Optimising the dose of clonidine to achieve sedation in ICU patients with population pharmacokinetics.

AIMS: The aim of this study was to investigate the population pharmacokinetics (PK) of clonidine in intensive care unit (ICU) patients to develop a dosing regimen for sedation. METHODS: We included 24 adult mechanically ventilated, sedated patients from a mixed medical and surgical ICU. Intravenous clonidine was added to standard sedation in doses of 600, 1200, or 1800 mug/day. Within each treatment group, four patients received a loading dose of half the daily dose administered in 4h. Patients gave an average of 12 samples per individual. In total, 286 samples were available for analysis. Model development was conducted with NONMEM and various covariates were tested. After modelling, doses to achieve a target steady-state plasma concentration of >1.5 ug/L were explored using stochastic Monte Carlo simulations for 1000 virtual patients. RESULTS: A two-compartment model was the best fit for the concentration-time data. Clearance (CL) increased linearly with 0.213% per hour; using allometric scaling, body weight was a significant covariate on the central volume of distribution (V1). Population PK parameters were: CL 17.1 (L/h), V1 124 (L/70kg), Q (inter-compartmental CL) 83.7 (L/h), and V2 (peripheral volume of distribution) 178 (L), with 33.3% CV inter-individual variability (IIV) on CL and 66.8% CV IIV on V1. Simulations revealed that a maintenance dose of 1200 mug/day provides target sedation concentrations of >1.5 mug/L in 95% of the patients. CONCLUSION: A population PK model for clonidine was developed in an adult ICU. A dosing regimen of 1200 mug/day provided a target sedation concentration of >1.5 mug/L.