Population pharmacokinetics of the two enantiomers of tramadol and O-demethyl tramadol after surgery in children

Few data are available on the stereoselective pharmacokinetics of tramadol in children. The aim of this study was to develop a population pharmacokinetic model for the (+)- and (−)-enantiomers of tramadol and its O-demethyl tramadol metabolite (M1) in children. Twenty-five children (1–8 yr) were included in this study. Tramadol was administered after surgery by continuous infusion (loading dose, 2 mg kg−1 i.v. over 10 min followed by continuous infusion of 8 mg kg−1 over 24 h). If pain relief was inadequate, additional 1 mg kg−1 i.v. bolus doses of tramadol were given over 10 min. A two-compartment structural model was used with NONMEM. For both enantiomers of tramadol, weight was the only patient characteristic parameter showing significant covariate effects on clearance (CL). CL increased by 5.7–6.1 litre h−1 between 8–12 and 13–16 kg, and by 2.4–3.3 litre h−1 between 13–16 and 17–33 kg. The rate constants associated with the metabolite elimination [0.144 h−1, (+)-M1 and 0.18 h−1, (−)-M1] were smaller than the elimination rate constants of the parent drugs [0.243 h−1, (+)-tramadol and 0.241 h−1, (−)-tramadol], suggesting that the metabolite disposition was rate-limited by its elimination. The presence of two subpopulations of patients was suspected on the basis of the observed bimodal distributions of the AUCM1/AUCtramadol ratios. The results of this study combine relationships between tramadol CL and patient covariates that may be useful for dose adjustment. Polymorphism is likely to contribute to the interpatient variability observed in the AUC M1/AUC tramadol ratios.