QSAR-based physiologically based pharmacokinetic (PBPK) modeling for 34 fentanyl analogs: model validation, human pharmacokinetic prediction and abuse risk insights

This study demonstrates that the QSAR-PBPK framework enables rapid prediction of human pharmacokinetics (PK) for understudied fentanyl analogs without relying on scarce experimental data. For structurally similar, clinically characterized analogs (e.g., sufentanil, alfentanil), predictions of key PK parameters (e.g., T_1/2, V_ss) fall within 1.3-1.7-fold of clinical data, supporting the framework's utility for generating testable hypotheses about the PK of understudied analogs. It not only fills the data gap for fentanyl analog hazard assessment but also provides a scalable modeling strategy for PK evaluation of other NPS or illicit drugs.