Pharmacokinetics and pharmacodynamics of remimazolam for procedural sedation in children and adolescents.

Abstract

BACKGROUND/INTRODUCTION 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 manuscript reports on the pharmacokinetics and pharmacodynamics of pediatric patients aged ≥6 to ≤18 years and a subsequent model-based optimization of the used dosing regimen. METHODS 31 patients were included in the trial and stratified across four treatment arms: bolus administration, infusion, bolus + fentanyl or infusion + fentanyl. The University of 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 modelling was performed in NONMEM ®. RESULTS A population pharmacokinetic model was developed for remimazolam and CNS7054. The elimination clearance of remimazolam was 0.70 L.min -1.70kg -1. A proportional odds model combined with a simplified Minto model described the observed UMSS well. The EC50 of remimazolam for UMSS ≥3 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 UMSS ≥3 at the end of the induction. Model-based optimization resulted in higher per kg dosages and the removal of the maximum allowable dose. Simulations indicated that the percentage of patients achieving UMSS ≥3 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 years old and adults (after correcting for size). In addition, the exposure-response relationship shows that to effectively use remimazolam for procedural sedation in children ≥6 years, the dosing regimen should be modified to allow for higher remimazolam exposures.