Exploring the pharmacokinetics of oral ketamine in children undergoing burns procedures

P>Aims: The aim of this study was to describe ketamine pharmacokinetics when administered orally to children suffering from burn injury in > 10% body surface area. Methods: Children (n = 20) were given ketamine 5 or 10 mg center dot kg-1 orally 20 min prior to presentation for surgical procedures. Anesthesia during procedures was maintained with a volatile anesthetic agent. Additional intravenous ketamine was given as a bolus (0.5-1 mg center dot kg-1) to nine children during the procedure while a further nine children were given an infusion (0.1 mg center dot kg-1 center dot h-1) continued for 4-19 h after the procedure. Blood was assayed for ketamine and norketamine on six occasions over the study duration of 8-24 h. Data were pooled with those from an earlier analysis (621 observations from 70 subjects). An additional time-concentration profile from an adult given oral ketamine was gleaned from the literature (17 observations). A population analysis was undertaken using nonlinear mixed-effects models. Results: The pooled analysis comprised 852 observations from 91 subjects. There were 20 children who presented for procedures related to burns management (age 3.5 sd 2.1 years, range 1-8 years; weight 14.7 sd 4.9 kg, range 7.9-25 kg), and these children contributed 214 ketamine and norketamine observations. A two-compartment (central, peripheral) linear disposition model fitted data better than a one-compartment model. Bioavailability of the oral formulation was 0.45 (90% CI 0.33, 0.58). Absorption half-time was 59 (90% CI 29.4, 109.2) min and had high between-subject variability (BSV 148%). Population parameter estimates, standardized to a 70-kg person, were central volume 21.1 (BSV 47.1%) l center dot 70 kg-1, peripheral volume of distribution 109 (27.5%) l center dot 70 kg-1, clearance 81.3 (46.1%) l center dot h-1 center dot 70 kg-1, and inter-compartment clearance 259 (50.1%) l center dot h-1 center dot 70 kg-1. Under the assumption that all ketamine was converted to norketamine, the volume of the metabolite was 151.9 (BSV 39.1%) l center dot 70 kg-1 with an elimination clearance of 64.4 (BSV 63.4%) l center dot h-1 center dot 70 kg-1 and a rate constant for intermediate compartments of 26.2 (BSV 52.1%) h-1 center dot 70 kg-1. Conclusions: The ketamine pharmacokinetics in children with minor burns are similar to those without burns. The peak ratio of norketamine/ketamine at 1 h is 2.8 after oral administration allowing an analgesic contribution from the metabolite at this time. There is low relative bioavailability (< 0.5) and slow variable absorption. Dose simulation in a child (3.5 years, 15 kg) suggests a dose regimen of oral ketamine 10 mg center dot kg-1 followed by intravenous ketamine 1 mg center dot kg-1 i.v. with the advent of short-duration surgical dressing change at 45 min.