A study on a long‑acting, PEG‑linked growth hormone (YPEG‑rhGH) in healthy older adults shows it raises IGF‑1 levels, but the boost is smaller in heavier or older people and less pronounced with longer dosing gaps. The drug follows a two‑compartment PK pattern, has mild side effects, and appears safe in this group.

Y-shape branched PEGylated recombinant human growth hormone (YPEG-rhGH) is a suitable drug for the treatment of growth hormone deficiency. The aim of this study was to establish a population pharmacokinetics/pharmacodynamics (PopPK/PD) model of YPEG-rhGH in the elderly. The safety and tolerability of the drug were investigated, and the possibility of flexible dosing regimen was explored. A total of 16 healthy elderly subjects and 36 healthy adults participated in the PopPK analysis. Only elderly subjects were included in the PopPK/PD analysis. After subcutaneous injection of the drug, serum samples were collected to analyze the time course of YPEG-rhGH concentrations and insulin-like growth factor-1 (IGF-1) levels. Additionally, the safety and tolerability of the investigational drug were evaluated. Results show that the pharmacokinetics of serum YPEG-rhGH after subcutaneous injection can be better described by a two-compartment model with first-order absorption and nonlinear elimination. The indirect response model (IDR) demonstrated good predictive capability for the relative baseline ratio of IGF-1 levels in elderly subjects following YPEG-rhGH administration. The magnitude of the increase in the relative baseline ratio of IGF-1 decreased with increasing weight, and increasing age marginally reduced the increase in the baseline ratio of YPEG-rhGH-increased IGF-1 in elderly people, but the effect decreased with increasing dosing intervals. All reported adverse reactions were mild. In the final model, AGE was identified as a significant covariate for K_a, V₁/F, and V_max, while WEIGHT significantly influenced V_max. The IDR model was consistent with the PK/PD profile of elderly subjects. The safety and tolerability of YPEG-rhGH injections in elderly subjects were favorable. <b>Clinical Trial Registration:</b> identifier CTR20230176.