Modeling the norketamine metabolite in children and the implications for analgesia

Herd, David W., Anderson, Brian J. and Holford, Nicholas H. G. (2007) Modeling the norketamine metabolite in children and the implications for analgesia. Paediatric Anaesthesia, 17 9: 831-840. doi:10.1111/j.1460-9592.2007.02257.x


Author Herd, David W.
Anderson, Brian J.
Holford, Nicholas H. G.
Title Modeling the norketamine metabolite in children and the implications for analgesia
Journal name Paediatric Anaesthesia   Check publisher's open access policy
ISSN 1155-5645
Publication date 2007
Sub-type Article (original research)
DOI 10.1111/j.1460-9592.2007.02257.x
Volume 17
Issue 9
Start page 831
End page 840
Total pages 10
Language eng
Subject 2703 Anesthesiology and Pain Medicine
2735 Pediatrics, Perinatology, and Child Health
Abstract Background: Norketamine, a metabolite of ketamine, is an analgesic with a potency one-third that of ketamine. The aim of this study was to describe norketamine pharmacokinetics in children in order to predict time-concentration profiles for this metabolite after racemic ketamine single dose and infusion administration. The possible analgesic potential resulting from norketamine concentration may then be predicted using simulation. Methods: Ketamine and norketamine data were available from two sources: (i) children presenting for procedural sedation in an emergency department given ketamine 1-1.5 mg·kg-1 IV as a bolus dose; and (ii) a literature search of those studies describing ketamine and norketamine time-concentration profiles after either IV or IM single-dose ketamine in adults and children. A population pharmacokinetic analysis was undertaken using nonlinear mixed effects models (NONMEM). A two-compartment (central, peripheral) linear disposition model was used to fit the parent drug. An additional metabolite compartment was linked to the central compartment by series of intermediate compartments to account for norketamine delayed formation. Norketamine volume of distribution was fixed equivalent to central volume. Simulation was used to predict norketamine time-concentration profiles in children given either ketamine as an i.v. bolus 2 mg·kg-1 or as an analgesic infusion 0.2 mg·kg -1·h-1 for 24 h. Results: The analysis comprised 621 observations from 70 subjects. There were 57 children (age 8.3, sd: 3.5 years, range: 1.5-14; weight 32.5, sd: 15.6 kg, range: 10.8-74.8) and 13 adults. Population parameter estimates for the parent drug, standardized to a 70 kg person using allometric models were central volume (V1) 22 (BSV 89.6%) l.70 kg-1, peripheral volume of distribution (V2) 129 (30.9%) l.70 kg -1, clearance other than that metabolized to norketamine (CLother) 47.8 (37.7%) l·h-1·70 kg-1 and intercompartment clearance (Q) 216 (54.5%) l·h-1·70 kg-1. The norketamine formation clearance (CL2M) was 12.4 (127%) l·h-1·70 kg-1, elimination clearance (CLM) was 13.5 (145%) l·h-1·70 kg-1, and the rate constant for intermediate compartments was 26.5 (59.1%) h-1. Conclusions: Ketamine has a longer elimination half-life (2.1 h) than norketamine (1.13 h). Simulation suggested that norketamine contributes to analgesia for 4 h after 2 mg·kg-1 i.v. bolus, provided the assumption that a norketamine concentration above 0.1 mg·l-1 contributes analgesia is true. Similarly, the norketamine metabolite may contribute to analgesia for 1.5 h after low-dose infusion (0.2 mg·kg -1·h-1) cessation.
Keyword Allometrics
Analgesia
Children
Ketamine
Norketamine
Pharmacokinetics
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Unknown

Document type: Journal Article
Sub-type: Article (original research)
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