Aims and objectives: To illustrate the complex interaction between ontogeny, i.e., age-dependent maturation, genetic polymorphisms and renal elimination clearance during infancy, based on developmental disposition of intravenous tramadol during infancy.
Background: Tramadol (M) is metabolized by O-demethylation (cytochrome P450 [CYP] 2D6) to the pharmacodynamic active metabolite O-demethyl tramadol (M1). This metabolite is subsequently eliminated by renal route while M1 formation will in part depend on ontogeny, i.e., age-dependent activity and CYP2D6 polymorphisms. However, these pathways do not mature simultaneously.
Methods: A pooled pharmacokinetic analysis of earlier reported time–concentration profiles in neonates and infants was performed with subsequent simulation of the impact of ontogeny, polymorphisms and renal elimination clearance during infancy.
Results: Tramadol plasma time–concentration profile changes with postmenstrual age. The highest metabolite concentrations occur in the 52-week infant, where M1 formation clearance (hepatic, CYP2D6) is already mature but metabolite elimination clearance (through glomerular filtration rate) is immature.
Discussion: The phenotypic observations might in part explain unanticipated (side-)effects of tramadol. In addition to the compound-specific clinical implications, it is important to stress that the maturational trends in the elimination processes described can be considered for other compounds (e.g., codeine) that undergo similar elimination routes.