Covariates of tramadol disposition in the first months of life

Background. Data on contributors to between-individual variability in overall tramadol clearance and O-demethyl tramadol (M1) formation in preterm neonates and young infants are limited. Methods. A population pharmacokinetic analysis of tramadol and M1 was undertaken using non-linear mixed effects model. Covariate analysis included weight, postmenstrual age (PMA), postnatal age (PNA), creatinaemia, (cardiac) surgery, cardiac defect, and cytochrome (CYP)2D6 polymorphisms, classified by CYP2D6 activity score. Results. In 57 patients (25-54 weeks PMA), 593 observations were collected. Tramadol clearance was described using a two-compartment, zero-order input, first-order elimination linear model. An additional compartment was used to characterize M1. Tramadol clearance at term age was 17.1 litre h(-1) (70 kg) 21 (CV, 37.2%). Size (37.8%) and PMA (27.3%) contribute to this variability. M1 formation clearance (CL2M1, i. e. the contribution of M1 synthesis to M clearance) was 4.11 litre h(-1) (70 kg) 21 (CV, 110.9%) at term age. Size and PMA were the major contributors to the variability (52.7%); the CYP2D6 activity score contributes 6.4% to this variability. Conclusions. Overall tramadol clearance estimates confirm earlier reports while CL2M1 variability is explained by size, PMA, and CYP2D6 polymorphisms. The CL2M1 is very low in preterm neonates, irrespective of the CYP2D6 polymorphism with subsequent rapid maturation. The slope of this increase depends on the CYP2D6 activity score. The current pharmacokinetic observations suggest a limited mu-opioid receptor-mediated analgesic effect of M1 in preterm neonates and a potential CYP2D6 polymorphism-dependent effect beyond term age.