Population Pharmacokinetics of Dexmedetomidine in Infants

Abstract

Despite limited pharmacokinetic (PK) data, dexmedetomidine is increasingly being used off-label for sedation in infants. We aimed to characterize the developmental PK changes of dexmedetomidine during infancy. In this open-label, single-center PK study of dexmedetomidine in infants receiving dexmedetomidine per clinical care, ≤10 blood samples per infant were collected. A set of structural PK models and residual error models were explored using nonlinear mixed-effects modeling in NONMEM. Covariates including postmenstrual age (PMA), serum creatinine, and recent history of cardiac surgery requiring cardiopulmonary bypass were investigated for their influence on PK parameters. Univariable generalized estimating equation models were used to evaluate the association of hypotension with dexmedetomidine concentrations. A total of 89 PK samples were collected from 20 infants with a median PMA of 44 weeks (range, 33-61). The median maximum dexmedetomidine infusion dose during the study period was 1.8 μg/(kg·h) (0.5-2.5), and 16/20 infants had a maximum dose >1 μg/(kg·h). A 1-compartment model best described the data. Younger PMA was a significant predictor of lower clearance. Infants with a history of cardiac surgery had ∼40% lower clearance compared to those without a history of cardiac surgery. For infants with PMA of 33 to 61 weeks and body weight of 2 to 6 kg, the estimated clearance and volume of distribution were 0.87 to 2.65 L/(kg·h) and 1.5 L/kg, respectively. No significant associations were found between dexmedetomidine concentrations and hypotension. Infants with younger PMA and recent cardiac surgery may require relatively lower doses of dexmedetomidine to achieve exposure similar to older patients and those without cardiac surgery.

Keywords: Precedex; neonate; pharmacokinetics; population pharmacokinetics.

Figure 1

Final population pharmacokinetic (PK) model diagnostic plots: observed versus population prediction (A) and individual prediction (B), conditional weighted residuals versus population predictions (C), and time after last dose (D). The solid line in A and B is the line of identity. The solid line in C and D is a reference line at y=0. The dashed lines in A, B, C, and D are smooth lines.

Figure 2

Eta for clearance (ETA_CL) versus postmenstrual age (PMA) (A), postnatal age (PNA) (B), serum creatinine (SCR) (C), and cardiac surgery within 48 hours of PK sample (D) for the base dexmedetomidine PK model. Each closed circle represents a patient.

Figure 3

Standardized visual predictive check of dexmedetomidine observation percentiles versus time after last dose (A). Open circles represent calculated percentiles. Dashed lines represent the 5^th, 50^th, and 95^th percentiles (bottom, middle, and top, respectively) of model predicted data. Visual predictive check of dexmedetomidine (B). Solid lines represent 5^th, 50^th, and 95^th percentiles (bottom, middle, and top, respectively) of model predicted data. Dashed lines represent 5^th, 50^th, and 95^th percentiles (bottom, middle, and top, respectively) of observed data. Dark grey area represents 95% confidence interval for the 50^th percentile of model predicted data. Light grey areas represent 95% confidence interval for the 5^th and 95^th percentiles (bottom and top) of model predicted data. Open circles represent observed data.