Enavogliflozin is a sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor approved for clinical use in South Korea. As SGLT2 inhibitors are a treatment option for patients with diabetes, enavogliflozin is expected to be prescribed in various populations. Physiologically based pharmacokinetic (PBPK) modelling can rationally predict the concentration–time profiles under altered physiological conditions. In previous studies, one of the metabolites (M1) appeared to have a metabolic ratio between 0.20 and 0.25. In this study, PBPK models for enavogliflozin and M1 were developed using published clinical trial data. The PBPK model for enavogliflozin incorporated a non-linear urinary excretion in a mechanistically arranged kidney model and a non-linear formation of M1 in the liver. The PBPK model was evaluated, and the simulated pharmacokinetic characteristics were in a two-fold range from those of the observations. The pharmacokinetic parameters of enavogliflozin were predicted using the PBPK model under pathophysiological conditions. PBPK models for enavogliflozin and M1 were developed and validated, and they seemed useful for logical prediction.

Background/Objectives: Di(2-ethylhexyl) adipate (DEHA), a biocompatible ester plasticizer, has gained interest as a potential pharmaceutical excipient, yet its pharmacokinetics remain poorly characterized. This study aimed to develop a physiologically based pharmacokinetic (PBPK) model for DEHA and its primary metabolite, mono(2-ethylhexyl) adipate (MEHA), in rats by integrating in vitro, in vivo, in silico, and physiological data. Methods: In vitro hydrolysis was evaluated across tissues using bis-(p-nitrophenyl) phosphate (BNPP) to distinguish BNPP-sensitive and -insensitive metabolism, and tissue-specific clearances were extrapolated to the whole body using a circulatory topology-based framework accounting for sequential extraction across tissues, venous blood, and lungs. Results: Both adipates underwent rapid BNPP-sensitive hydrolysis across multiple tissues, whereas DEHA additionally exhibited BNPP-insensitive metabolism. The framework yielded reasonable estimates of the observed arterial clearance in vivo. Following oral administration, DEHA showed a reproducible double-peak plasma profile, with lymphatic transport identified as the predominant absorption route responsible for the prolonged terminal phase. The final model adequately reproduced the plasma and mesenteric lymph concentration-time profiles of DEHA and MEHA following both intravenous and oral administration. Conclusions: By integrating multi-tissue metabolism, circulatory topology, and lymphatic absorption, this study provides a quantitative framework applicable to rapidly hydrolyzed, highly lipophilic ester compounds, including pharmaceutical excipients and ester prodrugs.