Pharmacokinetics and pharmacodynamics of intravenous dexmedetomidine in healthy Korean subjects

• Published in: Journal of clinical pharmacy and therapeutics Vol. 37; no. 6; pp. 698 - 703
• Main Authors: Lee, S., Kim, B.-H., Lim, K., Stalker, D., Wisemandle, W., Shin, S.-G., Jang, I.-J., Yu, K.-S.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-12-2012; Blackwell; Hindawi Limited
• Subjects: Adrenergic alpha-2 Receptor Agonists - administration & dosage; Adrenergic alpha-2 Receptor Agonists - pharmacokinetics; Adrenergic alpha-2 Receptor Agonists - pharmacology; Adult; Area Under Curve; Biological and medical sciences; dexmedetomidine; Dexmedetomidine - administration & dosage; Dexmedetomidine - pharmacokinetics; Dexmedetomidine - pharmacology; Dose-Response Relationship, Drug; Double-Blind Method; Humans; Hypnotics and Sedatives - administration & dosage; Hypnotics and Sedatives - pharmacokinetics; Hypnotics and Sedatives - pharmacology; Infusions, Intravenous; Korean; Male; Medical sciences; Models, Biological; Nonlinear Dynamics; pharmacodynamics; pharmacokinetics; Pharmacology. Drug treatments; population pharmacokinetics; Republic of Korea; Tissue Distribution; Asia; Korea; Republic of Korea; α2-Adrenergic receptor; Human; Population pharmacokinetics; Pharmacokinetic pharmacodynamic relationship; Agonist; Pharmacodynamics; Intravenous administration; Healthy subject; Korean; Biological activity; Dexmedetomidine; pharmacokinetics; α-Adrenergic receptor agonist
• ISSN: 0269-4727; 1365-2710
• DOI: 10.1111/j.1365-2710.2012.01357.x

Summary
What is known and Objective:  Dexmedetomidine is a selective alpha2‐adrenoreceptor agonist used for sedation in critically ill patients. The current study aimed to evaluate the pharmacokinetics (PKs), pharmacodynamics and tolerability of intravenous dexmedetomidine in healthy Korean subjects.
Methods:  A randomized, double‐blind, placebo‐controlled study with three parallel dosage groups was conducted. Twenty‐four subjects were randomly assigned to placebo or one of three dexmedetomidine dosing regimens, 3 μg/kg/h for 10 min followed by 0·17 μg/kg/h for 50 min (low dose), 6 μg/kg/h for 10 min followed by 0·34 μg/kg/h for 50 min (middle dose) and 3·7 μg/kg/h for 35 min followed by 0·7 μg/kg/h for 25 min (high dose). Serial blood samples for PK analysis were taken up to 12 h. PK parameters were determined using non‐compartmental methods (WinNonlin®), and a population PK model was developed using nonmem®. The sedative effect of dexmedetomidine was assessed by Ramsay sedation score and visual analogue scales/sedation. Adverse events, clinical laboratory tests, electrocardiograms, physical examinations and vital signs were monitored for tolerability assessment.
Results:  Six subjects were assigned to each of the three active treatment group or placebo group. The AUClast of the low‐, middle‐ and high‐dose group were 1096·8 ± 119·9 (mean ± SD) ng*h/L, 2643·0 ± 353·2 ng*h/L and 5600·6 ± 411·0 ng*h/L, respectively. PK of dexmedetomidine was best described using a two‐compartment model. The typical value of the population model can be calculated using the following equations: central volume of distribution (L) = 19·9 (age/27)0·954, peripheral volume of distribution (L) = 59·4, clearance (L/h) = 33·7 (albumin level/4·3)1·42 and inter‐compartment clearance (L/h) = 67·7. Sedative effects were significantly increased by dexmedetomidine compared to placebo. The blood pressure and heart rate were decreased, but oxygen saturation was maintained stable.
What is new and Conclusion:  Dexmedetomidine shows linear PK characteristics and dose‐dependent sedative effects. A two‐compartment population PK model was developed for healthy Korean subjects. The PK parameter estimates are similar in Koreans and Caucasians.