Tramadol disposition in the very young: an attempt to assess in vivo cytochrome P-450 2D6 activity

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 time–concentration profiles was undertaken using non-linearmixed-effects models (NONMEM), based on newly collected dataon tramadol and M1 time–concentration 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 h^–1 [70 kg]^–1) to reach 84% of the maturevalue by 44 weeks PCA (standardized to a 70 kg adult using allometric‘1/4 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 litre^–1is achieved after a bolus of tramadol hydrochloride 1 mg kg^–1and can be maintained by infusion of tramadol hydrochloride0.09 mg kg^–1 h^–1 at 25 weeks PCA, 0.14 mg kg^–1h^–1 at 30 weeks PCA, 0.17 mg kg^–1 h^–1 at 35weeks PCA, 0.18 mg kg^–1 h^–1 at 40 weeks, 0.19 mgkg^–1 h^–1 at 50 weeks PCA to 1 yr, 0.18 mg kg^–1h^–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 theimpact of CYP2D6 polymorphism on the variability in pharmacokinetics,metabolism and pharmacodynamics of tramadol remains to be established.