Pharmacokinetics of S-ketamine during prolonged sedation at the pediatric intensive care unit.

Abstract

S-ketamine is the S(+)-enantiomer of the racemic mixture ketamine, an anesthetic drug providing both sedation and analgesia. In clinical practice, significant interpatient variability in drug effect of S-ketamine is observed during long-term sedation. The aim of this study was to evaluate the pharmacokinetic variability of S-ketamine in children aged 0-18years during long-term sedation. Twenty-five children (median age: 0.42years, range: 0.02-12.5) received continuous intravenous administrations of 0.3-3.6mg/kg/h S-ketamine for sedation during mechanical ventilation. Infusion rates were adjusted to the desired level of sedation and analgesia based on the COMFORT-B score and Visual Analog Scale. Blood samples were drawn once daily at random time-points, and at 1 and 4hours after discontinuation of S-ketamine infusion. Time profiles of plasma concentrations of S-ketamine and active metabolite S-norketamine were analyzed using nonlinear mixed-effects modeling software. Clearance and volume of distribution were allometrically scaled using the ¾ power model. A total of 86 blood samples were collected. A 2-compartment and 1-compartment model adequately described the PK of S-ketamine and S-norketamine, respectively. The typical parameter estimates for clearance and central and peripheral volumes of distribution were: CLS-KETAMINE =112L/h/70kg, V1S-KETAMINE =7.7L/70kg, V2S-KETAMINE =545L/70kg, QS-kETAMINE =196L/h/70kg, and CLS-NORKETAMINE =53L/h/70kg. Interpatient variability of CLS-KETAMINE and CLS-NORKETAMINE was considerable with values of 40% and 104%, respectively, leading to marked variability in steady-state plasma concentrations. Substantial interpatient variability in pharmacokinetics in children complicates the development of adequate dosage regimen for continuous sedation.