BACKGROUND AND OBJECTIVES: Efsubaglutide alfa is a novel long-acting human glucagon-like peptide-1 receptor agonist. Clinical studies in patients with type 2 diabetes (T2D) have shown excellent glucose-lowering effects. This study aims to develop a population pharmacokinetic (popPK) model for efsubaglutide alfa to characterize its pharmacokinetic (PK) profile and assess the impact of intrinsic and extrinsic factors. METHODS: A popPK model was developed using a nonlinear mixed-effects model (NONMEM) based on 4173 plasma concentration measurements of efsubaglutide alfa from 911 participants, including 36 healthy subjects and 875 patients with T2D, across four clinical trials. These trials involved once-weekly subcutaneous injections of efsubaglutide alfa at doses ranging from 0.375 mg to 9.0 mg, with treatment durations spanning from 1 to 24 weeks. Diagnostic plots, visual predictive checks, nonparametric bootstrap methods, and simulations were employed to validate the model's robustness and performance. Covariates were identified using stepwise covariate modeling. RESULTS: A two-compartment model with first-order absorption and first-order elimination adequately described the PK characteristics of efsubaglutide alfa. Efsubaglutide alfa exhibited favorable absorption (K CONCLUSIONS: The final popPK model, incorporating significant covariates (baseline WT, baseline eGFR, Nab, STUDY, and ARM), provided robust and precise PK parameter estimates, confirming its applicability in both healthy subjects and those with T2D. The minimal and clinically insignificant impact of baseline WT and eGFR on drug exposure supports the conclusion that no dose adjustment is necessary based on these factors. Moreover, the higher absorption rate constant suggests a rapid onset of action, and the extended half-life supports less frequent dosing, potentially improving patient adherence. TRIAL REGISTRATION: The trials were registered at Clinicaltrials.gov (identifiers: NCT03745885, NCT04314622, NCT04994288, and NCT04998032).