initiation of remimazolam administration   10 minutes after start of remimazolam | 
| Injection pain caused by remimazolam administration | Question the patient to determine if pain occurs at the intravenous site where remimazolam is administered (check only if it occurs) | Initiation of remimazolam administration   3 minutes after start of remimazolam | 
| Adverse events up to 48 hours after surgery | All adverse events including nausea/vomiting, hypertension/hypotension(30% or more change in preoperative blood pressure), bradycardia (heart rate <50 beats per minute[bpm]), tachycardia (heart rate >100 bpm) | Initiation of remimazolam administration   48 hours after surgery | 
| Endogenous metabolites that occur as remimazolam is metabolized in the body (This is an exploratory check, meaning we do not know in advance what substances will be found) | Analyze collected blood and urine to determine the metabolites of remimazolam (Therefore, various laboratory methods can be used to detect endogenous metabolites, but it is not known in advance exactly how) | Immediately before the start of remimazolam   120 minutes after remimazolam cessation | 
| Total dose of remimazolam during general anesthesia | Determine the total dose of remimazolam during general anesthesia | Initiation of remimazolam administration   Cessation of remimazolam(up to 10 hours after start of remimazolam administration) | 
| Total dose of remifentanil during general anesthesia | Determine the total dose of remifentanil during general anesthesia | Initiation of remifentanil administration   Cessation of remifentanil(up to 10 hours after start of remifentanil administration) | 
| Operation time | Determine how long the surgery was performed | Start of surgery   End of surgery(up to 10 hours after start of surgery) | 
| Anesthesia time | Determine how long the general anesthesia was performed | Initiation of remimazolam administration   Exit to the PACU (within 30 minutes after remimazolam cessation) | 
| Flumazenil dosage | If the participants are not awake within 10 minutes after discontinuation of remimazolam, administer flumazenil and verify the total dosage (max: 1 mg). | Cessation of remimazolam   30 minutes after remimazolam cessation | 
| Pain score in PACU | If the participants are able to verbalize their pain, use a Numerical Rating Scale (NRS), otherwise use a Visual Analog Scale (VAS). Both scales are used to measure pain intensity on a scale of 0 to 10, with 0 being no pain and 10 being the worst pain imaginable. | PACU admission   PACU discharge (within 3 hours after PACU admission) | 
| Analgesic usage in PACU | Identify the type and dose of opioid or non-opioid pain medication used to control the participants' pain. | PACU admission   PACU discharge (within 3 hours after PACU admission) | 
| Delirium | Determine delirium during post-operative hospitalization through electronic medical records | After surgery   Hospital discharge (within 1 month after surgery) | 
| Postoperative complications | Identify any complications during post-operative hospitalization through electronic medical records | After surgery   Hospital discharge (within 1 month after surgery) | 
| Hospital stay after surgery | Identify the hospital length of stay after surgery | The day of surgery   Hospital discharge (within 1 month after surgery) |