Next-generation risk assessment: Integrating in vitro data and physiologically-based pharmacokinetic (PBPK) modeling for vancomycin nephrotoxicity evaluation

• PBPK is a valuable tool to account for physiologic and intersubject variability. • PBPK approach provides a reference dose of vancomycin that induces nephrotoxicity. • PBPK modeling-facilitated reverse dosimetry provides the PoD value of 0.5 mg/day. • Vancomycin PoD value obtained with PBPK can be applied in risk assessment. • The PDE of 0.05 mg/day for vancomycin can be used in cleaning validation protocols. Recognizing the need of implementing new approach methodologies (NAMs) in the pharmaceutical industry to establish health-based limits, this study employs an innovative strategy for deriving the permitted daily exposure (PDE) value, using vancomycin as a study case. We integrated in vitro toxicity data with physiologically based pharmacokinetic modeling-facilitated reverse dosimetry (PBPK-RD) to support setting health-based exposure limits, ensuring safety in the context of vancomycin-induced nephrotoxicity. A PBPK model for vancomycin was developed using PK-Sim v.11.3 in both rodents and humans, and its predictive performance was verified by comparing observed and simulated pharmacokinetic profiles. The PBPK-RD approach was then applied to translate in vitro concentration-response data into in vivo dose-response estimates in humans, resulting in a predicted Benchmark Dose Lower Confidence Limit (BMDL 5 ) value of 0.01 mg/kg/day. This value served as the Point of Departure (PoD) for Permitted Daily Exposure (PDE) calculation, corrected for body weight of 50 kg and accounting for uncertainty factors (F). F1 and F2 were set to 1 due to using human data and incorporating interindividual variability within the model, respectively. F3 was set to 10 to address potential chronic exposure effects, while F4 and F5 were each set to 1, reflecting confidence in the dataset and the conservative nature of the PoD. This approach derived a PDE of 0.05 mg/day, lower than the traditionally calculated PDE (0.2 mg/day) based on the lowest clinical dose as the PoD. This study demonstrates the potential of PBPK-RD as a NAM-based strategy for refining toxicological assessments within the pharmaceutical industry.