A phase I, two-center study of the pharmacokinetics and pharmacodynamics of dexmedetomidine in children.
BACKGROUND
To investigate dexmedetomidine in children, the authors performed an open-label study of the pharmacokinetics and pharmacodynamics of dexmedetomidine.


METHODS
Thirty-six children were assigned to three groups; 24 received dexmedetomidine and 12 received no drug. Three doses of dexmedetomidine, 2, 4, and 6 microg x kg x h, were infused for 10 min. Cardiorespiratory responses and sedation were recorded for 24 h. Plasma concentrations of dexmedetomidine were collected for 24 h and analyzed. Pharmacokinetic variables were determined using nonlinear mixed effects modeling (NONMEM program). Cardiorespiratory responses were analyzed.


RESULTS
Thirty-six children completed the study. There was an apparent difference in the pharmacokinetics between Canadian and South African children. The derived volumes and clearances in the Canadian children were V1 = 0.81 l/kg, V2 = 1.0 l/kg, Cl1 (systemic clearance) = 0.013 l x kg x min, Cl2 = 0.030 l x kg x min. The intersubject variabilities for V1, V2, and Cl1 were 45%, 38%, and 22%, respectively. Plasma concentrations in South African children were 29% less than in Canadian children. The volumes and clearances in the South African children were 29% larger. The terminal half-life was 110 min (1.8 h). Median absolute prediction error for the two-compartment mammillary model was 18%. Heart rate and systolic blood pressure decreased with time and with increasing doses of dexmedetomidine. Respiratory rate and oxygen saturation (in air) were maintained. Sedation was transient.


CONCLUSIONS
The pharmacokinetics of dexmedetomidine in children are predictable with a terminal half-life of 1.8 h. Hemodynamic responses decreased with increasing doses of dexmedetomidine. Respiratory responses were maintained, whereas sedation was transient.
Petroz
Guy C
GC
Department of Anaesthesia, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada. petroz@anaes.sickkids.on.ca
Sikich
Nancy
N
James
Michael
M
van Dyk
Hanlie
H
Shafer
Steven L
SL
Schily
Markus
M
Lerman
Jerrold
J
D000316:Adrenergic alpha-Agonists / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002648:Child; D002675:Child, Preschool; D016292:Procedural Sedation; D003625:Data Collection; D020927:Dexmedetomidine / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D005260:Female; D006207:Half-Life; D006339:Heart Rate / Q000187:drug effects; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D010100:Oxygen / Q000097:blood; D015656:Respiratory Mechanics / Q000187:drug effects
D000316:Adrenergic alpha-Agonists; D006454:Hemoglobins; D020927:Dexmedetomidine; D010100:Oxygen