Impact of GPR39 Inhibition on Tissue Oxygen Tension in Acute Myocardial Infarction: Modeling Using an Indirect Response Pharmacokinetics/Pharmacodynamics Approach
- 1Oregon Health and Science University
Abstract
In pre-clinal studies, VC108, a novel GPR39 inhibitor, increased myocardial O2 tension (mpO2) during different phases of acute myocardial infarction (AMI). The purpose of this work was to investigate the temporal effects of VC108 on mpO2 using a novel population PK/PD model developed from preclinical data using healthy animals and animals subjected to AMI protocols. PK/PD simulations were then performed to explore mpO2 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 mpO2 flux, a structural population PK/PD model was developed to capture mpO2 dynamics during different AMI phases: before and during coronary occlusion and after reperfusion. The model successfully captured basal mpO2 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 mpO2 at steady state after AMI. The probability of remaining below predefined damage thresholds (mpO2 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.
Related
- Enhancer of Zeste Homolog 2 Inhibition Attenuates Atrial Fibrillation Post-Myocardial Infarction Through Reduced Atrial Fibrosis
- CSF pharmacokinetics-pharmacodynamics of linezolid in critically brain injured patients, with or without central nervous system healthcare-associated infection. The PK-Pop-LCR Study: A Multicentre Pharmacokinetics and Pharmacodynamics Population Study
- Translational Pharmacokinetics and Pharmacodynamics of a Cationic mRNA-Lipid Nanoparticle from Mice to Non-Human Primates
- miR-20a-5p inhibition attenuates post-myocardial infarction ventricular remodeling in association with mTORC1/S6 signaling
- Dapagliflozin Attenuates Post-Infarction Myocardial Fibrosis Associated With the Inhibition of NLRP3-Dependent Inflammation
BibTeX
@misc{ronchi2026impact,
title = {{Impact of GPR39 Inhibition on Tissue Oxygen Tension in Acute Myocardial Infarction: Modeling Using an Indirect Response Pharmacokinetics/Pharmacodynamics Approach}},
author = {D. Ronchi and C. Roversi and S. Zannoni and A. De Carlo and R. Visentin and A. Tagliavini and M. Pergher and A. Pellacani and L. Morbioli and J. Franchi and C. Methner and a. Parazzoli and S. Kaul},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.24.754288},
url = {https://www.biorxiv.org/content/10.64898/2026.09.24.754288v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Impact of GPR39 Inhibition on Tissue Oxygen Tension in Acute Myocardial Infarction: Modeling Using an Indirect Response Pharmacokinetics/Pharmacodynamics Approach
AU - D. Ronchi
AU - C. Roversi
AU - S. Zannoni
AU - A. De Carlo
AU - R. Visentin
AU - A. Tagliavini
AU - M. Pergher
AU - A. Pellacani
AU - L. Morbioli
AU - J. Franchi
AU - C. Methner
AU - a. Parazzoli
AU - S. Kaul
PY - 2026
DA - 2026/09/24
PB - bioRxiv
DO - 10.64898/2026.09.24.754288
UR - https://www.biorxiv.org/content/10.64898/2026.09.24.754288v1
AB - In pre-clinal studies, VC108, a novel GPR39 inhibitor, increased myocardial O2 tension (mpO2) during different phases of acute myocardial infarction (AMI). The purpose of this work was to investigate the temporal effects of VC108 on mpO2 using a novel population PK/PD model developed from preclinical data using healthy animals and animals subjected to AMI protocols. PK/PD simulations were then performed to explore mpO2 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 mpO2 flux, a structural population PK/PD model was developed to capture mpO2 dynamics during different AMI phases: before and during coronary occlusion and after reperfusion. The model successfully captured basal mpO2 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 mpO2 at steady state after AMI. The probability of remaining below predefined damage thresholds (mpO2 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.
ER -