(T1230-05-31) Pharmacokinetics and Interspecies Scaling of Semaglutide, a GLP-1 Receptor Agonist

Purpose: The purpose of the present study was 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 of semaglutide were obtained in mice (n=3), rats (n=4), and dogs (n=4) following intravenous injection at doses of 0.4 mg/kg, 0.2 mg/kg, and 0.05 mg/kg, respectively. Plasma concentrations of semaglutide in each species were determined by the validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method (1). A population pharmacokinetic model incorporating an allometric equation was developed to simultaneously describe the pharmacokinetics of semaglutide in all animal species using S-ADAPT. By applying the average body weight, plasma concentration vs. time profiles and pharmacokinetic parameters of semaglutide were predicted for humans.

Results: The disposition parameters of semaglutide were well correlated with the body weight for all animal species using an allometric equation. A population pharmacokinetic model was thus developed by incorporating allometric scaling. The model could adequately describe all the available plasma concentration vs. time profiles of semaglutide in mice, rats, and dogs. The model-predicted clearance (CL) and the volume of distribution at steady state (Vss) were well comparable with the results from the non-compartmental analysis. The prediction error (PE%) for CL was 16.14% in mice, 14.46% in rats, and 12.61% in dogs. The PE% for Vss was 6.29% in mice, 28.48% in rats, and 14.35% in dogs. Finally, the developed model was used to predict the pharmacokinetics of semaglutide after intravenous (IV) injection for 70 kg humans. The model predicted median CL and Vss of semaglutide were 0.0465 L/hr and 4.53 L, respectively, for humans.

Conclusion: In summary, the pharmacokinetics of semaglutide was characterized in three different animal species. Based on the animal PK data, a population pharmacokinetic model incorporating allometric scaling was developed to simultaneously describe the PK of semaglutide in all animal species and predict the PK in humans. The developed model may be useful to better understand semaglutide pharmacokinetics, leading to optimized therapeutic efficacy.

References: 1. Lee TS, Park EJ, Choi M, Oh HS, An Y, Kim T, Kim TH, Shin BS, Shin S. Novel LC-MS/MS analysis of the GLP-1 analog semaglutide with its application to pharmacokinetics and brain distribution studies in rats. J Chromatogr B Analyt Technol Biomed Life Sci. 2023;1221:123688.

Acknowledgements: This work was supported by the National Research Foundation of Korea (NRF) (Grant no. NRF-2021R1A2B5B01001970).