Population Pharmacokinetics and Pharmacodynamics of Dexmedetomidine in Children Undergoing Ambulatory Surgery

Abstract

BACKGROUND:Dexmedetomidine (DEX) is an α-2 adrenergic agonist with sedative and analgesic properties. Although not approved for pediatric use by the Food and Drug Administration, DEX is increasingly used in pediatric anesthesia and critical care. However, very limited information is available regarding the pharmacokinetics of DEX in children. The aim of this study was to investigate DEX pharmacokinetics and pharmacodynamics (PK–PD) in Mexican children 2–18 years of age who were undergoing outpatient surgical procedures.METHODS:Thirty children 2–18 years of age with American Society of Anesthesiologists physical status score of I/II were enrolled in this study. DEX (0.7 μg/kg) was administered as a single-dose intravenous infusion. Venous blood samples were collected, and plasma DEX concentrations were analyzed with a combination of high-performance liquid chromatography and electrospray ionization-tandem mass spectrometry. Population PK–PD models were constructed using the Monolix program.RESULTS:A 2-compartment model adequately described the concentration–time relationship. The parameters were standardized for a body weight of 70 kg by using an allometric model. Population parameters estimates were as follows: mean (between-subject variability): clearance (Cl) (L/h × 70 kg) = 20.8 (27%); central volume of distribution (V1) (L × 70 kg) = 21.9 (20%); peripheral volume of distribution (V2) (L × 70 kg) = 81.2 (21%); and intercompartmental clearance (Q) (L/h × 70 kg) = 75.8 (25%). The PK–PD model predicted a maximum mean arterial blood pressure reduction of 45% with an IC50 of 0.501 ng/ml, and a maximum heart rate reduction of 28.9% with an IC50 of 0.552 ng/ml.CONCLUSIONS:Our results suggest that in Mexican children 2–18 years of age with American Society of Anesthesiologists score of I/II, the DEX dose should be adjusted in accordance with lower DEX clearance.

Dexmedetomidine: What’s New for Pediatrics? A Narrative Review

“…A maximum mean arterial blood pressure reduction of 45% was predicted with an inhibitory concentration IC50 of 0.501 ng/mL, and a maximum heart rate reduction of 28.9% with an IC50 of 0.552 ng/mL. Clearance was lower in the pediatric population [10]. This predictability of serum concentrations of DEX to elicit a particular hemodynamic response (reduced heart rate and the biphasic effect on mean arterial pressure) is consistent with the adult literature.…”

Dose rationale and pharmacokinetics of dexmedetomidine in mechanically ventilated new-borns: impact of design optimisation

“…It is metabolised by glucuronidation and CYP2A6 hydroxylation and subsequently excreted in urine almost exclusively as metabolite [2]. Its pharmacokinetics has been described by a two-compartmental model both in adults [3][4][5][6][7] and children [8][9][10][11][12]. Still, other investigators have also reported the disposition of dexmedetomidine according to one-compartment [13] and three-compartment [14][15][16] models.…”

Determination of blood dexmedetomidine in dried blood spots by LC-MS/MS to screen therapeutic levels in paediatric patients

“…It is expected that with the increasingly widespread use of DXM in the paediatric population and especially neonates and infants, cases of adverse effects may increase if the clinician does not have dosage recommendations based on PK-PD studies. Thus, having a precise and minimally invasive method for quantification of DXM can be an important contribution to enhance the efficacy and safety of this drug [11].…”

“…Currently there is a need for clinical and pharmacokinetic studies in paediatrics, which are useful to establish the optimal personalised dose; since the FDA has not approved it yet to be used in this population [10, 11]. In addition, other obstacles to perform such clinical trials have been the obtaining of the sample (venous puncture with catheter) and the amount of blood.…”