Prediction of the pharmacokinetics of the GLP-1 receptor agonist semaglutide in humans via a population pharmacokinetic model integrating interspecies scaling

Purpose: This study aimed to characterize the pharmacokinetics (PK) of semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, in different animal species and to develop a pharmacokinetic model incorporating allometric scaling for human PK prediction. Methods: Pharmacokinetic data were obtained following intravenous (IV) injection in mice (0.2 mg/kg, n = 9), rats (0.2 mg/kg, n = 4), and dogs (0.05 mg/kg, n = 4). Plasma concentrations of semaglutide were determined using a validated liquid chromatography-tandem mass spectrometry (LC–MS/MS) method. A population pharmacokinetic model incorporating an allometric equation was developed to simultaneously describe the pharmacokinetics of semaglutide in all animal species using S-ADAPT. Plasma concentration versus time profiles and pharmacokinetic parameters of semaglutide were predicted for humans by applying the average body weight. Results: The developed model adequately described the plasma concentration versus time profile of semaglutide in all animal species. The model-predicted pharmacokinetic parameters were well comparable with the observations, with the prediction errors (PE%) less than 17.73% for AUC, 20.63% for CL, and 37.76% for V_ss across the animal species. Finally, the developed model was used to predict the pharmacokinetics of semaglutide after IV injection in humans. For humans, the model-predicted median clearance (CL) and volume of distribution (V_ss) of semaglutide were 0.0397 L/h and 6.23 L, respectively. Conclusion: A population pharmacokinetic model incorporating allometric scaling was developed to simultaneously describe the PK of semaglutide in all animal species and predict its PK in humans. The developed model may be useful for better understanding the pharmacokinetics of semaglutide, leading to optimized therapeutic efficacy.