TY - JOUR
T1 - Development of an Optimized Pharmacokinetic Model of Dexmedetomidine Using Target-controlled Infusion in Healthy Volunteers
AU - Hannivoort, Laura N.
AU - Eleveld, Douglas J.
AU - Proost, Johannes H.
AU - Reyntjens, Koen M. E. M.
AU - Absalom, Anthony R.
AU - Vereecke, Hugo E. M.
AU - Struys, Michel M. R. F.
PY - 2015/8
Y1 - 2015/8
N2 - Background: Several pharmacokinetic models are available for dexmedetomidine, but these have been shown to underestimate plasma concentrations. Most were developed with data from patients during the postoperative phase and/or in intensive care, making them susceptible to errors due to drug interactions. The aim of this study is to improve on existing models using data from healthy volunteers.Methods: After local ethics committee approval, the authors recruited 18 volunteers, who received a dexmedetomidine target-controlled infusion with increasing target concentrations: 1, 2, 3, 4, 6, and 8ng/ml, repeated in two sessions, at least 1 week apart. Each level was maintained for 30min. If one of the predefined safety criteria was breached, the infusion was terminated and the recovery period began. Arterial blood samples were collected at preset times, and NONMEM (Icon plc, Ireland) was used for model development.Results: The age, weight, and body mass index ranges of the 18 volunteers (9 male and 9 female) were 20 to 70 yr, 51 to 110kg, and 20.6 to 29.3kg/m(2), respectively. A three-compartment allometric model was developed, with the following estimated parameters for an individual of 70 kg: V1 = 1.78 l, V2 = 30.3 l, V3 = 52.0 l, CL = 0.686 l/min, Q2 = 2.98 l/min, and Q3 = 0.602 l/min. The predictive performance as calculated by the median absolute performance error and median performance error was better than that of existing models.Conclusions: Using target-controlled infusion in healthy volunteers, the pharmacokinetics of dexmedetomidine were best described by a three-compartment allometric model. Apart from weight, no other covariates were identified.
AB - Background: Several pharmacokinetic models are available for dexmedetomidine, but these have been shown to underestimate plasma concentrations. Most were developed with data from patients during the postoperative phase and/or in intensive care, making them susceptible to errors due to drug interactions. The aim of this study is to improve on existing models using data from healthy volunteers.Methods: After local ethics committee approval, the authors recruited 18 volunteers, who received a dexmedetomidine target-controlled infusion with increasing target concentrations: 1, 2, 3, 4, 6, and 8ng/ml, repeated in two sessions, at least 1 week apart. Each level was maintained for 30min. If one of the predefined safety criteria was breached, the infusion was terminated and the recovery period began. Arterial blood samples were collected at preset times, and NONMEM (Icon plc, Ireland) was used for model development.Results: The age, weight, and body mass index ranges of the 18 volunteers (9 male and 9 female) were 20 to 70 yr, 51 to 110kg, and 20.6 to 29.3kg/m(2), respectively. A three-compartment allometric model was developed, with the following estimated parameters for an individual of 70 kg: V1 = 1.78 l, V2 = 30.3 l, V3 = 52.0 l, CL = 0.686 l/min, Q2 = 2.98 l/min, and Q3 = 0.602 l/min. The predictive performance as calculated by the median absolute performance error and median performance error was better than that of existing models.Conclusions: Using target-controlled infusion in healthy volunteers, the pharmacokinetics of dexmedetomidine were best described by a three-compartment allometric model. Apart from weight, no other covariates were identified.
KW - COMPUTER-CONTROLLED INFUSION
KW - ADULT HUMAN VOLUNTEERS
KW - INTENSIVE-CARE
KW - PROPOFOL
KW - PHARMACODYNAMICS
KW - HYDROCHLORIDE
KW - REMIFENTANIL
KW - SEDATION
U2 - 10.1097/ALN.0000000000000740
DO - 10.1097/ALN.0000000000000740
M3 - Article
C2 - 26068206
VL - 123
SP - 357
EP - 367
JO - Anesthesiology
JF - Anesthesiology
SN - 0003-3022
IS - 2
ER -