Background: Dexmedetomidine (DEX), a selective alpha2-adrenoceptor agonist is approved for sedation. In this study, the population pharmacokinetics (PK) of DEX during long-term (> 24 hours) infusion was characterized and compared to previous results obtained after short term infusion.
Methods: Data were obtained from 53 adults (62% male, 79% Caucasian, aged 18-87 years) enrolled in a Phase 4 study. DEX was administered as an optional loading dose (1 μg/kg), followed by a maintenance intravenous (IV) infusion that started at 0.84 μg/kg/h and was titrated to predefined sedation level. Plasma DEX concentrations (n = 291) were obtained at 2 and 4 hours after the infusion was started, within 15 minutes before the infusion was stopped, and 4 and 8 hours after the infusion was stopped. Interindividual variability (IIV) on clearance (Cl) and volume of distribution (Vd) and residual variability (RV) were estimated using exponential and log error models, respectively. Selected covariates were evaluated graphically.
Results: DEX PK was described by a 1-compartment model with first-order elimination. The mean parameter estimates (%SEM) were: 39.4 (9.7) L/h for Cl, and 152 (11.5) L for Vd. Estimated IIV for Cl and Vd were 63% and 68%, respectively, with RV approximately 59 %CV. DEX Cl was comparable to a previous estimate of 39.2 L/h demonstrated during short-term infusion in healthy subjects for less than 24 hours. Graphical covariate assessment indicated potential positive relationships between Cl and body weight, Vd and weight, as well as a possible relationship between DEX PK and age.
Conclusions: DEX PK after long-term infusion was consistent with DEX PK after short-term infusion.
American Society for Clinical Pharmacology and Therapeutics (ASCPT), Atlanta, Georgia, March 2010
By Jill Fiedler-Kelly, Elizabeth Ludwig, Q. Lu, D. Stalker