Tramadol disposition in the very young: an attempt to assess in vivo cytochrome P-450 2D6 activity |
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Authors: | Allegaert K Anderson B J Verbesselt R Debeer A de Hoon J Devlieger H Van Den Anker J N Tibboel D |
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Affiliation: | 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 |
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Abstract: | Background. Tramadol is potentially a very useful pain reliefmedication in neonates and infants. It is primarily metabolizedinto O-demethyl tramadol (M1) by CYP2D6. Data concerning tramadoldisposition and CYP2D6 activity in young infants are not available. Methods. A population pharmacokinetic analysis of tramadol andM1 timeconcentration profiles was undertaken using non-linearmixed-effects models (NONMEM), based on newly collected dataon tramadol and M1 timeconcentration profiles in neonatesand young infants (n=20) and published studies on intravenoustramadol in children and adults. M1 formation served as a surrogatefor CYP2D6 activity. Results. Tramadol clearance was described using a two-compartmentlinear model with zero-order input and first-order elimination.Clearance increased from 25 weeks post-conception age (PCA)(5.52 litre h1 [70 kg]1) to reach 84% of the maturevalue by 44 weeks PCA (standardized to a 70 kg adult using allometric1/4 power models). The central volume of distributiondecreased from 25 weeks PCA (256 litre [70 kg]1) to reach120% of its mature value by 87 weeks PCA. Formation clearanceto M1 contributed 43% of tramadol clearance, but had no relationshipwith PCA. There was a weak non-linear relationship between PCAand M1 metabolite clearance. Conclusions. Maturational clearance of tramadol is almost completeby 44 weeks PCA. A target concentration of 300 µg litre1is achieved after a bolus of tramadol hydrochloride 1 mg kg1and can be maintained by infusion of tramadol hydrochloride0.09 mg kg1 h1 at 25 weeks PCA, 0.14 mg kg1h1 at 30 weeks PCA, 0.17 mg kg1 h1 at 35weeks PCA, 0.18 mg kg1 h1 at 40 weeks, 0.19 mgkg1 h1 at 50 weeks PCA to 1 yr, 0.18 mg kg1h1 at 3 yr and 0.12 mg kg1 h1 in adulthood.CYP2D6 activity was observed as early as 25 weeks PCA, but theimpact of CYP2D6 polymorphism on the variability in pharmacokinetics,metabolism and pharmacodynamics of tramadol remains to be established. |
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Keywords: | analgesics opioid, tramadol drug, tramadol, age factors pharmacokinetics, tramadol, maturation, CYP2D6 activity |
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