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BJA Advance Access published online on August 12, 2005
British Journal of Anaesthesia, doi:10.1093/bja/aei218
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© The Board of Management and Trustees of the British Journal of Anaesthesia 2005. All rights reserved. For Permissions, please e-mail: journal.permissions@oupjournals.org
Accepted April 4, 2005

Clinical Investigation

Pharmacokinetics of levobupivacaine after caudal epidural administration in infants less than 3 months of age

G. A. Chalkiadis 1, B. J. Anderson 2, M. Tay 3, A. Bjorksten 1, and J. J. Kelly 1*

1 Department of Anaesthesia and Pain Management, Royal Children's Hospital, Flemington Rd, Parkville, Victoria 3052, Australia
2 Department of Anaesthesiology, University of Auckland, New Zealand
3 Department of Anaesthesia and Pain Management, Royal Children's Hospital, Flemington Rd, Parkville, Victoria 3052, Australia; Present address: Department of Paediatric Anaesthesia, KK Women's and Children's Hospital, Singapore

* To whom correspondence should be addressed.
J. J. Kelly, E-mail: julian.kelly{at}rch.org.au


  Abstract

Background. There are few data describing levobupivacaine pharmacokinetics in infants (<3 months) after caudal administration.

Methods. An open-label study was undertaken to examine the pharmacokinetics of levobupivacaine 2.5 mg ml-1, 2 mg kg-1 in children aged less than 3 months after single-shot caudal epidural administration. Plasma concentrations were determined at intervals from 0.5 to 4 h after injection. A population pharmacokinetic analysis of levobupivacaine time-concentration profiles (84 observations) from 22 infants with mean postnatal age (PNA) 2.0 (range 0.6-2.9) months was undertaken using non-linear mixed effects models (NONMEM). Time-concentration profiles were analysed using a one-compartment model with first-order input and first-order elimination. Estimates were standardized to a 70 kg adult using allometric size models.

Results. Population parameter estimates (between-subject variability) for total levobupivacaine were clearance (CLt) 12.8 [coefficient of variation (CV) 50.6%] litre h-1 70 kg-1, volume of distribution (Vt) 202 (CV 31.6%) litre 70 kg-1, absorption half-life (Tabs) 0.323 (CV 18.6%) h 70 kg-1. Estimates for the unbound drug were clearance (CLfree) 104 (CV 43.5%) litre h-1 70 kg-1, volume of distribution (Vfree) 1700 (CV 44.9%) litre 70 kg-1, absorption half-life (Tabsfree) 0.175 (CV 83.7%) h 70 kg-1. There was no effect attributable to PNA on CL or V. Time to peak plasma concentration (Tmax) was 0.82 (CV 18%) h. Peak plasma concentration (Cmax) was 0.69 (CV 25%) µg ml-1 for total levobupivacaine and 0.09 (CV 37%) µg ml-1 for unbound levobupivacaine.

Conclusions. Clearance in infants is approximately half that described in adults, suggesting immaturity of P450 CYP3A4 and CYP1A2 enzyme isoforms that metabolize levobupivacaine in infants. This lower clearance delays Tmax, which was noted to occur approximately 50 min after administration of caudal epidural levobupivacaine.

Keywords: anaesthetic techniques, regional, caudal; anaesthetics local, levobupivacaine; infants; neonates; pharmacokinetics, levobupivacaine.
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L. I. Cortinez, R. Fuentes, S. Solari, P. Ostermann, M. Vega, and H. R. Munoz
Pharmacokinetics of Levobupivacaine (2.5 mg/kg) After Caudal Administration in Children Younger Than 3 Years
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