Pharmacokinetics of remimazolam after intravenous infusion in anaesthetised children.

Abstract

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. 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. 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. 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. ChiCTR2200057629.