title: Tramadol disposition in the very young: an attempt to assess in vivo cytochrome P-450 2D6 activity.
abstract: 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 microg 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.
authors.affiliation: Neonatal Intensive Care Unit, Department of Paediatrics, University Hospital, Gasthuisberg, Leuven, Belgium. karel.allegaert@uz.kuleuven.ac.be
authors.forename: K
authors.initials: K
authors.lastname: Allegaert
authors.forename: B J
authors.initials: BJ
authors.lastname: Anderson
authors.forename: R
authors.initials: R
authors.lastname: Verbesselt
authors.forename: A
authors.initials: A
authors.lastname: Debeer
authors.forename: J
authors.initials: J
authors.lastname: de Hoon
authors.forename: H
authors.initials: H
authors.lastname: Devlieger
authors.forename: J N
authors.initials: JN
authors.lastname: Van Den Anker
authors.forename: D
authors.initials: D
authors.lastname: Tibboel
mesh_terms: D000328:Adult; D000701:Analgesics, Opioid / Q000493:pharmacokinetics*; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D016014:Linear Models; D008875:Middle Aged; D013997:Time Factors; D014147:Tramadol / Q000493:pharmacokinetics*
chemical_list: D000701:Analgesics, Opioid; D014147:Tramadol; D019389:Cytochrome P-450 CYP2D6