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.