Physiologically based pharmacokinetic modeling as a translational tool in forensic toxicology: from pig to human synthetic cannabinoid toxicokinetics using 5F-Cumyl-P7AICA and its major metabolite as a case study

Synthetic cannabinoids are increasingly associated with severe adverse events and fatalities. The SC 5F-Cumyl-P7AICA (5FC) is particularly concerning due to its high potency. Human studies of such compounds are ethically and practically constrained, highlighting the value of physiologically based pharmacokinetic/toxicokinetic (PBTK) modeling as a translational tool. Here, we developed a PBTK model for 5FC and its primary metabolite N-pentanoic acid (NPA) in pigs and translated it to humans for predicting systemic and tissue-specific exposure. Using the published toxicokinetic data in pigs receiving 200 µg/kg 5FC via intravenous (IV) and inhalation routes, a parent-metabolite PBTK model was built. Serum, whole blood, and fat tissue concentrations were used for calibration and evaluation. The model was used to predict various tissue concentrations in pigs as well as translated to humans using species-specific physiological parameters and in vitro-measured human plasma protein binding and subsequently compared with allometric scaling of a population TK model. The pig model accurately predicted mean concentration-time profiles (MRD: 1.49 and 2.19 for 5FC, 1.51 and 1.62 for NPA, IV and inhalation, respectively). Individual predictions fell within two-fold of observed values for all TK parameters. The human PBTK model predicted lower 5FC exposure compared to allometric scaling after both IV and inhalation dosing, while NPA exposure was comparable after IV and higher after inhalation dosing. Tissue-level simulations in humans showed organ-specific distribution patterns for both compounds. In conclusion, the PBTK model described 5FC and NPA disposition in pigs, including tissue concentrations and generated exploratory human systemic and tissue exposure predictions.