Midazolam was apparently more potent than remimazolam with estimated population mean IC50 values of 0.07 and 0.08 μg/mL (BIS and MOAA/S models, respectively) compared with 0.26 and 0.42 μg/mL (Tables 2 and 3). However, the pharmacodynamic response was significantly slower as shown by the smaller midazolam ke0 values (0.053 and 0.050 min−1 for BIS and MOAA/S, respectively) compared with 0.14 and 0.25 min−1 for remimazolam (Tables 2 and 3). Very high population mean values of the Hill coefficient were apparent for midazolam, particularly for the BIS model (8.6, Table 2), but those for remimazolam were unremarkable (1.6, 1.4 for the BIS and MOAA/S models, respectively; Tables 2 and 3). The maximal effect of remimazolam was apparently larger than that of midazolam (BIS population mean IMAX = 39.3 compared with 19.4 and MOAA/S logit = 21.9 compared with 9.5; Tables 2 and 3).
Simulations of the arterial and venous plasma concentrations of remimazolam after administration to subject #507 (Fig. 9) show how the recirculation model initially gives increasing arterial levels with a peak being reached approximately 10 seconds after the end of the infusion and that the venous concentrations exceed the arterial ones at approximately 5 minutes. The concentrations in the 2 compartments gradually become closer, but the venous levels are always higher (Fig. 9).
Context-sensitive half-times were simulated for both remimazolam (50 mg/h) and midazolam (0.075 mg/kg/h) using the population mean pharmacokinetic parameters (Table 1), after infusions of various lengths between 1 minute and 8 hours (Fig. 10). Because a mammillary model had been fitted to the midazolam plasma levels, there was no difference between the simulated arterial and venous concentrations. The context-sensitive half-times of midazolam increased with the duration of the infusion reaching a value of 60 minutes after an 8-hour infusion, in agreement with a literature figure of approximately 70 minutes.6 The recirculation model for remimazolam differentiated between arterial and venous plasma levels and the more relevant, as far as sedation is concerned, arterial context-sensitive half-times were simulated. The results were much shorter than those of midazolam and reached a steady-state value of between 7 and 8 minutes after an approximately 2-hour infusion (Fig. 10).
Context-sensitive half-times for the BIS scores were taken as the time for the score to increase from its minimum value to the average of the minimum and the baseline. Again, the simulated value for midazolam was long, at least 6 hours, after an 8-hour infusion (Fig. 11). In comparison, the maximal half-time for remimazolam was <1 hour and this figure was constant with infusions longer than 3 hours (Fig. 11). Because the MOAA/S data were categorical, a true context-sensitive half-time could not be estimated. However, the times for the score to increase from 4 to 5 after various lengths of infusion were considered useful parameters; a maximal value of 15 to 16 minutes was obtained with remimazolam infusions longer than 3 hours (Fig. 11). The 0.075 mg/kg/h dosing regimen for midazolam required more than an hour for any reduction in MOAA/S score. After 6- to 8-hour infusions, the time for the MOAA/S score to increase from 4 to 5 was 45 to 50 minutes.
Monte-Carlo simulations (1000) of a range of possible initial loading dose/maintenance dose regimens were undertaken as a guide for future studies. The distribution of the pharmacokinetic parameters was assumed to be the same as that found for recirculation model Rem-R13 and the pharmacodynamic parameters were obtained from MOAA/S model Rem-R13-MOA02. Some descriptive statistics of the variable pharmacokinetic and pharmacodynamic parameters from the Monte-Carlo simulations are shown in Table 6. The geometric means of these parameters are approximately equivalent to the population means estimated from the modeling (Tables 1, 3, and 6).
The optimal regimen, in terms of minimizing the numbers of dropouts, failures, and subjects with MOAA/S scores of zero, seemed to be a 6-mg initial loading dose followed by 3-mg maintenance doses. This delivered sedation with MOAA/S scores between 2 and 4 to at least 70% of the subjects from 2 minutes after the end of the loading dose until the end of the 18-minute procedure (Fig. 12). Estimates of percentage of subjects suitably sedated ranged from 70.5%, 3 minutes after the start of the infusion (95% confidence intervals: 67%–74%), to >90% (95% confidence intervals: 92%–94%) between 4 and 8 minutes later. Sedation was rapid (Fig. 12) with all subjects predicted to attain their minimum MOAA/S score after a single dose within 2 minutes of the end of the infusion. Taking account of those simulated subjects who would need a second dose of remimazolam at the 2-minute time point before being sufficiently sedated for initiation of the procedure, and omitting the dropouts, minimum MOAA/S scores are predicted to be attained by the end of the “top-up” infusion in 85% of subjects (95% confidence intervals: 81%–89%). The 30% of the putative subjects whose simulated sedation was not optimal included dropouts (8.6% and 7.3% with 60- and 15-second maintenance doses, respectively) whose MOAA/S score did not reach 3 after 2 doses. The pharmacodynamic parameters of these subjects included either a large IC50 or a small IMAX, i.e., the IMAX/IC50 ratio for these subjects was small, the geometric mean equaling 22.3 compared with 50.2 for the whole population (Table 6). There were also failures (11.5% and 15.2% with 60- and 15-second maintenance doses, respectively) whose MOAA/S score increased to 5 before the end of the procedure despite receiving 4 maintenance doses; in these cases, the IMAX/IC50 ratio was also small (geometric mean = 33.6), but larger than those of the dropouts. A few of the subjects (6.5%, 7.0% with 60- and 15-second maintenance doses, respectively) attained zero MOAA/S scores, i.e., loss of consciousness, usually 1 minute after the end of the initial loading dose; these subjects had higher than average IMAX/IC50 ratios (geometric mean = 114.9). Simulated recovery from sedation was generally rapid (Fig. 12) with 89% (95% confidence intervals: 87%–91%) of the successfully treated subjects (i.e., excluding dropouts and failures) having attained MOAA/S scores of 5 within 16 minutes of the end of the procedure. The pharmacodynamics of the subjects who recovered more slowly were characterized by a small value of the Hill coefficient (γ); the geometric mean for the 42 subjects with scores of <5 at the 40-minute time point (i.e., 22 minutes after the end of the procedure) equaled 0.56 compared with 1.42 for the whole population (Table 6).
Two population pharmacokinetic models were applied to the plasma levels of remimazolam and midazolam using the ADVAN6 subprogram of NONMEM: a conventional mammillary model with 3 or 4 compartments, and a more physiologically based recirculation model (Fig. 2).7 The assumption implicit in the simple compartmental models that the drug is instantaneously distributed throughout the central compartment is only valid with compounds whose distribution and clearance kinetics are relatively slow compared with blood flow. This was clearly not the case for remimazolam with its venous/arterial ratios being significantly >1 (Fig. 1). The physiologically based recirculation pharmacokinetic models overcome this deficiency by including both venous and arterial compartments as well as a compartment, consisting of cardiac blood and the lung, for the dose (e.g., online Appendix 1 [see Supplemental Digital Content 1, http://links.lww.com/AA/A339]). These models correctly fitted the observation that venous concentrations of remimazolam were significantly higher than arterial ones taken at the same time points between 2 and 4 hours after dosing and also indicated that the arterial levels will be higher up to approximately 5 minutes postdose (Fig. 9). This prediction has yet to be examined and it is probable that better models would have been found if both arterial and venous samples had been available within the first 15 minutes of the study. However, because of study logistics with a large number of procedures being repeatedly performed within a short time frame, venous samples were not started until the 2-hour time point. The mismatch between the venous and arterial plasma levels of remimazolam, which led to the recirculation model being investigated, was not anticipated, and it was assumed that early arterial concentrations would be sufficient to define the pharmacokinetics of both remimazolam and midazolam.
Although the recirculation model with clearance from the peripheral compartment displayed the lowest objective function, the absence of any venous data at early time points means that any conclusions about the site of the hydrolysis of remimazolam to CNS 7054 must be considered tentative. The degree of partitioning of remimazolam between red blood cells and plasma has not been determined, and “cardiac output” in the recirculation models (approximately 3.7 L/min) lies between the typical values of blood and plasma of approximately 5 and 2.5 L/min, respectively. The volumes of both arterial blood and the lungs/heart were initially assumed to be proportional to body weight to minimize any identifiability problems. However, it was found that allowing the arterial volume to be independent of body weight gave a significantly improved fit (models Rem-R07, Rem-R12, Rem-R13, online Appendix 2, see Supplemental Digital Content 2, http://links.lww.com/AA/A340) with physiologically reasonable pharmacokinetic parameters (Table 1: arterial volume approximately 1 L, BSV = 58%). On the other hand, if both the arterial and cardiac/pulmonary volumes were unfixed, physiologically unreasonable parameters resulted (online Appendix 2, see Supplemental Digital Content 2, http://links.lww.com/AA/A340) and fixing the volume of the lung to 1 L/70 kg was considered to be the best approach.
Whereas the quality of the recirculation models depended on the 2-, 3-, and 4-hour arterial concentrations being consistently smaller than the corresponding venous concentrations, the mammillary models required that they be similar. The relatively small, although statistically significant, difference between these midazolam plasma levels meant that the recirculation models did not minimize easily and the mammillary models (e.g., online Appendix 1 [see Supplemental Digital Content 1, http://links.lww.com/AA/A339]) were superior. The pharmacokinetic parameters obtained for midazolam were within literature ranges (elimination clearance: 0.30 ± 0.06 L/h/kg [0.25–0.54 L/h/kg5]; terminal half-life: 3.7 ± 0.3 hours [1.8–6.0 hours5]; volume of distribution: 1.59 ± 0.24 L/kg [1.0–3.1 L/kg5]).
The recirculation models were, however, much more appropriate for remimazolam with its greater elimination clearance. Thus, the difference in objective function between the same recirculation and mammillary models for remimazolam (Rem-R07/Rem-C03) and midazolam (Mdz-R07/Mdz-C03) were −326.4 and +156.0, respectively (Table 4). With its elimination clearance being 3 times that of midazolam (population means: 66.7 and 22.6 L/h) and its steady-state volume of distribution significantly less (population means: 89.0 and 121 L), both the terminal half-life and mean residence times of remimazolam were only 20% to 25% of those of its comparator (Table 1), indicating that it is likely to be a superior drug in terms of rapid recovery from sedation.
Other than a clear relationship between gender/body weight and cardiac output, no covariate effects were observed for the pharmacokinetic parameters of remimazolam. In particular, there was no significant relationship between body weight and elimination clearance (Fig. 3), which indicates that there will be no advantage in dosing healthy subjects by weight, rather than as a fixed dose, in terms of consistency of exposure to remimazolam within the weight range studied (65–90 kg).
No attempts were made to model the pharmacokinetics and pharmacodynamics simultaneously because the quality of the kinetic data was so much more reliable, and a 2-stage approach was used. The pharmacokinetic parameters for each subject were first estimated, using a mammillary compartmental model for midazolam and a recirculation model for remimazolam, and then used to simulate arterial concentration profiles for the pharmacodynamic modeling. Sigmoid inhibitory effect pharmacodynamic models were successfully fitted to the BIS and MOAA/S data resulting from treatment with remimazolam and midazolam. The BIS data are continuous and the models never exactly fitted the extreme values (i.e., E0 and E0 − IMAX). The MOAA/S scores, however, were categorical and the extreme values were often achieved by the models, particularly scores of 5 (full alertness). The effect of this is that the MOAA/S graphs appear much steeper (Figs. 6 and 7) even though the population pharmacodynamic parameters, ke0, IC50, and Hill coefficient, were broadly comparable (Tables 2 and 3).
Midazolam was apparently more potent than remimazolam with an IC50 of 0.07 (BIS), 0.08 (MOAA/S) μg/mL compared with 0.26 (BIS), 0.42 (MOAA/S) μg/mL for remimazolam (Tables 2 and 3). However, the Hill equation (see sigmoid inhibitory effect equation in Methods) assumes that the whole concentration/effect range is covered by the data. This can be assumed to be true for remimazolam, because complete anesthesia (MOAA/S scores of zero) was induced in 14 of 30 subjects given the higher doses (0.1–0.3 mg/kg) but not for midazolam, which was administered as a single 0.075 mg/kg dose (1 of 18 subjects with MOAA/S scores <1). As a result, the maximal effect (IMAX) appeared to be approximately 2-fold greater for remimazolam; higher midazolam doses would have defined its pharmacodynamic parameters better, increasing IMAX and probably changing IC50 significantly. There was a marked difference in the values of ke0, the rate constant for equilibration of the drug between plasma and the effect site; the population mean values for midazolam were approximately 0.05 min−1 compared with 0.14 min−1 (BIS) and 0.25 min−1 (MOAA/S) for remimazolam. The larger figure for remimazolam combined with its shorter pharmacokinetic half-life suggests that recovery from sedation will be considerably more rapid.
A limited covariate analysis of the pharmacodynamic parameters suggested that sex might be a predictor of sensitivity to remimazolam for both the BIS and MOAA/S models (Table 5) with males having approximately 40% smaller values of IC50 than females. It cannot be concluded from these fairly limited data that sex is a genuine predictor of sensitivity to remimazolam, but the possibility should be borne in mind in future studies.
The simulated population mean context-sensitive half-times also enable some comparisons to be made between remimazolam and midazolam. The relatively short pharmacokinetic half-time for remimazolam of 7 to 8 minutes compared with approximately 60 minutes for midazolam (Fig. 10) indicates that recovery from sedation or anesthesia will be much more rapid. In addition, the context-sensitive half-time of remimazolam appears to be relatively insensitive to the duration of the infusion, reaching its maximum after a 2-hour infusion compared with at least 8 hours for midazolam. A similar picture is provided by analogous simulations of the BIS and MOAA/S data (Fig. 11).
Preliminary Monte-Carlo simulations examined all 25 possible combinations of 5 initial loading doses (5–9 mg) followed by 5 smaller maintenance doses (2.5–4.5 mg) using ModelMaker, simulation software that could be programmed to recognize when a maintenance dose was needed and introduce it during an individual run. Additional Monte-Carlo simulations were then performed with NONMEM, using the combination that appeared to deliver the most consistent sedation of 2 to 4 on the MOAA/S scale. Single 1-minute, 6-mg infusions, followed by a 3-mg dose 2 minutes later if necessary, are predicted to lead to rapid sedation within 3 minutes of the start of treatment in >80% (95% confidence intervals: 81%–89%) of subjects but with loss of consciousness (MOAA/S = 0) in a small minority (approximately 7%, Fig. 12). The simulations also indicated that lower doses (e.g., 3 mg given over 15 or 60 seconds) at intervals no shorter than 2 minutes are adequate to maintain sedation in most subjects. The rapid onset of the effects of remimazolam means that maintenance doses will be able to be given more accurately than those of slower-acting drugs such as midazolam. The simulations highlighted subjects, characterized by a low IMAX/IC50 ratio, who would be relatively insensitive to the effects of remimazolam. These included dropouts (approximately 8%) whose minimum MOAA/S score was >2 and failures (11%–15%) whose sedation was not controlled for the total length of the procedure with only four 3-mg maintenance doses. Because the choice of procedural length and number of maintenance doses was somewhat arbitrary, the latter category could be managed by increasing the number of allowable maintenance doses. The problem of the dropouts could probably also be overcome by permitting the first maintenance dose to equal the 6-mg initial loading dose if the MOAA/S score were still >3 at the 2-minute time point. Recovery from sedation resulting from treatment with remimazolam appears to be rapid, with almost 90% (95% confidence intervals: 87%–91%) of the successfully treated subjects predicted to be fully alert with MOAA/S scores of 5 within 16 minutes of the end of the procedure (Fig. 12).
Population pharmacokinetic and pharmacodynamic models developed for remimazolam and midazolam fitted the observed data well. Simulations based on these models show that remimazolam delivers extremely rapid sedation, with its maximal effect being reached within 3 minutes of the start of treatment. This property will enable maintenance doses to be given more accurately than slower-acting drugs. No covariate effects considered to be clinically relevant were observed, suggesting that dosing by body weight may offer no advantage over fixed doses in terms of consistency of exposure to remimazolam within the weight range studied (65–90 kg).
Name: Hugh R. Wiltshire, PhD.
Contribution: This author performed the modeling and helped to prepare the manuscript.
Attestation: Hugh R. Wiltshire has approved the final manuscript.
Conflicts of Interest: Hugh R. Wiltshire has consulted for PAION UK Ltd.
Name: Gavin J. Kilpatrick, PhD.
Contribution: This author helped design the study.
Attestation: Gavin J. Kilpatrick has approved the final manuscript.
Conflicts of Interest: Gavin J. Kilpatrick was an employee and director of PAION at the time of conduct of the study. Dr. Kilpatrick owns shares and share options in PAION.
Name: Gary S. Tilbrook, PhD.
Contribution: This author helped analyze the data.
Attestation: Gary S. Tilbrook has approved the final manuscript.
Conflicts of Interest: Gary S. Tilbrook was an employee of PAION at the time of conduct of the study.
Name: Keith M. Borkett, BSc.
Contribution: This author helped design the study and prepare the manuscript.
Attestation: Keith M. Borkett has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.
Conflicts of Interest: Keith M. Borkett was an employee of PAION at the time of conduct of the study.
This manuscript was handled by: Tony Gin, MD, FRCA, FANZCA.
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APPENDIX: SUPPLEMENTAL FIGURE LEGENDS Supplemental Figure 1.
Plots of predicted and individual predicted against observed concentrations for remimazolam after IV administration to healthy volunteers at various doses (recirculation model Rem-R13). DV = dependent variable (i.e, concentration).
Supplemental Figure 2.
Plots of individual-weighted residuals (IWRES) against time for remimazolam after IV administration to healthy volunteers at various doses (recirculation model Rem-R13).
Supplemental Figure 3.
Plots of individual-weighted residuals (IWRES) (Bispectral Index data) against time for remimazolam after IV administration to healthy volunteers at various doses (model Rem-R13-BIS01).
Supplemental Figure 4.
Plots of predicted and individual-predicted against observed Bispectral Index (BIS) scores after IV administration of remimazolam to healthy volunteers at various doses (model Rem-R13-BIS01).
Supplemental Figure 5.
Plot showing the correspondence between observed and predicted Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scores after a 1-minute, 0.075 mg/kg IV infusion of midazolam (model Mdz-C51-MOA02).
Supplemental Digital Content
© 2012 International Anesthesia Research Society