Protein Binding and Population Pharmacokinetics of Dexmedetomidine after Prolonged Infusions in Adult Critically Ill Patients

Dexmedetomidine (DEX) is a highly selective α2-adrenoceptor agonist with high protein binding of 94%. Critical illness may affect protein binding and the pharmacokinetic (PK) parameters of many drugs, including DEX. In critically ill patients receiving prolonged infusions of DEX, there is little information documenting the relationship between key pathophysiologic factors and DEX protein binding or PK parameters. The purpose of this study was to characterize the protein binding and PK profile of prolonged DEX infusion in critically ill patients.Critically ill, adult intensive care unit patients at a university hospital in Hong Kong were studied. The association between the pathophysiologic changes of critical illness and protein binding was evaluated using a generalized estimating equation. A population pharmacokinetic model to establish the PK profile of DEX was developed, and key pathophysiologic covariate effects of severity of illness, organ dysfunction measures, and altered protein binding on DEX PK parameters in this critically ill population were evaluated.A total of 22 critically ill patients and 1 healthy control were included. Mean protein binding of DEX in the critically ill patients was 90.4% (95% CI, 89.1-91.7), which was 4% lower than that in the healthy control. The PK data were adequately described by a 2-compartment model. The estimated population mean (relative standard error [RSE]) values of systemic clearance (CL), volume of distribution of the central compartment (V2), intercompartmental clearance (Q), and Vd in the peripheral compartment (V3) were 38.6 (11.7) L/h, 32.1 (46.1) L, 114.5 (58.3) L/h and 95.1 (30.6) L, respectively. The corresponding estimated interindividual variability expressed as CV% (RSE) was 52.4 (23.8) for CL, 172.9 (19.3) for V2, 123.7 (33.7) for Q, and 106 (39.9) for V3. No significant explanatory pathophysiologic covariates were identified.Although a marginally significant reduction of protein binding in critically ill patients was demonstrated, the magnitude of the difference was unlikely to be of clinical significance. Higher alanine aminotransferase concentration was associated with decreased protein binding. No significant pathophysiologic covariates were associated with the observed PK parameters. The high interindividual variability of PK parameters supports the current practice of dose titration to ensure the desired clinical effects of DEX infusion in the intensive care unit setting.