Optimising the dose of clonidine to achieve sedation in intensive care unit patients with population pharmacokinetics

Abstract

Aims: The aim of this study was to investigate the population pharmacokinetics (PK) of clonidine in intensive care unit (ICU) patients in order 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 μg/d. Within each treatment group, 4 patients received a loading dose of half the daily dose administered in 4 hours. 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 μg/L were explored using stochastic Monte Carlo simulations for 1000 virtual patients.

Results: A 2-compartment model was the best fit for the concentration-time data. Clearance (CL) increased linearly with 0.213%/h; 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/70 kg), intercompartmental CL 83.7 (L/h), and peripheral volume of distribution 178 (L), with 33.3% CV interindividual variability on CL and 66.8% CV interindividual variability on V1. Simulations revealed that a maintenance dose of 1200 μg/d provides target sedation concentrations of >1.5 μg/L in 95% of the patients.

Conclusion: A population PK model for clonidine was developed in an adult ICU. A dosing regimen of 1200 μg/d provided a target sedation concentration of >1.5 μg/L.

Keywords: clonidine; population pharmacokinetics; sedation.

FIGURE 1

Individual clonidine concentration: time profiles on semi‐logarithmic scale. Numbers 9–32 indicate the ID numbers of the patients. Patients 9–12 received clonidine 600 μg/d; patients 13–16 received 600 μg/d with a loading dose of 300 μg in 4 hours; patients 17–20 received 1200 μg/d; patients 21–24 received 1200 μg/d with a loading dose of 600 μg in 4 hours; patients 25–28 received 1800 μg/d; and patients 29–32 received 1800 μg/d with a loading dose of 900 μg in 4 h. The horizontal grey solid line denotes the total infusion duration. The thick horizontal grey solid line represents the duration of the loading dose, while the thin horizontal grey solid line represents the duration of the maintenance dose. In patient 11, continuous infusion was terminated for 2 hours due to hypotension

FIGURE 2

Goodness‐of‐fit plots of the final population pharmacokinetic model of clonidine. A, Individual predicted vs observed concentrations; B, population predicted vs observed concentrations; C, conditional weighted residuals (CWRES) vs population predicted; D, time after start infusion vs CWRES. The solid line is the line of identity. The red dashed line represents the local regression smooth line (loess smooth)

FIGURE 3

Visual predictive check of the final population pharmacokinetic model of clonidine. Dots represent observed data points; the solid black line represents the 50th percentile of observed data; the dashed black lines represent the 5^th and 95^th percentiles of the population pharmacokinetic model. Shaded areas depict the model predicted 95% confidence intervals of the simulated percentiles

FIGURE 4

Simulations of 1000 individuals using continuous intravenous (IV) clonidine for 4 days in patients 53–113 kg, mean 84 kg. A, Continuous IV clonidine of 1200 μg/d (50 μg/h); B, continuous IV clonidine of 1200 μg/d (50 μg/h) and 150 μg IV bolus in 30 minutes; C, continuous IV clonidine of 1200 μg/d (50 μg/h) and 600 μg loading dose in 6 hours. The solid lines represent the median value, while the dashed lines represent the 5^th and 95^th percentile, respectively. The shaded grey areas depict the 90% prediction interval