Tramadol (TM) is a centrally acting opioid analgesic, commonly implicated in drug overdose, driving under the influence or drug facilitated sexual assault investigations (Fernando et al 2026). Interpretation of tramadol concentrations in clinical and forensic toxicology poses a number of challenges owing to the impact of inter-individual variation in drug disposition and response, much of which is attributable to drug-gene interaction. The purpose of the present study was to develop a racemic and enantiomeric physiologically based pharmacokinetic (PBPK) model for tramadol and its active metabolite, O-desmethyltramadol, and to predict the effect of CYP2D6 phenotype on enantiomeric drug exposure. A PBPK model of racemic and enantiomeric tramadol and O-desmethyltramadol has been developed in PK-Sim® software, using sixteen clinical reference studies. Good model performance was shown through goodness-of-fit plots, low average geometric mean fold errors (GMFE) of predicated against observed for AUClast (1.39) and Cmax (1.54), and low mean relative deviation (MRD) (1.49) across all models. For the drug-gene interaction simulations, 35 out of 40 and 36 out of 40 of the predicted Cmax and AUClast were within two-fold of the observed values. Overall, this study presents the applicability for the use of PBPK modelling and simulation in improving interpretation of toxicological results within forensic science by providing a more individualised approach. Further, the novel model can be employed in future drug-drug interaction simulations.
Fernando H et al (2026). J. Toxicol. Environ. Health Sci 14:1-23.