A Clinical Study to Explore the Effect of Carboxylesterase 1 (CES1) Genotype on Pharmacokinetics, Safety, and Efficacy of Remimazolam
Trial Snapshot
- Phase
- Not Applicable
- Status
- Recruiting
- Enrollment
- 120
- Locations
- 1
- Primary Endpoint
- Dose-adjusted steady-state concentration of remimazolam
Study Overview
Brief Summary
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.
Study Design
- Study Type
- Observational
- Observational Model
- Cohort
- Time Perspective
- Prospective
Eligibility Criteria
- Ages
- 19 Years to 70 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •American Society of Anesthesiologists (ASA) physical status 1 or 2
- •Age 19-70 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
Arms & Interventions
CES1 without or without single nucleotide polymorphism (SNP)
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.
Intervention: Remimazolam besylate (Drug)
Outcomes
Primary Outcomes
Dose-adjusted steady-state concentration of remimazolam
Time Frame: Immediately before the initiation of remimazolam administration ~ 120 minutes after the cessation of remimazolam
Determine the dose-adjusted steady-state concentration of remimazolam using Liquid Chromatography-Mass Spectrometry/Mass Spectrometry (LC-MS/MS)
Maintenance dose of remimazolam for maintaining general anesthesia
Time Frame: Immediately before the initiation of remimazolam administration ~ 120 minutes after the cessation of remimazolam
Hourly maintenance dose of remimazolam for maintaining general anesthesia
Total dose of remimazolam used to induce general anesthesia
Time Frame: Initiation of remimazolam administration ~ 5 minutes after start of remimazolam
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).
Secondary Outcomes
- Percentage maintained BIS >60 during general anesthesia(Initiation of remimazolam administration ~ Cessation of remimazolam(up to 10 hours after start of remimazolam administration))
- Changes in BIS during induction and maintenance of anesthesia(Initiation of remimazolam administration ~ 30 minutes after cessation of remimazolam)
- Time to LOC after remimazolam administration during anesthesia induction(Initiation of remimazolam administration ~ 5 minutes after start of remimazolam)
- Time to bispectral index(BIS) < 60 after remimazolam administration during anesthesia induction(Initiation of remimazolam administration ~ 10 minutes after start of remimazolam)
- Changes in BIS during anesthesia induction and maintenance(Initiation of remimazolam administration ~ 30 minutes after cessation of remimazolam)
- Postanesthesia care unit (PACU) length of stay(PACU admission ~ PACU discharge (within 3 hours after PACU admission))
- Emergence delirium(Immediately after extubation ~ 3 hours after PACU admission)
- Resedation(Immediately after extubation ~ 3 hours after PACU admission)
- Precipitation(Initiation of remimazolam administration ~ 10 minutes after start of remimazolam)
- Injection pain caused by remimazolam administration(Initiation of remimazolam administration ~ 3 minutes after start of remimazolam)
- Adverse events up to 48 hours after surgery(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)(Immediately before the start of remimazolam ~ 120 minutes after remimazolam cessation)
- 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(Initiation of remifentanil administration ~ Cessation of remifentanil(up to 10 hours after start of remifentanil administration))
- Operation time(Start of surgery ~ End of surgery(up to 10 hours after start of surgery))
- Anesthesia time(Initiation of remimazolam administration ~ Exit to the PACU (within 30 minutes after remimazolam cessation))
- Flumazenil dosage(Cessation of remimazolam ~ 30 minutes after remimazolam cessation)
- Pain score in PACU(PACU admission ~ PACU discharge (within 3 hours after PACU admission))
- Analgesic usage in PACU(PACU admission ~ PACU discharge (within 3 hours after PACU admission))
- Delirium(After surgery ~ Hospital discharge (within 1 month after surgery))
- Postoperative complications(After surgery ~ Hospital discharge (within 1 month after surgery))
- Hospital stay after surgery(The day of surgery ~ Hospital discharge (within 1 month after surgery))
Investigators
Byung Gun Lim
Professor
Korea University Guro Hospital