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.

Population Pharmacokinetics and Pharmacodynamics of the Therapeutic and Adverse Effects of Ketamine in Patients With Treatment‐Refractory Depression

“…In a larger population‐based modeling approach study, the reported bioavailability after i.m. administration in children was 41% 24 . This and our estimated value of ~ 64% reflects the current dosing recommendation of i.m.…”

“…This agrees with studies that reported a 2-compartment model to be the best fit for observed ketamine concentrations in both children and adults. [24][25][26][27] A previous study reported an absolute bioavailability of 93% after i.m. administration.…”

Ketamine Pharmacokinetics

“…Study 27. Hornik et al 37 9 (2020) performed a pharmacokinetic analysis of earlier published data 10 on the influence of the nitric oxide donor sodium nitroprusside on S-ketamine and R,S-ketamine pharmacodynamics. In 20 volunteers both formulations were administered on separate occasions and the concentrations of R-and/or S-ketamine and metabolites (norketamine, dehydronorketamine, and hydroxynorketamine) were measured in arterial plasma.…”

Assessment of Ketamine Adult Anesthetic Doses in Pediatrics Using Pharmacokinetic Modeling and Simulations

“…Similar values were reported when the population pharmacokinetic data were pooled to racemic ketamine plasma concentrations collected in children with burns. A recent study reported similar estimates in 0.02‐ to 17.6‐year‐old children after the administration of a racemic mixture via IV and IM routes (elimination clearance, 38.9 L/hour/70 kg; steady‐state distribution volume 184.8 L/70 kg). ( S )‐Ketamine administration as a 3.6 mg/kg/hour intravenous infusion in 0.02‐ to 12.5‐year‐old children under intensive care showed faster clearance (112 L/hr/70 kg) and larger volume (552 L/70 kg) compared to the racemic mixture.…”