BJA Advance Access originally published online on June 10, 2005
British Journal of Anaesthesia 2005 95(2):231-239; doi:10.1093/bja/aei170
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Tramadol disposition in the very young: an attempt to assess in vivo cytochrome P-450 2D6 activity
1 Neonatal Intensive Care Unit, Department of Paediatrics, University Hospital, Gasthuisberg, Leuven, Belgium. 2 Department of Paediatric Surgery and 3 Department of Paediatrics, Erasmus Medical Centre, Sophia's Children Hospital, Rotterdam, The Netherlands. 4 Department of Anaesthesiology, University of Auckland, Auckland, New Zealand. 5 Center for Clinical Pharmacology, University Hospital, Gasthuisberg, Leuven, Belgium. 6 Division of Pediatric Clinical Pharmacology, Children's National Medical Center, Washington, DC, USA. 7 Departments of Pediatrics, Pharmacology and Physiology, George Washington University School of Medicine and Health Sciences, Washington, DC, USA
* Corresponding author: Neonatal Intensive Care Unit, Department of Paediatrics, University Hospital, Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium. E-mail: karel.allegaert{at}uz.kuleuven.ac.be
Background. Tramadol is potentially a very useful pain relief medication in neonates and infants. It is primarily metabolized into O-demethyl tramadol (M1) by CYP2D6. Data concerning tramadol disposition and CYP2D6 activity in young infants are not available.
Methods. A population pharmacokinetic analysis of tramadol and M1 time–concentration profiles was undertaken using non-linear mixed-effects models (NONMEM), based on newly collected data on tramadol and M1 time–concentration profiles in neonates and young infants (n=20) and published studies on intravenous tramadol in children and adults. M1 formation served as a surrogate for CYP2D6 activity.
Results. Tramadol clearance was described using a two-compartment linear model with zero-order input and first-order elimination. Clearance increased from 25 weeks post-conception age (PCA) (5.52 litre h–1 [70 kg]–1) to reach 84% of the mature value by 44 weeks PCA (standardized to a 70 kg adult using allometric ‘1/4 power’ models). The central volume of distribution decreased from 25 weeks PCA (256 litre [70 kg]–1) to reach 120% of its mature value by 87 weeks PCA. Formation clearance to M1 contributed 43% of tramadol clearance, but had no relationship with PCA. There was a weak non-linear relationship between PCA and M1 metabolite clearance.
Conclusions. Maturational clearance of tramadol is almost complete by 44 weeks PCA. A target concentration of 300 µg litre–1 is achieved after a bolus of tramadol hydrochloride 1 mg kg–1 and can be maintained by infusion of tramadol hydrochloride 0.09 mg kg–1 h–1 at 25 weeks PCA, 0.14 mg kg–1 h–1 at 30 weeks PCA, 0.17 mg kg–1 h–1 at 35 weeks PCA, 0.18 mg kg–1 h–1 at 40 weeks, 0.19 mg kg–1 h–1 at 50 weeks PCA to 1 yr, 0.18 mg kg–1 h–1 at 3 yr and 0.12 mg kg–1 h–1 in adulthood. CYP2D6 activity was observed as early as 25 weeks PCA, but the impact of CYP2D6 polymorphism on the variability in pharmacokinetics, metabolism and pharmacodynamics of tramadol remains to be established.
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