PMID- 38529396 OWN - NLM STAT- MEDLINE DCOM- 20240327 LR - 20240327 IS - 1664-2392 (Print) IS - 1664-2392 (Electronic) IS - 1664-2392 (Linking) VI - 15 DP - 2024 TI - Safety, tolerability, pharmacokinetics and pharmacokinetic-pharmacodynamic modeling of cetagliptin in patients with type 2 diabetes mellitus. PG - 1359407 LID - 10.3389/fendo.2024.1359407 [doi] LID - 1359407 AB - 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. CI - Copyright (c) 2024 Zhou, Zhou, Wang, Xie, Lv, Zhao, Wang, Luo, Xie and Shao. FAU - Zhou, Chen AU - Zhou C AD - Phase I Clinical Trial Unit, the First Affiliated Hospital with Nanjing Medical University, Nanjing, China. FAU - Zhou, Sufeng AU - Zhou S AD - Phase I Clinical Trial Unit, the First Affiliated Hospital with Nanjing Medical University, Nanjing, China. AD - Department of Clinical Pharmacology, Pharmacy College, Nanjing Medical University, Nanjing, China. FAU - Wang, Jie AU - Wang J AD - Phase I Clinical Trial Unit, the First Affiliated Hospital with Nanjing Medical University, Nanjing, China. AD - Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China. FAU - Xie, Lijun AU - Xie L AD - Phase I Clinical Trial Unit, the First Affiliated Hospital with Nanjing Medical University, Nanjing, China. FAU - Lv, Zhanhui AU - Lv Z AD - Phase I Clinical Trial Unit, the First Affiliated Hospital with Nanjing Medical University, Nanjing, China. AD - Department of Clinical Pharmacology, Pharmacy College, Nanjing Medical University, Nanjing, China. FAU - Zhao, Yuqing AU - Zhao Y AD - Phase I Clinical Trial Unit, the First Affiliated Hospital with Nanjing Medical University, Nanjing, China. FAU - Wang, Lu AU - Wang L AD - Phase I Clinical Trial Unit, the First Affiliated Hospital with Nanjing Medical University, Nanjing, China. FAU - Luo, Huan AU - Luo H AD - Clinical Development Department, Beijing Sun-novo Pharmaceutical Research Co., Ltd, Beijing, China. FAU - Xie, Daosheng AU - Xie D AD - Clinical Development Department, Beijing Sun-novo Pharmaceutical Research Co., Ltd, Beijing, China. AD - Clinical Development Department, Beijing Noahpharm Medical Technology Co., Ltd, Beijing, China. FAU - Shao, Feng AU - Shao F AD - Phase I Clinical Trial Unit, the First Affiliated Hospital with Nanjing Medical University, Nanjing, China. AD - Department of Clinical Pharmacology, Pharmacy College, Nanjing Medical University, Nanjing, China. LA - eng PT - Journal Article PT - Randomized Controlled Trial DEP - 20240311 PL - Switzerland TA - Front Endocrinol (Lausanne) JT - Frontiers in endocrinology JID - 101555782 RN - 0 (Hypoglycemic Agents) RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - 0 (Glycated Hemoglobin) RN - 0 (C-Peptide) RN - 0 (Blood Glucose) RN - TS63EW8X6F (Sitagliptin Phosphate) RN - 89750-14-1 (Glucagon-Like Peptide 1) RN - 0 (Insulin) SB - IM MH - Adult MH - Humans MH - *Diabetes Mellitus, Type 2 MH - Hypoglycemic Agents/adverse effects MH - *Dipeptidyl-Peptidase IV Inhibitors/adverse effects MH - Glycated Hemoglobin MH - C-Peptide MH - Blood Glucose MH - Sitagliptin Phosphate/pharmacology/therapeutic use MH - Glucagon-Like Peptide 1 MH - Insulin/therapeutic use PMC - PMC10961402 OTO - NOTNLM OT - cetagliptin OT - dipeptidyl peptidase-4 OT - pharmacodynamics OT - pharmacokinetics OT - type 2 diabetes mellitus COIS- 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. EDAT- 2024/03/26 06:45 MHDA- 2024/03/27 06:43 PMCR- 2024/01/01 CRDT- 2024/03/26 03:44 PHST- 2023/12/21 00:00 [received] PHST- 2024/02/19 00:00 [accepted] PHST- 2024/03/27 06:43 [medline] PHST- 2024/03/26 06:45 [pubmed] PHST- 2024/03/26 03:44 [entrez] PHST- 2024/01/01 00:00 [pmc-release] AID - 10.3389/fendo.2024.1359407 [doi] PST - epublish SO - Front Endocrinol (Lausanne). 2024 Mar 11;15:1359407. doi: 10.3389/fendo.2024.1359407. eCollection 2024.