A Comprehensive Review on the Pharmacokinetics and Drug-Drug Interactions of Approved GLP-1 Receptor Agonists and a Dual GLP-1/GIP Receptor Agonist

Abstract

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are peptide-derived analogs that were initially investigated to treat type 2 diabetes. Recently, a drug targeting the receptors of both GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) (tirzepatide) has been introduced to the market, and its indications have expanded to include treating obesity. Here, we review the pharmacokinetics, pharmacokinetic drug-drug interactions (DDIs), and pharmacokinetic modeling approaches of four currently available GLP-1 RAs (exenatide, liraglutide, dulaglutide, and semaglutide) and tirzepatide. To address the extremely short half-life (2 min) of native human GLP-1, structural modifications have been applied to GLP-1 RAs and a dual GLP-1/GIP RA. These include amino acid sequence substitutions, fatty acid conjugation using a linker, and fusion with albumin or the IgG fragment crystallizable (Fc) region, resulting in minimal metabolism and renal excretion. Due to their diverse structures, the pharmacokinetic profiles vary, and a prolonged half-life may be associated with an increased risk of adverse events. Clinically significant drug-metabolizing enzyme- and transporter-mediated DDIs are yet to be reported. Mechanism-of-action-mediated DDIs are currently limited to those involving delayed gastric emptying, and most studies have found them to be clinically insignificant. However, significant changes in exposure were observed for oral contraceptives and levothyroxine following the administration of tirzepatide and oral semaglutide, respectively, indicating the need for close monitoring in these instances. Thirty models have been developed to predict pharmacokinetics and physiologically based pharmacokinetic modeling can be useful for assessing mechanism-of-action-mediated DDIs. Alterations in the volume of distribution and clearance resulting from other mechanisms of action (eg, reduced fat mass, changes in cytochrome P450 activity, and glomerular filtration rate) are key factors in determining pharmacokinetics. However, the DDIs mediated by these factors remain poorly understood and require further investigation to ensure that GLP-1 RAs can be safely used with concomitant medications.

Keywords: GIP; GLP-1; drug−drug interactions; pharmacokinetics; physiologically based pharmacokinetic model.

Figure 1

Molecular weights and amino acid sequences of human GLP-1 (A), exendin-4 (B), exenatide (C), liraglutide (D), dulaglutide (E), semaglutide (F), human GIP (G), and tirzepatide (H), with substituted amino acids marked in different colors. Created in BioRender. Min, J. (2025) https://BioRender.com/o27r742.

Figure 2

Continued.

Figure 2

Mean plasma concentration-time profiles (A–G) and pharmacokinetic parameters (H) of GLP-1 RAs and a dual GLP-1/GIP RA. (A) Mean + standard deviation (SD) plasma concentration-time profile of exenatide IR following a single dose of 10 µg in healthy participants (n = 39). Data obtained from the US FDA clinical pharmacology biopharmaceutics review of Byetta^®. (B) Mean + standard deviation (SD) plasma concentration-time profile of exenatide ER following a single dose of 2.5 mg in type 2 diabetes participants (n = 14). Adapted from Fineman M, Flanagan S, Taylor K et al. Pharmacokinetics and pharmacodynamics of exenatide extended-release after single and multiple dosing. Clin Pharmacokinet. 2011;50(1):65–74, with permission of Springer Nature. Permission conveyed through copyright clearance center, inc. (C) Mean plasma concentration-time profile of liraglutide following 1.8 mg and 3 mg doses at steady state in obese participants (n = 30 and 32, respectively). Data obtained from US FDA clinical pharmacology biopharmaceutics review of liraglutide. (D) Mean plasma concentration-time profile of dulaglutide following a single dose of 0.1–12 mg in healthy participants. Data obtained from US FDA clinical pharmacology biopharmaceutics review of dulaglutide. (E) Mean + standard deviation (SD) plasma concentration-time profile of oral semaglutide following a single dose of 10 mg in healthy participants (n = 11). Data obtained from US FDA clinical pharmacology biopharmaceutics review of Rybelsus^®. (F) Mean plasma concentration-time profile of semaglutide following 0.5 mg and 1 mg doses at steady state in healthy participants (n = 8). Data obtained from US FDA clinical pharmacology biopharmaceutics review of semaglutide. (G) Mean + standard deviation (SD) plasma concentration-time profile of tirzepatide following a single dose of 0.25–8 mg in healthy participants. Data obtained from US FDA clinical pharmacology biopharmaceutics review of tirzepatide. (H) Pharmacokinetic parameters of approved GLP-1 RAs and a dual GLP-1/GIP RA. A power model was used for the statistical analysis of dose proportionality for AUC_0-∞ and C_max. Data points were digitized using GetData Graph Digitizer (version 2.26) from graphical representations. Created in GraphPad Prism 10 (GraphPad Software, San Diego, CA, USA).

Figure 3

Flowchart illustrating the process of pharmacokinetic DDIs mediated by the mechanisms of action of approved GLP-1 RAs and a dual GLP-1/GIP RA; 1) GLP-1 RAs or a dual GLP-1/GIP RA (perpetrator) administration triggers receptor activation in GLP-1 receptor-expressing organs, leading to drug efficacy → 2) Physiological changes in the human body due to the drug effect → 3) Pharmacokinetic changes of small-molecule drugs (victim) influenced by these physiological changes. Created in BioRender. Min, J. (2025) https://BioRender.com/g44y018.