Pharmacokinetic and Pharmacodynamic Modeling of Clonidine and Midazolam for Sedation in Pediatric Intensive Care

Background Clonidine and midazolam are routinely used in the pediatric intensive care unit for pain and sedation management, but target concentration and optimal dose are poorly defined for both drugs. The CloSed study is a multicenter, double‐blind, randomized, active‐controlled noninferiority trial with a 1:1 randomization between clonidine and midazolam. Aims Data from the prematurely terminated CloSed trial were used to study the population pharmacokinetic–pharmacodynamic relationships for clonidine and midazolam to inform the optimal use of both drugs in mechanically ventilated children. Methods Twenty‐eight patients (0–6 years) were included; 13 received midazolam, and 15 received clonidine. Morphine was administered to all patients as background analgesia. A total of 317 and 306 observed COMFORT‐B scores for midazolam and clonidine, respectively, were available to build the pharmacokinetic–pharmacodynamic model. Pharmacokinetic models were developed using findings from previously published pharmacokinetic studies to augment the trial data. A one‐compartment model described clonidine pharmacokinetics, while a single compartment for midazolam and its metabolite described its pharmacokinetics. A joint inhibitory sigmoid model that included a postanesthesia effect was used to describe the concentration–effect relationship, using the COMFORT‐B score as the pharmacodynamic endpoint. Results The final models adequately described the observed data. Simulations based on the final models showed that a clonidine dose of 4 μg/kg loading dose followed by a 3 μg/kg/h infusion, and a midazolam dose of 200 μg/kg loading dose followed by a 200 μg/kg/h infusion would be required to achieve adequate sedation. Conclusion The CloSed data suggest that higher doses of clonidine and midazolam than are commonly used in clinical practice should be considered to provide adequate sedation in critically ill children.