Phase I Clinical Trial Unit, the First Affiliated Hospital with Nanjing Medical University, Nanjing, China.
Department of Clinical Pharmacology, Pharmacy College, Nanjing Medical University, Nanjing, China.
Front Endocrinol (Lausanne). 2024 Mar 11;15:1359407. doi: 10.3389/fendo.2024.1359407. eCollection 2024.
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.
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.
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 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 model could fit the observed data well. Total bilirubin (TBIL) was a covariate of volume of peripheral compartment distribution (V), and V increased with the increase of TBIL.
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.
评估西他列汀（CAS 号：2243737-33-7）在 2 型糖尿病（T2DM）中国患者中的安全性、耐受性、药代动力学（PK）和药效动力学（PD）。建立了群体 PK/PD 模型来量化患者中西他列汀的 PK 和 PD 特征。
本研究纳入 32 例 T2DM 中国成年人。受试者随机分为西他列汀（50mg 或 100mg）、安慰剂或沙格列汀（100mg）组，每天一次，连续 14 天。采集血样进行 PK 和 PD 分析。在口服葡萄糖耐量试验（OGTT）（第 15 天）后评估对血糖、胰岛素、C 肽和胰高血糖素的影响。还进行了 HbA1c 和糖化白蛋白（GA）的影响以及安全性评估。同时，使用 Phoenix 通过序贯两步分析方法建立了群体 PK/PD 模型。
多次口服后，西他列汀吸收迅速，平均半衰期为 34.9-41.9 小时。每周一次连续给药 1 周后达到稳态，蓄积程度适中。50mg 西他列汀诱导的 DPP-4 抑制强度和持续时间与沙格列汀相当，而 100mg 西他列汀的 DPP-4 抑制持续时间（≥80%）明显长于沙格列汀。与安慰剂组相比，50mg 和 100mg 西他列汀组的血浆活性 GLP-1 AUEC 分别增加了 2.20 倍和 3.36 倍。OGTT 后，西他列汀组的血糖降低，胰岛素和 C 肽增加。同时，GA 有降低的趋势，而 HbA1c 无降低趋势。与西他列汀和沙格列汀相关的所有不良事件均被评估为轻度。成功建立了群体 PK/PD 模型。两室模型和 Sigmoid-E 模型均能很好地拟合观察数据。总胆红素（TBIL）是外周分布容积（V）的协变量，V 随 TBIL 的增加而增加。
西他列汀耐受性良好，抑制血浆 DPP-4 活性，增加血浆活性 GLP-1 水平，在 T2DM 患者中表现出一定的降糖作用趋势。建立的群体 PK/PD 模型充分描述了西他列汀的 PK 和 PD 特征。
