Speaker
Description
Background: Sepsis remains a major global health challenge, with limited effective therapies targeting dysregulated host responses. Patient heterogeneity represents a critical barrier to treatment optimization. Currently, XueBiJing injection is the only effective agent shown to modulate dysregulated host responses. This study aimed to characterize the pharmacokinetics of XueBiJing in patients with sepsis and to elucidate the pharmacokinetic basis for addressing patient heterogeneity. Methods: A clinical pharmacokinetic study involving 34 patients was conducted using an intensive sampling strategy to characterize the pharmacokinetics of XueBiJing compounds. Patient baseline characteristics, concomitant medication data, drug-drug interaction (DDI) assessments, animal model validation, and physiologically based pharmacokinetic (PBPK) modeling were integrated to evaluate the combined effects of pathophysiological alterations and polypharmacy on XueBiJing pharmacokinetics. Results: Systemic exposure exhibited limited variability between patients with sepsis and healthy individuals, with exposure ratios ranging from 1.1 to 1.7. DDI evaluations indicated favorable pharmacokinetic compatibility between XueBiJing and 90 co-administered medications. A rat edema model showed that furosemide significantly altered XueBiJing pharmacokinetics, likely by modulating edema status and renal function. PBPK modeling further indicated that systemic exposure resulted from interactions among hepatic and/or renal function, hypoalbuminemia, hyperdynamic states, and edema. Conclusions: The interplay of these determinants, together with a favorable safety profile, may contribute to the robust therapeutic efficacy of XueBiJing. These findings support a fixed-dosing strategy in sepsis treatment and provide insights for the development and precise application of therapies targeting dysregulated host responses.
