Population Pharmacokinetics of Intramuscular and Intravenous Ketamine in Children

Abstract

Ketamine is an N-methyl D-aspartate receptor antagonist used off-label to facilitate dissociative anesthesia in children undergoing invasive procedures. Available for both intravenous and intramuscular administration, ketamine is commonly used when vascular access is limited. Pharmacokinetic (PK) data in children are sparse, and the bioavailability of intramuscular ketamine in children is unknown. We performed 2 prospective PK studies of ketamine in children receiving either intramuscular or intravenous ketamine and combined the data to develop a pediatric population PK model using nonlinear mixed-effects methods. We applied our model by performing dosing simulations targeting plasma concentrations previously associated with analgesia (>100 ng/mL) and anesthesia awakening (750 ng/mL). A total of 113 children (50 intramuscular and 63 intravenous ketamine) with a median age of 3.3 years (range 0.02 to 17.6 years), and median weight of 14 kg (2.4 to 176.1) contributed 275 plasma samples (149 after intramuscular, 126 after intravenous ketamine). A 2-compartment model with first-order absorption following intramuscular administration and first-order elimination described the data best. Allometrically scaled weight was included in the base model for central and peripheral volume of distribution (exponent 1) and for clearance and intercompartmental clearance (exponent 0.75). Model-estimated bioavailability of intramuscular ketamine was 41%. Dosing simulations suggest that doses of 2 mg/kg intravenously and 8 mg/kg or 6 mg/kg intramuscularly, depending on age, provide adequate sedation (plasma ketamine concentrations >750 ng/mL) for procedures lasting up to 20 minutes.

Keywords: bioavailability; children; intramuscular; intravenous; ketamine; pharmacokinetics.

© 2018, The American College of Clinical Pharmacology.

Figures

Figure 1

Final model goodness-of-fit plots: observed concentrations vs. population predictions (A) and individual predictions (B), and conditional weighted residuals against population predictions (C) and time after first dose (D).

Figure 2

Final model standardized visual predictive check plot. 8% of observations are outside of the 90% prediction interval.

Figure 3

10th percentile simulated plasma concentration time curve in 5 individual children after administration of ketamine doses ranging from 1 to 10 mg/kg via intramuscular route: (A) 6-kg child; (B) 11-kg child; (C) 17-kg child; (D) 28-kg child; (E) 56-kg child.

Figure 4

10th percentile simulated plasma concentration time curve in 5 individual children not supported with ECMO after administration of ketamine doses ranging from 0.5 to 5 mg/kg via intravenous route: (A) 6-kg child; (B) 11-kg child; (C) 17-kg child; (D) 28-kg child; (E) 56-kg child.