Physiologically Based Pharmacokinetic–Pharmacodynamic-Based Quantification of Exposure–Response for Sodium Tanshinone IIA Sulfonate in Normal and Cerebral Ischemia–Reperfusion Injury Rats

Sodium tanshinone IIA sulfonate (STS) injection is clinically used to protect against cerebral ischemia–reperfusion injury (CIRI). This study aimed to establish physiologically based pharmacokinetic–pharmacodynamic (PBPK–PD) models for normal and CIRI rats and to quantitatively characterize the time–concentration–effect relationship, as well as disease-specific mechanistic differences. A middle cerebral artery occlusion rat model was established. STS was administered via the tail vein, and blood samples were collected at serial time points. High-performance liquid chromatography and enzyme-linked immunosorbent assay were used to quantify plasma STS concentrations and inflammatory markers, respectively, whereas equilibrium dialysis was performed to determine protein binding. PK-Sim and Python were used to establish a PBPK model, which was subsequently extrapolated to humans to construct PBPK–PD models. The results showed that plasma STS concentrations were consistently higher in the model rats than in normal rats. STS significantly reduced inflammatory levels in model rats, with a delayed onset of pharmacological effect. Human PBPK model simulations indicated that STS is rapidly eliminated in healthy individuals, while its elimination is reduced under pathological conditions. This study provides a robust modeling framework and methodological reference for dose optimization and prediction of clinical efficacy of STS in the treatment of CIRI.