Developmental pharmacology of tramadol during infancy: ontogeny, pharmacogenetics and elimination clearance

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 post-menstrual 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.