Population Pharmacokinetic/Pharmacodynamic Modeling of Volagidemab, a Glucagon Receptor Antagonist, in Healthy Chinese and US Subjects Following Single Subcutaneous Administration.
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.
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).
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.
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.
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).
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.
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.
Authors
Hu Hu, Zhu Zhu, Tang Tang, Zhu Zhu, Yu Yu, Huang Huang, Yan Yan, Xu Xu, He He
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