Background

Remimazolam (CNS 7056) is a new ultra–short-acting benzodiazepine for intravenous sedation and anesthesia. Its pharmacokinetics and pharmacodynamics have been reported for bolus administration. This study aimed to investigate the pharmacokinetics and pharmacodynamics of remimazolam after continuous infusion.

Methods

Twenty healthy male volunteers (20 to 38 yr, 64 to 99 kg) received remimazolam as continuous intravenous infusion of 5 mg/min for 5 min, 3 mg/min for the next 15 min, and 1 mg/min for further 15 min. Pharmacokinetics of remimazolam and its metabolite were determined from arterial plasma concentrations. Sedation was assessed using the Modified Observer’s Assessment of Alertness and Sedation scale. Pharmacokinetic-pharmacodynamic modeling was performed by population analysis. Hemodynamics and the electrocardiogram were also investigated.

Results

Pharmacokinetics was best described by a three-compartment model for remimazolam and a two-compartment model with transit compartment for the metabolite. Remimazolam showed a high clearance (1.15 ± 0.12 l/min, mean ± SD), a small steady-state volume of distribution (35.4 ± 4.2 l) and a short terminal half-life (70 ± 10 min). The simulated context-sensitive halftime after an infusion of 4 h was 6.8 ± 2.4 min. Loss of consciousness was observed 5 ± 1 min after start, and full alertness was regained 19 ± 7 min after stop of infusion. Pharmacodynamics of Modified Observer’s Assessment of Alertness and Sedation score was best described by a sigmoid probability model with effect site compartment. The half-maximum effect site concentration for a Modified Observer’s Assessment of Alertness and Sedation score less than or equal to 1 was 695 ± 239 ng/ml. The equilibration half-time between central and effect compartment was 2.7 ± 0.6 min. Mean arterial blood pressure decreased by 24 ± 6%, and heart rate increased by 28 ± 15%. Spontaneous breathing was maintained throughout the study. There was no significant prolongation of the QT interval of the electrocardiogram observed.

Conclusions

Remimazolam was characterized by a pharmacokinetic–pharmacodynamic profile with fast onset, fast recovery, and moderate hemodynamic side effects.

Editor’s Perspective
What We Already Know about This Topic
  • Remimazolam is rapidly metabolized to an inactive metabolite by tissue esterases

  • When administered as a 1-min infusion, it produced rapid onset and dose-dependent sedation at doses of 0.05 mg/kg and higher

  • Its pharmacokinetics when administered as a 1-min infusion was characterized by relatively high elimination clearance, a small steady-state volume of distribution, and a short elimination half-life

What This Article Tells Us That Is New
  • Twenty adult male volunteers receiving remimazolam as continuous intravenous infusion at 5 mg/min for 5 min, then 3 mg/min for 15 min, and 1 mg/min for 15 min lost consciousness 5 ± 1 (mean ± SD) min after starting the infusion and were fully alert 19 ± 7 min after stopping it

  • Remizolam produced moderate hemodynamic effects and no clinically significant effect on cardiac repolarization

  • The disposition of remimazolam was characterized by a multicompartmental pharmacokinetic model with small distribution volumes and a high elimination clearance with small interindividual variability; its context-sensitive half time after a 4-h infusion was predicted to be 7 ± 2 min

Remimazolam (CNS 7056, PAION UK Ltd., United Kingdom) is a new benzodiazepine for intravenous use that is being developed as an ultra–short-acting agent for procedural sedation, and for induction and maintenance of general anesthesia.1–5  Remimazolam is an ester-based drug that is rapidly hydrolyzed in the body by tissue carboxylesterases to an inactive metabolite, CNS 7054.6  A phase I study in volunteers, in which remimazolam was administered as intravenous bolus injection, revealed a relatively high clearance, a small steady-state volume of distribution, and a short elimination half-life.7  Remimazolam produced deep sedation with fast onset and recovery. The pharmacokinetic and pharmacodynamic data of this previous phase I study were used to develop a recirculatory pharmacokinetic model and pharmacodynamic models relating the estimated remimazolam effect site concentrations to the Bispectral Index (BIS) of the electroencephalogram (EEG) and to the Modified Observer’s Assessment of Alertness and Sedation score as clinical measures of sedation.8  The pharmacokinetic–pharmacodynamic models obtained from this study had, however, some limitations. First, remimazolam was administered as a bolus injection over 1 min. However, for other drugs it was observed that pharmacokinetics models based on data from bolus administrations may be less appropriate compared with an administration of the drug as a continuous infusion.9  Further, the pharmacokinetic analysis was based on a combination of arterial and venous samples, whereas arterial measurements are generally preferable for pharmacokinetic–pharmacodynamic modeling.10  Although the published recirculatory model is of great interest from a scientific point of view, a three-compartment mammillary model would be necessary for model-based dosing regimens like target-controlled infusion. Lastly, the BIS index was originally developed for propofol, and it has been reported that the correlation between depth of sedation and the BIS index was weaker for the benzodiazepine agonist midazolam.11 

The present study was therefore conducted in order to develop linear mammillary compartment models of remimazolam and its metabolite CNS 7054 based on arterial plasma concentrations after longer lasting continuous intravenous infusion. For the purpose of pharmacodynamic modeling, the sedative effect was assessed by the Modified Observer’s Assessment of Alertness and Sedation scores and by the Narcotrend index of the EEG. The spontaneous EEG was further recorded continuously from multiple electrode positions to identify other suitable EEG variables for the assessment of remimazolam-induced sedation. Because an effect of remimazolam on cardiac repolarization was not fully analyzed in previous trials, the QT interval of the electrocardiogram was also assessed using a 12-lead Holter electrocardiogram recording.

This part of the study presents the pharmacokinetics and clinical pharmacodynamics including the Modified Observer’s Assessment of Alertness and Sedation scores, whereas the pharmacodynamics with respect to the EEG is reported in Part II.

This was a prospective, open-label, randomized, two-arm, single-center, crossover phase 1 clinical trial which was performed in accordance with the guidelines for Good Clinical Practice and the Declaration of Helsinki. The trial was approved by the local ethics committee (ethics committee of the medical faculty of the Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany) on May 12, 2017 (reference No. AZ113_17). The trial was registered to the EudraCT database (No. 2017-000455-12). Consolidated Standards of Reporting Trials guidelines were followed, and the study was clinically monitored by the Center for Clinical Studies, Erlangen, Germany. The trial took place at the Department of Anesthesiology of the University Hospital Erlangen, Germany between July and October 2017.

Subjects

After written informed consent, 25 volunteers were enrolled. It was the aim of the present phase I study to characterize the basic pharmacokinetics and pharmacodynamics of remimazolam after continuous infusion. To limit potential sources of interindividual variability like age, weight, and sex, the study was conducted in a relatively homogenous population with the following inclusion criteria: healthy male volunteers with an age between 18 and 40 yr, a body weight between 60 and 100 kg, a body mass index between 20 and 30 kg/m2, and an American Society of Anesthesiologists Physical Status classification of 1. Subjects with hypersensitivity to benzodiazepines or flumazenil, with clinically relevant cardiovascular, hematologic, gastrointestinal, hepatic, renal, endocrine, pulmonary, neurologic, psychiatric, allergic, or skin disorder were excluded. Further exclusion criteria were any kind of cardiovascular disorder known to increase the possibility of QT prolongation, an abnormal 12-lead electrocardiogram including Fridericia’s corrected QT interval at or above 450 ms, QRS interval at or above 110 ms, PR more than 200 ms, second- or third-degree atrioventricular block or any rhythm other than sinus rhythm. Exclusion criteria were also a resting heart rate (HR) below 50 bpm or at or above 90 bpm, a resting systolic arterial blood pressure below 90 mmHg or at or above 140 mmHg, or a resting diastolic arterial blood pressure below 50 mmHg or at or above 90 mmHg. Further exclusion criteria were intake of medications with a pronounced effect on the central nervous system (CNS) such as neuroleptics, antidepressants, hypnotics, anxiolytics, or antiepileptics within three months before the trial, and intake of any medication within one week before the trial. Subjects with a history of drug or alcohol abuse within two years before the trial or with use of tobacco or e-cigarettes within six months before the trial were excluded. Further exclusion criteria were participation in an investigational drug or medical device trial within two months before the present trial, as well as blood donation of more than 300 ml within one month before this trial.

Protocol

Each subject passed four visit days. Informed consent, assessment of medical history, physical examination, routine electrocardiogram, and routine laboratory assessments were performed at visit 1. Visit 2 and visit 3 served as remimazolam visit and control visit in which the volunteers received either remimazolam or sterile sodium chloride 0.9% infusion, respectively. The sequence of the remimazolam visit and the control visit was randomized using sealed envelopes containing the individual visit sequence for each subject. These envelopes were prepared by an independent statistician before the study started, using a computer-generated randomization list. For each subject, the envelope with the individual visit sequence was opened by the investigator after enrollment. Visit 3 was performed one to ten days after visit 2. Visit 4, which was performed within five days after visit 3, was a close-out visit with physical examination, routine electrocardiogram, and routine laboratory assessments.

During the remimazolam visit, the subjects received remimazolam (2 mg/ml in sterile sodium chloride 0.9%) as continuous intravenous infusion through a venous cannula in the dominant forearm with an infusion rate of 5 mg/min in the first 5 min, 3 mg/min in the following 15 min, and 1 mg/min in the last 15 min. Thus, each subject received 85 mg remimazolam in 35 min. The infusion rates were based on the results of a previous study7  and aimed to produce a moderate to deep sedation. Furthermore, the infusion rates were selected to provide concentration plateaus which matched the therapeutic and supratherapeutic ranges from a previous QT trial. In parallel to remimazolam, an infusion of sterile saline solution 0.9% was administered from approximately 30 min before start of remimazolam administration until approximately 240 min thereafter at a rate of 100 to 150 ml/h.

During the control visit the subjects received only a sterile saline solution 0.9% at a rate of 100 to 150 ml/h for about 4 h.

During the remimazolam visit, the following assessments were performed: arterial blood sampling for pharmacokinetic analyses, assessment of sedation, continuous EEG monitoring and recording, continuous electrocardiogram recording, hemodynamic monitoring, and assessment of side effects and adverse events.

During the control visit, the following assessments were performed: continuous electrocardiogram recording, hemodynamic monitoring, and assessment of side effects and adverse events.

Blood Sampling

Approximately 30 min before the start of remimazolam infusion, an arterial catheter was placed in the distal radial artery of the nondominant arm. Pharmacokinetic blood samples of 4 ml each were drawn into plastic tubes containing ethylenediaminetetraacetic acid (Vacutainer K3 EDTA, Becton Dickinson, Germany). A blank sample was taken before the start of remimazolam infusion. Further samples were taken 1, 3, 5, 7, 10, 15, 20, 25, 30, 35, 36, 37, 39, 42, 45, 50, 55, 65, 80, 95, 125, 155, 185, 215, 275 and 395 min after the start of remimazolam infusion. After each sample, the arterial catheter was flushed with 2 ml of saline solution. The samples were kept on ice water and were centrifuged within 40 min after collection at approximately 2,000g for 10 min at approximately 4°C in a cooled centrifuge. The plasma was separated within 15 min into polypropylene tubes (Nunc cryogenic vial cryo tubes, Thermo Fisher Scientific, USA) and stored at −70°C. The samples were analyzed within two months after collection.

Drug Assay

Plasma concentrations of remimazolam and CNS 7054 were measured by Aptuit Srl (Italy) using high-performance liquid chromatography (HPLC) with tandem mass spectrometric detection. Deuterium labeled d4-remimazolam and d4-CNS 7054 were used as internal standards. The compounds were extracted from 50 µl plasma by protein precipitation.

The HPLC system (Waters Acquity UPLC) used a 50 × 3 mm BETASIL Phenyl-Hexyl 5-µm column. Gradient elution with two mobile phases (phase A: water plus 0.01% formic acid, phase B: acetonitrile) was performed at a flow rate of 1.2 ml/min and room temperature. The approximate elution times were 0.6 min for CNS 7054 and 0.8 min for remimazolam, respectively. Tandem mass spectrometry was performed using a Biosystems/MDS SCIEX API-4000 instrument with a TurboIonSpray interface at 650°C. Nominal mass transitions from precursor ion to product ion were 439.1 to 407.2 for remimazolam, and 425.1 to 362.9 for CNS 7054, respectively. The method was validated over the range of 2 to 2,000 ng/ml for remimazolam and 20 to 20,000 ng/ml for CNS 7054, respectively, using a sample volume of 50 µL. Quality control samples were prepared in human plasma at 6, 200 and 1,500 ng/ml for remimazolam, and at 60, 2,000 and 15,000 ng/ml for CNS 7054, respectively. Inter- and intraassay coefficients of variation were at or below 6.6% for remimazolam and at or below 5.1% for CNS 7054, respectively. Accuracy was 105 ± 6% (range: 86 to 121%) for remimazolam and 106 ± 5% (range: 89 to 121%) for CNS 7054, respectively.

Assessment of Sedation

Sedation was assessed using the Modified Observer’s Assessment of Alertness and Sedation scale (table 1).12  The Modified Observer’s Assessment of Alertness and Sedation score was assessed every 2 min, starting immediately before remimazolam infusion until three subsequent Modified Observer’s Assessment of Alertness and Sedation scores of 5 (alert) were recorded after stop of remimazolam administration. The time to loss of consciousness was defined as the time to the first Modified Observer’s Assessment of Alertness and Sedation score less than 2. The time to return of full alertness was defined as the time to the first of the three subsequent Modified Observer’s Assessment of Alertness and Sedation scores of 5 after stop of remimazolam administration.

Table 1.

Modified Observer’s Assessment of Alertness and Sedation 2, 3, 2M Scale

Modified Observer’s Assessment of Alertness and Sedation 2, 3, 2M Scale
Modified Observer’s Assessment of Alertness and Sedation 2, 3, 2M Scale

The eyelid reflex and the corneal reflex were further tested using a cotton swab every 2 min, once a Modified Observer’s Assessment of Alertness and Sedation score at or below 3 and at or below 2 had been reached, respectively. These tests were performed until recovery of the reflexes.

When after stop of remimazolam infusion, the Modified Observer’s Assessment of Alertness and Sedation score had recovered to a value of 1, the subject was asked every 2 min to state his name (orientation to person), the date of the day (orientation to time), and the location (orientation to location). These questions were repeated until the subject answered correctly.

Pharmacokinetic–pharmacodynamic Modeling

The pharmacokinetic–pharmacodynamic modeling is described in full detail in paragraph S1 of the Supplemental Digital Content (http://links.lww.com/ALN/C147). In brief, pharmacokinetics of the parent drug remimazolam and its metabolite CNS 7054 were modeled using linear mammillary two- or three-compartment models linked by a transit compartment to account for the formation of the metabolite (fig. 1). Pharmacokinetic models were parametrized using the elimination clearance, intercompartmental clearances (Q2, Q3), and volumes of distributions (V1, V2, V3). Because the Modified Observer’s Assessment of Alertness and Sedation scale is not an interval ratio scale but an ordinal scale, probability models were used for pharmacodynamic modeling. We tested two types of models: an ordinal logistic regression model and a sigmoid probability model. An effect compartment was assumed as site of action. Pharmacokinetic and pharmacodynamic modeling was performed by population analysis with nonlinear mixed effect modeling using the software NONMEM 7.4.1 (ICON plc, Ireland). Interindividual parameter variability was modeled using log-normal distributions.

Fig. 1.

Combined pharmacokinetic model, consisting of a three-compartment model for the parent drug remimazolam, a two-compartment model for the metabolite CNS 7054, and a transit compartment for the formation of the metabolite. It is assumed that 100% of the eliminated amount of remimazolam enters the transit compartment. V1, 1M, central volumes of distribution; V2, 3, 2M, peripheral volumes of distribution; CL, CLM, elimination clearances; Q2, 3, 2M, intercompartmental clearances; KM, transit rate constant; D, dose.

Fig. 1.

Combined pharmacokinetic model, consisting of a three-compartment model for the parent drug remimazolam, a two-compartment model for the metabolite CNS 7054, and a transit compartment for the formation of the metabolite. It is assumed that 100% of the eliminated amount of remimazolam enters the transit compartment. V1, 1M, central volumes of distribution; V2, 3, 2M, peripheral volumes of distribution; CL, CLM, elimination clearances; Q2, 3, 2M, intercompartmental clearances; KM, transit rate constant; D, dose.

Close modal

EEG Monitoring and Recording

Continuous EEG monitoring was performed using the Narcotrend-Compact M monitor (MT MonitorTechnik, Germany) with three electrodes placed on the subject’s forehead. Narcotrend monitoring started 30 min before start of remimazolam infusion and was continued until 90 min after stop of remimazolam infusion.

The raw EEG signals obtained from a multi-channel EEG device (Natus-Nicolet V32, Natus Europe, Germany) were recorded continuously from electrodes positioned according to the international 10 to 20 system at F3, F4, C3, C4, O1, and O2, with Cz as common reference. The multichannel EEG was recorded from 30 min before start of remimazolam infusion until 90 min after stop of infusion.

The monitoring, recording, and analysis of the EEG are reported in full detail in Part II of this study.

Electrocardiogram Recording and Analysis

For offline electrocardiogram analysis, a continuous 12-lead Holter electrocardiogram was recorded on a flash card using an H-12+ electrocardiogram continuous 12-lead digital recorder (Mortara Instrument, USA). During the remimazolam visit, the electrocardiogram recording was started approximately 60 min before start of remimazolam administration (time point zero) and was terminated after the last blood sample had been drawn. During control visit, the Holter electrocardiogram was recorded from approximately 60 min before the time corresponding to time point zero for approximately 390 min thereafter. Additionally, a five-lead routine electrocardiogram was continuously recorded for online cardiovascular monitoring during both remimazolam and control visit within the same time periods as the 12-lead Holter electrocardiogram.

The 12-lead Holter electrocardiogram data were analyzed offline by a blinded team at ERT Ltd. (United Kingdom), following the International Conference on Harmonisation Guideline E14.13  Details of the electrocardiogram analysis are given in paragraph S2 of the Supplemental Digital Content (http://links.lww.com/ALN/C147). In brief, digital electrocardiogram signals of 10 s duration each were extracted at the following time points: 45, 30, and 15 min before and 5, 10, 15, 20, 30, 40, 65, 110, 120, 180, 240 and 360 min after start of remimazolam infusion. On-screen measurements of the RR, PR, QRS, and QT interval durations were performed, and the individually heart-rate–corrected QT interval (QTcI) was determined as primary endpoint of the electrocardiogram analysis. The net effect of remimazolam on QTcI was assessed as the control-corrected change from baseline at each time point (i.e., the change from baseline during the remimazolam visit minus the corresponding change from baseline during the control visit). The effect of remimazolam on the QTcI interval was considered significant if the upper bound of the two-sided 90% CI of the control-corrected change from baseline exceeded 10 ms.

Hemodynamic Monitoring

During the remimazolam visit, systolic arterial blood pressure, diastolic arterial blood pressure, and mean arterial blood pressure were continuously monitored via the arterial catheter. Heart rate was continuously monitored using the routine five-lead electrocardiogram. Oxygen saturation (Spo2) was continuously monitored by peripheral arterial pulse oximetry. Hemodynamics were monitored using a Draeger Infinity M540 machine (Dräger Medical GmbH, Germany). Values were recorded before remimazolam administration and approximately every 3 min thereafter until the last blood sample had been drawn. If Spo2 levels fell below 93%, oxygen was administered through a nasal cannula. Airway patency was checked and, if appropriate, the lower jaw was manually elevated. At Spo2 levels below 90%, assisted ventilation via a face mask was performed until Spo2 levels returned to values at or above 93%.

During the control visit, systolic arterial blood pressure, diastolic arterial blood pressure, mean arterial blood pressure, and HR were intermittently monitored approximately every 15 min from approximately 60 min before time point zero for approximately 390 min thereafter, using a blood pressure cuff on the upper arm and the five-lead electrocardiogram, respectively. The Spo2 was continuously monitored from approximately 60 min before time point zero for approximately 390 min thereafter, but no values were recorded unless a cardiovascular or respiratory adverse event occurred.

Routine Laboratory Assessments, Adverse Events

Routine laboratory assessments of hematologic, clinical chemistry, and coagulation parameters were performed at visit 1 and at the end of study visit 4. The number, nature, severity, duration, and outcome of adverse events were recorded from visit 1 until visit 4.

Simulations

Various simulations were performed to illustrate the pharmacokinetic and pharmacodynamic profile of remimazolam and its metabolite. The time to maximum concentration of CNS 7054 and the time to maximum remimazolam effect site concentration after a bolus dose of remimazolam were simulated using the individual pharmacokinetic and pharmacodynamic parameters. Using the typical parameters of the final pharmacokinetic and pharmacodynamic models of remimazolam, we determined the context-sensitive decrement times (i.e., the times for a defined decrease [25%, 50%, and 75%] of the plasma and of the effect site concentration after continuous target controlled infusion of variable length).14  To compare the pharmacokinetic profiles of remimazolam and midazolam, context-sensitive half-time was also simulated for midazolam, using the typical parameters from a previous study.15  The infusion rates for a target-controlled infusion with remimazolam, propofol, and remifentanil were simulated using the typical parameters from the final pharmacokinetic model of remimazolam and from previous studies on propofol16  and remifentanil,17  assuming a body weight of 75 kg, an age of 25 yr, and a lean body mass of 60 kg.

Statistics

Data are presented as median with range or as mean ± SD if not stated otherwise. To capture patterns in the data, smoother lines were added in the figures using locally weighted scatterplot smoothing. The evaluation and selection of pharmacokinetic–pharmacodynamic models was based on the objective function (OFV). Model selection was primarily based on the Bayes information criterion defined as BIC = OFV + Ln(Nobs) • Npar, where Nobs is the number of observations and Npar is the number of parameters to be estimated. The model with the lowest Bayes information criterion was selected as best model. The difference in the OFV between two models was further tested for significance by the chi-square test with the degree of freedom being equal to the difference in the number of model parameters. P < 0.05 was considered as statistical significant.

Twenty-five subjects were screened for this study. Three subjects who provided informed consent were not eligible because of abnormal laboratory values at screening. Two subjects were further excluded, one subject because of a vasovagal syncope during arterial cannulation and one subject because of a positive urine drug screening test on the treatment day. The remaining 20 subjects received remimazolam as scheduled and completed the study successfully. The demographic data are summarized in table 2.

Table 2.

Demographics of the Study Population

Demographics of the Study Population
Demographics of the Study Population

Pharmacokinetics of Remimazolam

All blood samples were drawn as scheduled. One remimazolam plasma concentration at 395 min after start of infusion was below the limit of quantification of 2 ng/ml. This sample was removed from the dataset for pharmacokinetic analysis. Thus, 519 concentration measurements were used for pharmacokinetic modeling of remimazolam. The individual time courses of the remimazolam plasma concentrations are shown in figure 2. The maximum remimazolam plasma concentration during infusion was 2,088 ± 196 ng/ml measured at 5 (3 to 20) min. The remimazolam plasma concentration at the end of infusion (t = 35 min) was 1,032 ± 148 ng/ml.

Fig. 2.

Measured plasma concentrations of remimazolam. The small inset plot shows the predicted plasma concentrations during the first hour. Each line represents the data of one subject.

Fig. 2.

Measured plasma concentrations of remimazolam. The small inset plot shows the predicted plasma concentrations during the first hour. Each line represents the data of one subject.

Close modal

A three-compartment model was identified as best structural model. Covariate analysis revealed only for the central volume of distribution V1 an influence of body weight (BW), whereas age did not show any effect on pharmacokinetics of remimazolam. The best fit was achieved when V1 was scaled proportional to weight: V1,i = V1,TV • (BW/75). Table 3 summarizes the parameter estimates of the final pharmacokinetic model. Remimazolam showed a high clearance of 1.15 ± 0.12 l/min with a small interindividual coefficient of variation of 11%, and small volumes of distribution (Vss = 35.4 ± 4.2 l). The rapid distribution, slow distribution, and elimination half-lives of remimazolam were 1.3 ± 0.3, 18.1 ± 2.5, and 70 ± 10 min, respectively. The simulations revealed short context-sensitive decrement times for remimazolam (fig. 3). After an infusion of 4 h, the context-sensitive halftime was 6.8 ± 2.4 min. More detailed results of the pharmacokinetic modeling of remimazolam are given in paragraph S3 of the Supplemental Digital Content (http://links.lww.com/ALN/C147).

Table 3.

Parameter Estimates for the Final Pharmacokinetic Model of Remimazolam

Parameter Estimates for the Final Pharmacokinetic Model of Remimazolam
Parameter Estimates for the Final Pharmacokinetic Model of Remimazolam
Fig. 3.

Time required for a 25%, 50%, and 75% decrease of remimazolam plasma concentration after continuous infusion of variable length (context-sensitive decrement times). Simulations were performed using the final pharmacokinetic model with the typical parameter estimates for a body weight of 75 kg.

Fig. 3.

Time required for a 25%, 50%, and 75% decrease of remimazolam plasma concentration after continuous infusion of variable length (context-sensitive decrement times). Simulations were performed using the final pharmacokinetic model with the typical parameter estimates for a body weight of 75 kg.

Close modal

Pharmacokinetics of CNS 7054

In each subject, the first plasma concentration of CNS 7054 (taken 1 min after start of infusion) was below the limit of quantification of 20 ng/ml. These samples were removed from the dataset for pharmacokinetic analysis. Thus, 500 concentration measurements were used for pharmacokinetic modeling of CNS 7054. The individual time courses of the CNS 7054 plasma concentrations are shown in figure 4. A maximum CNS 7054 plasma concentration of 5,340 ± 687 ng/ml was measured 52 ± 9 min after start of infusion. A combined three- and two-compartment model with a transit compartment was used for pharmacokinetic modeling of CNS 7054 (fig. 1). The pharmacokinetic parameters of the parent drug remimazolam were fixed to the individual estimates of the best pharmacokinetic model. During development of the pharmacokinetic model, it was found that the model was significantly improved if one assumed an additional lag-time for the formation of CNS 7054. Based on the covariate analysis, a proportional increase of V2M and Q2M with body weight was included in the final pharmacokinetic model of CNS 7054:

Fig. 4.

Measured plasma concentrations of the metabolite CNS 7054. Each gray line represents the data of one subject.

Fig. 4.

Measured plasma concentrations of the metabolite CNS 7054. Each gray line represents the data of one subject.

Close modal
formula
formula

Table 4 summarizes the parameter estimates of the final pharmacokinetic model. When compared with the parent drug, CNS 7054 showed a low clearance of 0.078 ± 0.017 L/min. The distribution and elimination half-lives of CNS 7054 were 1.8 ± 0.5 and 116 ± 22 min, respectively. The simulated time to the maximum concentration of CNS 7054 after a bolus dose of remimazolam was 33 ± 8 min. More detailed results of pharmacokinetic modeling of the metabolite are given in paragraph S4 of the Supplemental Digital Content (http://links.lww.com/ALN/C147).

Table 4.

Parameter Estimates for the Final Pharmacokinetic Model of CNS 7054

Parameter Estimates for the Final Pharmacokinetic Model of CNS 7054
Parameter Estimates for the Final Pharmacokinetic Model of CNS 7054

Pharmacodynamics: Sedation

The Modified Observer’s Assessment of Alertness and Sedation score was assessed in all volunteers as scheduled. One assessment could not be performed because of clinical circumstances. Thus, 604 Modified Observer’s Assessment of Alertness and Sedation score values were used for pharmacodynamic modeling. The time courses of the Modified Observer’s Assessment of Alertness and Sedation scores are shown in figure 5. There was a rapid decrease of the Modified Observer’s Assessment of Alertness and Sedation score from baseline (Modified Observer’s Assessment of Alertness and Sedation score = 5 in all subjects) to values less than 2 (i.e., loss of consciousness) within 5 ± 1 (range: 4 to 8) min after start of remimazolam infusion. During the remimazolam infusion, the Modified Observer’s Assessment of Alertness and Sedation score stayed between 0 and 2. All subjects lost the eyelid reflex within 6 (4 to 14) min after start of remimazolam infusion. Loss of corneal reflex occurred in 11 subjects within 12 (4 to 26) min after start of remimazolam infusion. The recovery after stop of remimazolam administration was fast. The subjects were orientated to person, location, and time 19 ± 6 (10 to 34) min after stop of infusion. Full alertness (Modified Observer’s Assessment of Alertness and Sedation score of 5) was regained 19 ± 7 (range: 7 to 33) min after stop of infusion. Eyelid and corneal reflex were regained 12 (1 to 29) min and 5 (−19 to 11) min after stop of remimazolam administration, respectively.

Fig. 5.

Observed Modified Observer’s Assessment of Alertness and Sedation (MOAA/S) scores. Each gray line represents the data of one subject. The blue line shows the median. The gray bars at the top indicate the remimazolam infusion.

Fig. 5.

Observed Modified Observer’s Assessment of Alertness and Sedation (MOAA/S) scores. Each gray line represents the data of one subject. The blue line shows the median. The gray bars at the top indicate the remimazolam infusion.

Close modal

Pharmacodynamic Modeling of Modified Observer’s Assessment of Alertness and Sedation Score

For modeling of the Modified Observer’s Assessment of Alertness and Sedation scores, a logistic regression model and a model with sigmoid probability functions were investigated. The model with sigmoid probability functions was selected as best basic pharmacodynamic model. Covariate analysis revealed no significant effects. The final pharmacodynamic model was therefore as following:

formula

where P(MOAA/S ≤ m) is the probability for a Modified Observer’s Assessment of Alertness and Sedation score ≤ m, CE is the effect site concentration, EC50,m is the effect site concentrations for a 50% probability of Modified Observer’s Assessment of Alertness and Sedation ≤ m, and γ defines the steepness of the probability functions. The EC50,m were parametrized in an incremental manner: EC50,4 = θ1, EC50,3 = EC50,4 + θ2, EC50,2 = EC50,3 + θ3, EC50,1 = EC50,2 + θ4, EC50,0 = EC50,1 + θ5, with θ2,3,4,5 ≥ 0. Table 5 summarizes the parameter estimates together with the results of the bootstrap analysis. The corresponding values of the EC50,i in the population are given in table 6. The equilibration half-time between central and effect compartment was 2.7 ± 0.6 min. The simulated time to maximum effect site concentration after a bolus dose of remimazolam was 2.9 ± 0.4 min. The individual and typical cumulative probabilities of the different Modified Observer’s Assessment of Alertness and Sedation scores are depicted in figure 6. The simulated probabilities to achieve exactly a particular Modified Observer’s Assessment of Alertness and Sedation score are shown in figure 7. After an infusion of 4 h, the context-sensitive halftime of the effect site concentration was 12 ± 2 min (fig. 8). More detailed results of pharmacodynamic modeling of Modified Observer’s Assessment of Alertness and Sedation score are given in paragraph S5 of the Supplemental Digital Content (http://links.lww.com/ALN/C147).

Table 5.

Parameter Estimates for the Final Pharmacodynamic Model of Modified Observer’s Assessment of Alertness and Sedation Score

Parameter Estimates for the Final Pharmacodynamic Model of Modified Observer’s Assessment of Alertness and Sedation Score
Parameter Estimates for the Final Pharmacodynamic Model of Modified Observer’s Assessment of Alertness and Sedation Score
Table 6.

Half-maximum Effect Site Concentrations of Remimazolam

Half-maximum Effect Site Concentrations of Remimazolam
Half-maximum Effect Site Concentrations of Remimazolam
Fig. 6.

Cumulative probabilities for the different Modified Observer’s Assessment of Alertness and Sedation (MOAA/S) scores, as predicted by the final pharmacodynamic model. The grey and blue lines show the predictions for the individual and typical parameter estimates, respectively. CE, effect site concentration of remimazolam.

Fig. 6.

Cumulative probabilities for the different Modified Observer’s Assessment of Alertness and Sedation (MOAA/S) scores, as predicted by the final pharmacodynamic model. The grey and blue lines show the predictions for the individual and typical parameter estimates, respectively. CE, effect site concentration of remimazolam.

Close modal
Fig. 7.

Probabilities to achieve exactly a particular Modified Observer’s Assessment of Alertness and Sedation (MOAA/S) score, as predicted by the final pharmacodynamic model with the typical parameter estimates. CE, effect site concentration of remimazolam.

Fig. 7.

Probabilities to achieve exactly a particular Modified Observer’s Assessment of Alertness and Sedation (MOAA/S) score, as predicted by the final pharmacodynamic model with the typical parameter estimates. CE, effect site concentration of remimazolam.

Close modal
Fig. 8.

Context-sensitive decrement times for the effect site concentration of Modified Observer’s Assessment of Alertness and Sedation (MOAA/S) score as predicted by the final and pharmacokinetic–pharmacodynamic model with the typical parameter estimates for a body weight of 75 kg.

Fig. 8.

Context-sensitive decrement times for the effect site concentration of Modified Observer’s Assessment of Alertness and Sedation (MOAA/S) score as predicted by the final and pharmacokinetic–pharmacodynamic model with the typical parameter estimates for a body weight of 75 kg.

Close modal

Pharmacodynamics: EEG

The EEG effects of remimazolam and the pharmacodynamic modeling are reported in Part II of this study.

Hemodynamics

Blood pressure decreased (fig. 9A) and heart rate increased (fig. 9B) during remimazolam infusion. The maximum decrease of mean arterial blood pressure compared with baseline was 24 ± 6% (range: 10 to 34%), and the maximum increase of HR was 28 ± 15% (range: 4 to 56%). The minimum value of systolic arterial blood pressure during remimazolam infusion was 96 ± 8 (range: 81 to 106) mmHg. The Spo2 decreased during the first 5 min of remimazolam infusion (fig. 9C). In total, 28 short episodes with Spo2 values less than 93% occurred in 15 subjects with a median duration of 0.3 (range: 0.1 to 1.1) min. In eight subjects, there were a total of nine short episodes of Spo2 values less than 90% with a median duration of 0.5 (range: 0.4 to 1.1) min. Decrease of Spo2 was successfully treated by oxygen administration via a nasal cannula with a median duration of 42 (range: 24 to 62) min, or by manual elevation of the lower jaw with a median duration of 26 (range: 0.7 to 43) min. The volunteers kept spontaneous breathing, with exception of two short episodes of mask ventilation in one subject lasting 4 and 5 s, respectively. The remimazolam plasma concentrations at these time points were about 1,800 ng/ml and the Modified Observer’s Assessment of Alertness and Sedation scores were 2 and 1, respectively.

Fig. 9.

Time courses of mean arterial blood pressure (A), heart rate (B), and arterial oxygen saturation (C). Each gray line represents the data of one subject, the blue lines show the mean values. The gray bars at the bottom indicate the remimazolam infusion.

Fig. 9.

Time courses of mean arterial blood pressure (A), heart rate (B), and arterial oxygen saturation (C). Each gray line represents the data of one subject, the blue lines show the mean values. The gray bars at the bottom indicate the remimazolam infusion.

Close modal

Electrocardiogram

The analysis of the 12-lead Holter electrocardiogram showed no clinically significant effect of remimazolam on the PR interval and on QRS duration. The largest control-corrected change of the QTcI interval from baseline was 3.7 ms (90% CI, −1.2 to 8.5 ms), which was observed 15 min after start of remimazolam infusion (fig. 10). The upper bound of the 90% CI of the control-corrected QTcI change from baseline never exceeded 10 ms, demonstrating no indication of any clinically significant effect of remimazolam on cardiac repolarization.

Fig. 10.

Time course of the control-corrected change from baseline of the QTcI interval. Data are shown as mean and 90% CI. The gray bars at the bottom indicate the remimazolam infusion.

Fig. 10.

Time course of the control-corrected change from baseline of the QTcI interval. Data are shown as mean and 90% CI. The gray bars at the bottom indicate the remimazolam infusion.

Close modal

Adverse Events

Besides the effects on blood pressure, heart rate, and oxygen saturation, the main adverse event was involuntary movements, which were observed in nine subjects. Psychomotor hyperactivity, cough, hiccup, sneezing, and apnea (lasting 0.9 min) were observed in one subject, respectively. All adverse events were classified as mild or moderate. No clinically significant changes or trends were found in any of the clinical laboratory parameters. Concerning vital signs, no clinically significant changes or trends were observed at the last visit compared with baseline.

The present study aimed to characterize the pharmacokinetics and pharmacodynamics of remimazolam after continuous infusion. A standard three-compartment model described the measured plasma concentrations of remimazolam appropriately. Wiltshire et al. reported that a three-compartment model was not appropriate, but that a recirculation model was needed.8  However, Wiltshire et al. administered remimazolam as bolus injection over 1 min and in this situation the assumption of instantaneous mixing, which is essential for mammillary compartment models, may be violated. In the present study, slower continuous infusions were used, so that the initial mixing may be less important. Because of the different model structures, the results of this study and the study by Wiltshire et al. cannot be directly compared. However, the estimates of elimination clearance (1.14 l/min in this study vs. 1.11 l/min in the Wiltshire study), steady-state volume (35 l vs. 37 l), and terminal half-life (70 min vs. 55 min) were very similar. There was no effect of age found in the present study, which is in accordance with the findings in the study by Wiltshire et al., who found no effect of age and body weight. With respect to body weight, a proportional scaling of the central compartment of distribution improved the model in the present study. The improvement, however, was relatively small, which means that this body weight effect was not completely evident. One has, however, to consider that the populations in both the present and the previous study were relatively homogenous, so that one cannot draw definite conclusions concerning covariate effects. A body weight effect is important only for the initial loading dose, whereas the maintenance infusion rate depends on clearance and would therefore be independent of weight in the studied range of 64 to 99 kg. Because we did not include women, we cannot rule out an influence of sex on remimazolam pharmacokinetics. However, Wiltshire et al. did not find any significant influence of sex on the pharmacokinetics of remimazolam.8  In addition, it has been reported that the abundance of hepatic carboxylesterases showed no effect of sex.18  Because remimazolam is metabolized by carboxylesterases, it is therefore unlikely that the elimination clearance of remimazolam will be different between men and women.

Showing a high clearance, small volumes, and short half-lives, remimazolam can be characterized as a well-controllable drug, particularly as the interindividual variability of clearance was also small. Concerning the administration of remimazolam as target-controlled infusion, one might argue that because of its pharmacokinetics, target-controlled infusion may not differ considerably from constant rate infusion. However, target-controlled infusion simulations showed that it would take nearly 1 h until the steady state is approximately achieved with remimazolam, whereas it takes only about 10 min for the ultra–short-acting opioid remifentanil (fig. 11). Therefore, use of target-controlled infusion might be beneficial for administration of remimazolam.

Fig. 11.

Simulated infusion rates for a target-controlled infusion with a constant target concentration of propofol, remimazolam and remifentanil, respectively. For remimazolam, the final pharmacokinetic model with the typical parameter estimates for a body weight of 75 kg was used. Pharmacokinetic models from previous studies were used for propofol16  and remifentanil,17  assuming a body weight of 75 kg, an age of 25 yr, and a lean body mass of 60 kg. The infusion rate is expressed as ratio of the actual infusion rate and the infusion rate at steady state, as this ratio is independent of the target concentration. The initial bolus dose is not shown.

Fig. 11.

Simulated infusion rates for a target-controlled infusion with a constant target concentration of propofol, remimazolam and remifentanil, respectively. For remimazolam, the final pharmacokinetic model with the typical parameter estimates for a body weight of 75 kg was used. Pharmacokinetic models from previous studies were used for propofol16  and remifentanil,17  assuming a body weight of 75 kg, an age of 25 yr, and a lean body mass of 60 kg. The infusion rate is expressed as ratio of the actual infusion rate and the infusion rate at steady state, as this ratio is independent of the target concentration. The initial bolus dose is not shown.

Close modal

The pharmacokinetics of the metabolite CNS 7054 was modeled by a standard mammillary model with two compartments and a transit compartment to account for the formation of the metabolite. In each subject, the CNS 7054 concentration 1 min after start of infusion was below the limit of quantification, and these data were removed from the analyses. It has been reported that removing below the limit of quantification samples can lead to a significant bias of the model if their proportion is higher than 10%.19  In the present study, however, these below the limit of quantification samples encompassed only about 4% of the total number of samples, and it affected the samples at one time point. Therefore, the impact was probably small. As the model for CNS 7054 was based on the model for remimazolam, the parameter estimates for CNS 7054 depend also on the parameter estimates for remimazolam and cannot be directly compared with the results of other studies. However, the average estimates of clearance (0.076 l/min) and time to maximum remimazolam effect site concentration after a bolus dose of remimazolam (33 min) were similar to those reported in the previous volunteer study (clearance: 0.070 l/min, time to maximum remimazolam effect site concentration after a bolus dose of remimazolam: 20 to 30 min, respectively),7  whereas the terminal half-life was shorter than in the previous study (116 min vs. 173 min).7 

The pharmacodynamic modeling of the Modified Observer’s Assessment of Alertness and Sedation scores was investigated with a logistic regression model and with a sigmoid model (Hill equation) for the cumulative probabilities. Although these two models are both characterized by concentration-effect curves with a sigmoid shape, the logistic regression model showed a worse quality of fit. This may be explained by the different behavior of the two models at baseline when no drug was present. In this case, the probability to achieve a Modified Observer’s Assessment of Alertness and Sedation score at or below 4 equals zero for the sigmoid model but not for the logistic regression model. However, because all subjects in this study were alert (Modified Observer’s Assessment of Alertness and Sedation score = 5) at baseline, the sigmoid model was more appropriate. Whereas the final pharmacodynamic model showed a quite good accordance of observed and predicted probability for Modified Observer’s Assessment of Alertness and Sedation at or below 1, 2, 3, or 4, the probability for Modified Observer’s Assessment of Alertness and Sedation score = 0 was less well predicted (fig. 11S in the Supplemental Digital Content, http://links.lww.com/ALN/C147). For effect site concentrations between 1,400 and 2,000 ng/ml, the observed probability of Modified Observer’s Assessment of Alertness and Sedation score = 0 was lower than predicted. However, when assessing the Modified Observer’s Assessment of Alertness and Sedation score, the discrimination between Modified Observer’s Assessment of Alertness and Sedation scores of 0 and 1 was difficult as the volunteers showed some delayed repeated movements with the arm or leg after the trapezius squeeze, and it was not completely clear whether this was a response on the stimulus (i.e., Modified Observer’s Assessment of Alertness and Sedation score = 1) or some involuntary movement (i.e., Modified Observer’s Assessment of Alertness and Sedation score = 0). Therefore, some Modified Observer’s Assessment of Alertness and Sedation assessments with a score value of 1 might have correctly been rated as 0. Correspondingly, the EC50 for a Modified Observer’s Assessment of Alertness and Sedation score of 0 might be overestimated.

There was large overlap of the EC50 values for Modified Observer’s Assessment of Alertness and Sedation scores of 2, 3, and 4 (table 6). Correspondingly, the model revealed only a small probability to achieve a Modified Observer’s Assessment of Alertness and Sedation score of exactly 2 or 3 (fig. 7). For clinical practice this would imply that it might be hard to titrate a patient to moderate sedation. However, one has to consider that the observed overlap might be explained by the infusion scheme of the present study which led to a fast transition from a Modified Observer’s Assessment of Alertness and Sedation score of 5 to 0 or 1, so that the intermediate levels were observed quite seldom.

The equilibration between plasma and effect site concentration was relatively fast with a time to peak of about 3 min. Correspondingly, the context-sensitive half-time for the effect site concentration was also short (fig. 8), particularly when compared with midazolam, which showed a much longer context-sensitive half-time (122 min vs. 12 min after an infusion of 8 h, fig.12). When compared with the results of the previous phase I study,8  the ke0 of remimazolam was very similar (0.27 min−1 in the current vs. 0.25 min−1 in the previous study), whereas the EC50 of remimazolam tended to be lower in the previous study (938 ng/ml, 551 ng/ml, 412 ng/ml, 321 ng/ml, and 216 ng/ml for Modified Observer’s Assessment of Alertness and Sedation score = 0, ≤1, ≤2, ≤3, and ≤4, respectively). This may be explained by the use of different models and by a different time resolution of the Modified Observer’s Assessment of Alertness and Sedation assessments. The higher EC50 for Modified Observer’s Assessment of Alertness and Sedation score = 0 in the present study is probably due to some uncertainty in the assessment described above. Generally, the pharmacodynamic model for Modified Observer’s Assessment of Alertness and Sedation score allows to define target concentrations for specific levels of sedation which can then be realized by target-controlled infusion using the present pharmacokinetic model. However, one has to consider the relatively large interindividual variability for the deeper levels of sedation (fig. 6).

Fig. 12.

Context-sensitive half times of the effect site concentration of remimazolam and midazolam. The context-sensitive half time of remimazolam was simulated using the final pharmacokinetic–pharmacodynamic model of this study. The context-sensitive half time of midazolam was simulated using the results of a previous study on midazolam.15 

Fig. 12.

Context-sensitive half times of the effect site concentration of remimazolam and midazolam. The context-sensitive half time of remimazolam was simulated using the final pharmacokinetic–pharmacodynamic model of this study. The context-sensitive half time of midazolam was simulated using the results of a previous study on midazolam.15 

Close modal

The effects of remimazolam on hemodynamics were moderate. Heart rate increased by about 20 bpm, mean arterial blood pressure decreased by about 20 mmHg, and the systolic arterial blood pressure never fell less than 80 mmHg. Therefore, these effects might be considered as clinically minor relevant. In previous studies with single doses of remimazolam, there were similar increases of heart rate but no changes of blood pressure reported.2,7  This may be explained by the short administration of remimazolam in these studies compared with the longer lasting continuous infusion in the present study. The subjects maintained spontaneous breathing, and the decrease of Spo2 during remimazolam infusion could be easily treated by chin lift and oxygen supply via a nasal cannula. This means for clinical use of remimazolam that in case of rapidly increasing concentrations during induction with high doses, temporary respiratory depression and oxygen desaturation may occur in patients breathing room air. On the other hand, even for the relatively high concentrations in the present study, only one subject stopped breathing for a very short time.

Because the QT interval of the electrocardiogram is considered a relevant endpoint in drug development,20  this trial was also designed to evaluate the effect of remimazolam on cardiac repolarization. The infusion scheme of the present study achieved approximately steady-state plasma concentrations (fig. 2), avoiding rapid HR changes and thus minimizing the confounding influence of QT-RR hysteresis.21  The use of QTcI further eliminated the effect of increasing HR throughout the remimazolam infusion. The upper bound of the 90% CI of the control-corrected QTcI change from baseline never approached or exceeded 10 ms. Thus, there was no signal of any clinically significant effect of remimazolam on cardiac repolarization at an exposure that is anticipated to be used in or exceeds that in procedural sedation and anesthesia.

Other treatment-related adverse events were generally moderate with respect to incidence and severity. The main adverse events were involuntary movements, whereas we did not observe headache and somnolence which were reported in the previous phase I study.7 

There are several limitations of the present study. First, one has to consider that the study population was small and relatively homogenous, because this was a phase I study which aimed for a first characterization of remimazolam pharmacokinetics and pharmacodynamics after infusion. Therefore, we cannot draw definite conclusions concerning the effect of weight, age, and sex on remimazolam pharmacokinetics and pharmacodynamics in obese, children, and elderly subjects. The present pharmacokinetic model is, however, at least a first step toward target-controlled infusion with remimazolam in non-obese young subjects, particularly because there did not exist any compartment model of remimazolam for target-controlled infusion yet. Future studies may provide data to refine the pharmacokinetic and pharmacodynamic model of remimazolam for use in broader populations.

Second, the applied infusion scheme caused a relatively fast increase of the plasma concentration within the first 5 min after start of infusion. Correspondingly, the Modified Observer’s Assessment of Alertness and Sedation score dropped relatively fast to values less than 2. Similarly, there was a fast increase of the Modified Observer’s Assessment of Alertness and Sedation scores after stop of remimazolam infusion. As the Modified Observer’s Assessment of Alertness and Sedation score was assessed every 2 min, Modified Observer’s Assessment of Alertness and Sedation scores of 2 and 3 were observed relatively seldom, thereby limiting the results of the pharmacodynamic modeling. A further problem with the Modified Observer’s Assessment of Alertness and Sedation score assessment was the correct discrimination between a score of 0 and 1 in the presence of involuntary movements.

In conclusion, remimazolam showed a high clearance, small volumes of distribution, short half-lives, and a fast onset and recovery of sedation. It is therefore a drug with good controllability. The pharmacokinetics of remimazolam after longer-lasting continuous infusion was similar to that reported after bolus administration. The hemodynamic effects were moderate, and there was no clinically significant effect of remimazolam on cardiac repolarization.

Acknowledgments

The authors thank Robert B. Kleiman, M.D., (ERT Inc., Philadelphia, Pennsylvania) for performing the electrocardiogram analysis, and Aptuit Srl (Verona, Italy) for performing the remimazolam assay. The authors further thank Rainer Knoll, Dipl. Bioingenieur (Department of Anesthesiology, University of Erlangen-Nürnberg, Erlangen, Germany) for processing of the blood samples, and Gabriele Göhring-Waldeck, Laboratory Technician (Department of Anesthesiology, University of Erlangen-Nürnberg, Erlangen, Germany) for help in study organization.

Research Support

Supported by a grant from PAION UK Ltd., Cambridge, United Kingdom.

Competing Interests

Drs. Schüttler and Fechner are scientific advisors of PAION UK Ltd., Cambridge, United Kingdom. The remaining authors declare no competing interests.

1.
Worthington
MT
,
Antonik
LJ
,
Goldwater
DR
,
Lees
JP
,
Wilhelm-Ogunbiyi
K
,
Borkett
KM
,
Mitchell
MC
:
A phase Ib, dose-finding study of multiple doses of remimazolam (CNS 7056) in volunteers undergoing colonoscopy.
Anesth Analg
2013
;
117
:
1093
100
2.
Borkett
KM
,
Riff
DS
,
Schwartz
HI
,
Winkle
PJ
,
Pambianco
DJ
,
Lees
JP
,
Wilhelm-Ogunbiyi
K
:
A Phase IIa, randomized, double-blind study of remimazolam (CNS 7056) versus midazolam for sedation in upper gastrointestinal endoscopy.
Anesth Analg
2015
;
120
:
771
80
3.
Pambianco
DJ
,
Borkett
KM
,
Riff
DS
,
Winkle
PJ
,
Schwartz
HI
,
Melson
TI
,
Wilhelm-Ogunbiyi
K
:
A phase IIb study comparing the safety and efficacy of remimazolam and midazolam in patients undergoing colonoscopy.
Gastrointest Endosc
2016
;
83
:
984
92
4.
Wesolowski
AM
,
Zaccagnino
MP
,
Malapero
RJ
,
Kaye
AD
,
Urman
RD
:
Remimazolam: Pharmacologic considerations and clinical role in anesthesiology.
Pharmacotherapy
2016
;
36
:
1021
7
5.
Rex
DK
,
Bhandari
R
,
Desta
T
,
DeMicco
MP
,
Schaeffer
C
,
Etzkorn
K
,
Barish
CF
,
Pruitt
R
,
Cash
BD
,
Quirk
D
,
Tiongco
F
,
Sullivan
S
,
Bernstein
D
:
A phase III study evaluating the efficacy and safety of remimazolam (CNS 7056) compared with placebo and midazolam in patients undergoing colonoscopy.
Gastrointest Endosc
2018
;
88
:
427
437.e6
6.
Kilpatrick
GJ
,
McIntyre
MS
,
Cox
RF
,
Stafford
JA
,
Pacofsky
GJ
,
Lovell
GG
,
Wiard
RP
,
Feldman
PL
,
Collins
H
,
Waszczak
BL
,
Tilbrook
GS
:
CNS 7056: A novel ultra-short-acting benzodiazepine.
Anesthesiology
2007
;
107
:
60
6
7.
Antonik
LJ
,
Goldwater
DR
,
Kilpatrick
GJ
,
Tilbrook
GS
,
Borkett
KM
:
A placebo- and midazolam-controlled phase I single ascending-dose study evaluating the safety, pharmacokinetics, and pharmacodynamics of remimazolam (CNS 7056): Part I. Safety, efficacy, and basic pharmacokinetics.
Anesth Analg
2012
;
115
:
274
83
8.
Wiltshire
HR
,
Kilpatrick
GJ
,
Tilbrook
GS
,
Borkett
KM
:
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.
Anesth Analg
2012
;
115
:
284
96
9.
Schnider
TW
,
Minto
CF
,
Gambus
PL
,
Andresen
C
,
Goodale
DB
,
Shafer
SL
,
Youngs
EJ
:
The influence of method of administration and covariates on the pharmacokinetics of propofol in adult volunteers.
Anesthesiology
1998
;
88
:
1170
82
10.
Chiou
WL
:
The phenomenon and rationale of marked dependence of drug concentration on blood sampling site. Implications in pharmacokinetics, pharmacodynamics, toxicology and therapeutics (Part I).
Clin Pharmacokinet
1989
;
17
:
175
99
11.
Ibrahim
AE
,
Taraday
JK
,
Kharasch
ED
:
Bispectral index monitoring during sedation with sevoflurane, midazolam, and propofol.
Anesthesiology
2001
;
95
:
1151
9
12.
Chernik
DA
,
Gillings
D
,
Laine
H
,
Hendler
J
,
Silver
JM
,
Davidson
AB
,
Schwam
EM
,
Siegel
JL
:
Validity and reliability of the Observer’s Assessment of Alertness/Sedation Scale: Study with intravenous midazolam.
J Clin Psychopharmacol
1990
;
10
:
244
51
13.
International Conference on Harmonisation: The clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs. Guideline E14
May 12, 2005
14.
Hughes
MA
,
Glass
PS
,
Jacobs
JR
:
Context-sensitive half-time in multicompartment pharmacokinetic models for intravenous anesthetic drugs.
Anesthesiology
1992
;
76
:
334
41
15.
Albrecht
S
,
Ihmsen
H
,
Hering
W
,
Geisslinger
G
,
Dingemanse
J
,
Schwilden
H
,
Schüttler
J
:
The effect of age on the pharmacokinetics and pharmacodynamics of midazolam.
Clin Pharmacol Ther
1999
;
65
:
630
9
16.
Marsh
B
,
White
M
,
Morton
N
,
Kenny
GN
:
Pharmacokinetic model driven infusion of propofol in children.
Br J Anaesth
1991
;
67
:
41
8
17.
Minto
CF
,
Schnider
TW
,
Egan
TD
,
Youngs
E
,
Lemmens
HJ
,
Gambus
PL
,
Billard
V
,
Hoke
JF
,
Moore
KH
,
Hermann
DJ
,
Muir
KT
,
Mandema
JW
,
Shafer
SL
:
Influence of age and gender on the pharmacokinetics and pharmacodynamics of remifentanil. I. Model development.
Anesthesiology
1997
;
86
:
10
23
18.
Boberg
M
,
Vrana
M
,
Mehrotra
A
,
Pearce
RE
,
Gaedigk
A
,
Bhatt
DK
,
Leeder
JS
,
Prasad
B
:
Age-dependent absolute abundance of hepatic carboxylesterases (CES1 and CES2) by LC-MS/MS proteomics: Application to PBPK modeling of oseltamivir in vivo pharmacokinetics in infants.
Drug Metab Dispos
2017
;
45
:
216
23
19.
Ahn
JE
,
Karlsson
MO
,
Dunne
A
,
Ludden
TM
:
Likelihood based approaches to handling data below the quantification limit using NONMEM VI.
J Pharmacokinet Pharmacodyn
2008
;
35
:
401
21
20.
Shah
RR
:
The significance of QT interval in drug development.
Br J Clin Pharmacol
2002
;
54
:
188
202
21.
Malik
M
,
Hnatkova
K
,
Novotny
T
,
Schmidt
G
:
Subject-specific profiles of QT/RR hysteresis.
Am J Physiol Heart Circ Physiol
2008
;
295
:
H2356
63