Pharmacokinetics and Exploratory Exposure-Response Analysis of Chikusetsusaponin IVa in Myocardial...

Background: Myocardial ischemia/reperfusion injury (MIRI) remains a major limitation to effective cardioprotection. Chikusetsusaponin IVa (CS-IVa) has shown promising cardioprotective activity; however, its pharmacokinetic behavior and exposure-response relationship under MIRI pathological conditions remain insufficiently characterized. This study aimed to evaluate the disease-state-related pharmacokinetics of CS-IVa in MIRI rats and to explore its concentration-effect relationship using a revised descriptive PK framework. Methods: A rat MIRI model was established by ligation and reperfusion of the left anterior descending coronary artery. The cardioprotective effects of CS-IVa were evaluated using echocardiography, hemodynamic parameters, myocardial infarct size, histopathological examination, and biochemical markers of myocardial injury and oxidative stress. Plasma CS-IVa concentrations were quantified by UHPLC-MS/MS over 0-24 h after administration. Non-compartmental pharmacokinetic parameters were statistically compared between normal and MIRI rats. To address model reliability and parameter identifiability, candidate PK models with different structural assumptions and weighting schemes were systematically re-evaluated. The selected descriptive PK model was further assessed using the leave-one-rat-out robustness analysis. An exploratory exposure-response analysis was performed using CK-MB as the longitudinal PD endpoint, and a Ke0 sensitivity analysis was conducted to evaluate the robustness of the downstream effect-compartment interpretation. Data-driven models were retained only as supplementary exploratory predictive analyses. Results: CS-IVa improved cardiac function; reduced myocardial infarct size; attenuated histopathological injury; decreased serum CK-MB, cTnI, LDH and plasma MDA levels; and restored SOD activity in MIRI rats. In normal rats, systemic exposure to CS-IVa increased with dose escalation. Compared with normal rats at 15 mg/kg, MIRI rats showed markedly altered pharmacokinetic behavior, including reduced C_max and AUC, delayed T_max, shortened apparent half-life, and increased apparent volume of distribution. After systematic model re-evaluation, a one-compartment model with first-order absorption, no lag time, and unweighted fitting was selected as the revised working descriptive PK model, providing a better balance between model fit, parameter stability, and parsimony. The leave-one-rat-out analysis supported the robustness of this revised model. The exploratory concentration-effect analysis revealed a temporal dissociation between plasma CS-IVa exposure and CK-MB response, suggesting a delayed pharmacodynamic response. Ke0 sensitivity analysis indicated that effect-compartment-based PD fitting was sensitive to Ke0 selection; accordingly, the exposure-response analysis is interpreted as exploratory rather than as a definitive mechanistic PK/PD model. Conclusions: CS-IVa exerted cardioprotective effects in MIRI rats, while MIRI markedly altered its overall pharmacokinetic behavior. The revised analysis supports disease-state-related PK changes and an exploratory exposure-response delay between plasma CS-IVa exposure and CK-MB response. These findings provide a pharmacokinetic basis for understanding CS-IVa under MIRI pathological conditions; however, further studies incorporating individual-level PD endpoints, tissue distribution data, and clinically relevant formulations are needed before translational dosing recommendations can be made.