Target-mediated drug disposition modeling of liraglutide in rats: Implications of target engagement for pharmacodynamic predictions.

Target-mediated drug disposition (TMDD) is a pharmacokinetic phenomenon in which high-affinity binding to specific receptors leads to nonlinear pharmacokinetics. This study evaluated the pharmacokinetics and pharmacodynamics of the GLP-1 receptor agonist liraglutide in normal and diabetic rats, and developed a TMDD model to mechanistically link receptor dynamics to pharmacological outcomes. Liraglutide was administered intravenously across a wide dose range (0.005-0.8 mg/kg in normal rats; 0.005-0.2 mg/kg in diabetic rats). Plasma concentrations of liraglutide were determined using validated LC-MS/MS methods. Noncompartmental analysis revealed dose-dependent increases in clearance and volume of distribution at lower doses, consistent with TMDD behavior. A TMDD model adequately captured the observed concentration-time profiles across all dose levels. In diabetic rats, the pharmacodynamic response, measured as blood glucose reduction, exhibited a saturating relationship with both dose and plasma exposure (AUC). In contrast, the individually predicted AUC of the drug-receptor complex (AUC) showed a linear correlation with the area under the effect curve (AUEC; β = 0.93, 95% CI 0.64-1.21), suggesting that receptor occupancy may serve as a more relevant determinant of pharmacodynamic response than plasma drug concentration. Simulations further revealed dose-dependent receptor depletion and saturable drug-receptor complex formation, providing mechanistic explanations for the prolonged pharmacological effects and nonlinear exposure-response relationship of GLP-1 receptor agonists. These findings support the utility of TMDD modeling for linking receptor dynamics to pharmacodynamic outcomes and provide a translational framework for rational dose optimization of peptide therapeutics.