Pharmacokinetics of remimazolam after intravenous infusion in anaesthetised children

Abstract

Background: The pharmacokinetic properties of the new benzodiazepine remimazolam have been studied only in adults. We investigated the pharmacokinetics of remimazolam after i.v. infusion in anaesthetised paediatric patients.

Methods: Twenty-four children (2-6 yr, ASA physical status 1-2, BMI 15-18 kg m^-2) undergoing general anaesthesia with sevoflurane were enrolled. During surgery, remimazolam was administered as an i.v. infusion over 1 h at 5 mg kg^-1 h^-1 for 5 min, followed by 1.5 mg kg^-1 h^-1 for 55 min. Plasma concentrations of remimazolam and its metabolite CNS7054 were determined from arterial blood samples using ultra-high performance liquid chromatography-mass spectrometry. Pharmacokinetic modelling was performed by population analysis.

Results: Pharmacokinetics were best described by a three-compartment model for remimazolam and a two-compartment model for CNS7054 linked by a transit compartment. Remimazolam showed a high clearance of 15.9 (12.9, 18.2) ml kg^-1 min^-1 (median, Q₂₅, Q₇₅), a small central volume of distribution of 0.11 (0.08, 0.14) L kg^-1 and a short terminal half-life of 67 (49, 85) min. The context-sensitive half-time after an infusion of 4 h was 17 (12, 21) min. The metabolite CNS7054 showed a low clearance of 0.89 (0.33, 1.40) ml kg^-1 min^-1, a small central volume of distribution of 0.011 (0.005, 0.016) L kg^-1, and a long terminal half-life of 321 (230, 770) min.

Conclusions: Remimazolam in children was characterised by a high clearance and short context-sensitive half-time. When normalised to weight, pharmacokinetic properties were similar to those reported for adults.

Clinical trial registration: ChiCTR2200057629.

Keywords: CNS7054; benzodiazepine; children; metabolite; paediatric anaesthesia; pharmacokinetics; remimazolam.