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Objective: Previous experiments have demonstrated that BGM0504, a GLP-1R/GIPR dual agonist drug by molecular dynamics-guided optimization, had enhanced agonistic activity compared to tirzepatide. This study aims to investigate its safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) in Chinese healthy volunteers., Methods: A randomized, double-blind, placebo-controlled and dose-escalation Phase I study was conducted as follows: a single dose (2.5 mg) and once-weekly administration for 2 weeks to reach target doses (5, 10 and 15 mg) by titration., Results: A total of 40 volunteers received at least one dose of BGM0504 or placebo. The PK profile of BGM0504 was investigated over a wide dose range and supported once-weekly administration. It was observed that C max and AUC of BGM0504 were linearly proportional to the dose from 2.5-15 mg. The change in body weight (%) from baseline in BGM0504 groups was greater than that in the placebo group, with -3.24%, -6.26%, -7.09% and - 8.30% in 2.5, 5, 10 and 15 mg groups, respectively, indicating a certain dose correlation. Meanwhile, the potential roles of BGM0504 in glycaemic control were also observed. The most frequent adverse events reported were gastrointestinal (vomiting, nausea, decreased appetite, diarrhoea and abdominal distension)., Conclusion: BGM0504 was generally safe and well tolerated with favourable PK profile and potential role in weight loss was also confirmed. These findings support subsequent development of BGM0504 for type 2 diabetes mellitus (T2DM) and obesity., (© 2025 John Wiley & Sons Ltd.)

Aims: To evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of cetagliptin (CAS number:2243737-33-7) in Chinese patients with type 2 diabetes mellitus (T2DM). A population PK/PD model was developed to quantify the PK and PD characteristics of cetagliptin in patients., Materials and Methods: 32 Chinese adults with T2DM were enrolled in this study. The subjects were randomly assigned to receive either cetagliptin (50 mg or 100 mg), placebo, or sitagliptin (100 mg) once daily for 14 days. Blood samples were collected for PK and PD analysis. Effects on glucose, insulin, C-peptide, and glucagon were evaluated following an oral glucose tolerance test (OGTT) (day15). Effects on HbA1c and glycated albumin (GA), and safety assessments were also conducted. Meanwhile, a population PK/PD model was developed by a sequential two-step analysis approach using Phoenix., Results: Following multiple oral doses, cetagliptin was rapidly absorbed and the mean half-life were 34.9-41.9 h. Steady-state conditions were achieved after 1 week of daily dosing and the accumulation was modest. The intensity and duration of DPP-4 inhibition induced by 50 mg cetagliptin were comparable with those induced by sitagliptin, and 100 mg cetagliptin showed a much longer sustained DPP-4 inhibition (≥80%) than sitagliptin. Compared with placebo group, plasma active GLP-1 AUEC 0-24h increased by 2.20- and 3.36-fold in the 50 mg and 100 mg cetagliptin groups. A decrease of plasma glucose and increase of insulin and C-peptide were observed following OGTT in cetagliptin groups. Meanwhile, a tendency of reduced GA was observed, whereas no decreasing trend was observed in HbA1c. All adverse events related to cetagliptin and sitagliptin were assessed as mild. A population PK/PD model was successfully established. The two-compartment model and Sigmoid-E max model could fit the observed data well. Total bilirubin (TBIL) was a covariate of volume of peripheral compartment distribution (V 2 ), and V 2 increased with the increase of TBIL., Conclusions: Cetagliptin was well tolerated, inhibited plasma DPP-4 activity, increased plasma active GLP-1 levels, and exhibited a certain trend of glucose-lowering effect in patients with T2DM. The established population PK/PD model adequately described the PK and PD characteristics of cetagliptin., Competing Interests: Authors HL and DX were employed by Beijing Sun-novo Pharmaceutical Research Co., Ltd. Author DX was employed by Beijing Noahpharm Medical Technology Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This study was funded by CGene Tech (Suzhou, China) Co, Ltd. The funder had the following involvement in the study: Funding acquisition, Writing – review & editing., (Copyright © 2024 Zhou, Zhou, Wang, Xie, Lv, Zhao, Wang, Luo, Xie and Shao.)