Pharmacokinetics and Pharmacodynamics of Remimazolam for Procedural Sedation in Children and Adolescents

Abstract

Background: Remimazolam is not approved for use in pediatric patients. The pharmacokinetics of remimazolam have been reported to be similar to those of adult patients after scaling for body size. This article reports on the pharmacokinetics and pharmacodynamics of pediatric patients aged 6 to 18 yr and a subsequent model-based optimization of the used dosing regimen.

Methods: Thirty-one patients were included in the trial and stratified across four treatment arms: bolus administration, infusion, bolus plus fentanyl, or infusion plus fentanyl. The University of Michigan (Ann Arbor, Michigan) Sedation Scale (UMSS) was used to assess the depth of sedation. Blood samples were drawn to measure the concentrations of remimazolam and its metabolite CNS7054. Population pharmacokinetic pharmacodynamic modeling was performed in NONMEM (GloboMax LLC, USA).

Results: A population pharmacokinetic model was developed for remimazolam and CNS7054. The elimination clearance of remimazolam was 0.70 l · min -1 · 70 kg -1 . A proportional odds model combined with a simplified Minto model described the observed UMSS well. The EC50 of remimazolam for a UMSS score of 3 or greater was 777 ng · ml -1 in the absence of fentanyl, and decreased to 655, 533, and 287 ng/ml for concomitant fentanyl steady state concentrations of 1, 2, or 4 ng · ml -1 , respectively. Simulations confirmed that the studied dosing regimen resulted in 9.2 to 22.0% of patients not reaching a UMSS score of 3 or greater at the end of the induction. Model-based optimization resulted in higher per-kilogram dosages and the removal of the maximum allowable dose. Simulations indicated that the percentage of patients achieving a UMSS score of 3 or greater can be expected to be high (88 to 97%).

Conclusions: This study has shown that the pharmacokinetics of remimazolam are likely different between children 6 yr or older and adults (after correcting for size). In addition, the exposure-response relationship shows that to effectively use remimazolam for procedural sedation in children 6 yr or older, the dosing regimen should be modified to allow for higher remimazolam exposures.

Fig. 1.

Example of pharmacokinetic pharmacodynamic data collected in this study in representative patients from the studied dosing regimen arms. Measured pharmacokinetic samples are shown with solid circles. Observed University of Michigan Sedation Scale scores are depicted with a solid orange line. The pink shaded area denotes observations that were obtained after rescue medication was used. For context, the remimazolam and fentanyl dosing regimens were visualized using the population pharmacokinetic models developed in this study (black solid line) and Ginsberg et al. (blue solid line), respectively.

Fig. 2.

Structure of final joint population pharmacokinetic model for remimazolam and CNS7054. Remimazolam pharmacokinetics are described by a three-compartment model with volumes of distribution V1, V2, and V3 and elimination and intercompartmental clearance CL, Q2, and Q3. CNS7054 pharmacokinetics are described by a one-compartment model with volume of distribution Vm and linear elimination clearance CLm. The formation of CNS7054 is described by a series of transit compartments with N compartments and mean transit time MTT. In this model, we assumed that 100% of remimazolam is metabolized to CNS7054 (f_m = 1.00). Plasma samples were assumed to be taken from the central compartments for remimazolam (V1) and CNS7054 (Vm) as indicated by the arrows.

Fig. 3.

Steady state pharmacodynamic interaction between fentanyl and remimazolam. The predicted probability for University of Michigan Sedation Scale (UMSS) = k with k ∈ {0, 1, 2, 3} for different combinations of remimazolam–fentanyl according to our final pharmacodynamic model. The remimazolam effect-site concentration driving the pharmacodynamic effect is depicted on the x-axis. The background fentanyl regimens, expressed as predicted effect-site concentrations, are depicted by different line types: no fentanyl coadministration (solid black line), 1 ng · ml^–1 (dashed black line), 2 ng · ml^–1 (solid red line), and 4 ng · ml^–1 (dashed red line). The range of predicted remimazolam effect-site concentrations from this study are denoted by the orange shaded area.

Fig. 4.

Predicted cumulative remimazolam dose versus time for the optimized dosing regimen versus the observed cumulative remimazolam dose from this study. Solid blue and orange lines represent the median observed cumulative remimazolam dose (milligrams) versus time from this study and the predicted cumulative dose according to the optimized dosing regimen, respectively. Dashed lines represent the 90% percentile of the observed and predicted cumulative remimazolam doses.