Population Pharmacokinetic/Pharmacodynamic Modeling of Volagidemab, a Glucagon Receptor Antagonist, in Healthy Chinese and US Subjects Following Single Subcutaneous Administration.

AIMS: Volagidemab, a fully human IgG2 monoclonal antibody, is a competitive glucagon receptor (GCGR) inhibitor that blocks endogenous glucagon (GCG) activity. This study developed a population pharmacokinetics/pharmacodynamics (PopPK/PD) model and established the exposure-response (E-R) relationship for Volagidemab.

METHODS

Data from healthy Chinese and US subjects administered a single subcutaneous (SC) dose of Volagidemab were analyzed. A PopPK/PD model characterized drug disposition and effect. E-R analyses evaluated the relationship between plasma GCG concentrations and fasting plasma glucose (FPG).

RESULTS

Volagidemab exhibited dose-dependent PK, characterized by a nonlinear distribution and linear elimination model incorporating a single transit absorption compartment. The PD response, defined as the log-transformed fold change in GCG, was well described by an Emax model. Body mass index (BMI) was identified as a significant covariate for apparent central volume of distribution (Vc). Empirical Bayes (EBE) estimates indicated no clinically meaningful differences in PopPK/PD parameters between Chinese and US subjects. E-R analysis demonstrated a linear relationship between GCG fold change and FPG. Baseline FPG was identified as a significant covariate influencing the slope, suggesting greater glucose reduction in individuals with higher baseline FPG. Simulations showed a distinct plateau in the E-R relationship, with minimal additional therapeutic effect observed between 35 and 42 mg.

CONCLUSIONS

This analysis confirms minimal ethnic differences in the PK/PD of Volagidemab between healthy Chinese and US subjects. The limited impact of covariates supports dose bridging, facilitating clinical development in China.