Impact of GPR39 Inhibition on Tissue Oxygen Tension in Acute Myocardial Infarction: Modeling Using an Indirect Response Pharmacokinetics/Pharmacodynamics Approach

In pre-clinal studies, VC108, a novel GPR39 inhibitor, increased myocardial O 2 tension (mpO 2 ) during different phases of acute myocardial infarction (AMI). The purpose of this work was to investigate the temporal effects of VC108 on mpO 2 using a novel population PK/PD (popPK/PD) model developed from pre-clinical data using healthy animals and animals subjected to AMI protocols. PK/PD simulations were then performed to explore mpO 2 dynamic in untested experimental scenarios. VC108 PK data fitted well to a two-compartment model with linear elimination with body weight, sex, and nominal dose identified as significant covariates influencing clearance and/or central compartment volume. Applying indirect effect model principles for representing mpO 2 flux, a structural popPK/PD model was developed to capture mpO 2 dynamics during different AMI phases: before and during coronary occlusion and after reperfusion. The model successfully captured basal mpO 2 homeostasis, ischemic decline, and reperfusion overshoot, while quantifying the contribution of VC108 to collateral blood flow and functional recovery. Dose-response relationships were simulated to measure the effect of different VC108 dose levels on permanent damage, i.e. a reduction in mpO 2 at steady state after AMI. The probability of remaining below predefined damage thresholds (mpO 2 reduction of 5% to 20%) increased with dose in both sexes, with females consistently achieving greater protection that plateaued around 1□mg/kg of VC108 for higher permanent damage. This model represents a valuable tool to describe, for the first time, VC108 efficacy data and pharmacokinetics with ischemia–reperfusion dynamics and quantify its effect in untested dose levels.