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Abstract：
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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 AUEC0-24h 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-Emax model could fit the observed data well. Total bilirubin (TBIL) was a covariate of volume of peripheral compartment distribution (V2), and V2 increased with the increase of TBIL.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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 AUEC0-24h 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-Emax model could fit the observed data well. Total bilirubin (TBIL) was a covariate of volume of peripheral compartment distribution (V2), and V2 increased with the increase of TBIL.
UNASSIGNED: 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.
摘要：
■为了评估安全性，耐受性,药代动力学（PK），西格列汀（CAS号：2243737-33-7）在中国2型糖尿病（T2DM）患者中的药效学（PD）。建立了群体PK/PD模型来量化患者西格列汀的PK和PD特征。
■32名中国2型糖尿病患者纳入本研究。受试者被随机分配接受西格列汀（50mg或100mg），安慰剂,或西格列汀（100mg）每天一次，共14天。收集血液样品用于PK和PD分析。对葡萄糖的影响，胰岛素，C-肽，和胰高血糖素在口服葡萄糖耐量试验（OGTT）（第15天）后进行评估。对糖化血红蛋白和糖化白蛋白（GA）的影响，并进行了安全性评估.同时,使用Phoenix通过序贯两步分析方法建立了人群PK/PD模型.
■多次口服后，西格列汀吸收迅速，平均半衰期为34.9-41.9h。每天给药1周后达到稳态条件，积累适度。50mg西格列汀诱导的DPP-4抑制的强度和持续时间与西格列汀诱导的强度和持续时间相当，100mg西格列汀显示出比西格列汀更长的持续DPP-4抑制作用（≥80%）。与安慰剂组相比，在50mg和100mg西格列汀组中，血浆活性GLP-1AUEC0-24h分别增加2.20和3.36倍。在西格列汀组中，OGTT后观察到血浆葡萄糖降低，胰岛素和C肽增加。同时,观察到GA降低的趋势，而HbA1c没有下降趋势。所有与西格列汀和西格列汀相关的不良事件均评估为轻度。成功建立了种群PK/PD模型。两室模型和Sigmoid-Emax模型可以很好地拟合观察到的数据。总胆红素（TBIL）是外周室分布体积（V2）的协变量，V2随TBIL的增加而增加。
■西格列汀的耐受性良好，抑制血浆DPP-4活性，血浆活性GLP-1水平升高，2型糖尿病患者有一定的降糖作用趋势。建立的群体PK/PD模型充分描述了西格列汀的PK和PD特征。
■32名中国2型糖尿病患者纳入本研究。受试者被随机分配接受西格列汀（50mg或100mg），安慰剂,或西格列汀（100mg）每天一次，共14天。收集血液样品用于PK和PD分析。对葡萄糖的影响，胰岛素，C-肽，和胰高血糖素在口服葡萄糖耐量试验（OGTT）（第15天）后进行评估。对糖化血红蛋白和糖化白蛋白（GA）的影响，并进行了安全性评估.同时,使用Phoenix通过序贯两步分析方法建立了人群PK/PD模型.
■多次口服后，西格列汀吸收迅速，平均半衰期为34.9-41.9h。每天给药1周后达到稳态条件，积累适度。50mg西格列汀诱导的DPP-4抑制的强度和持续时间与西格列汀诱导的强度和持续时间相当，100mg西格列汀显示出比西格列汀更长的持续DPP-4抑制作用（≥80%）。与安慰剂组相比，在50mg和100mg西格列汀组中，血浆活性GLP-1AUEC0-24h分别增加2.20和3.36倍。在西格列汀组中，OGTT后观察到血浆葡萄糖降低，胰岛素和C肽增加。同时,观察到GA降低的趋势，而HbA1c没有下降趋势。所有与西格列汀和西格列汀相关的不良事件均评估为轻度。成功建立了种群PK/PD模型。两室模型和Sigmoid-Emax模型可以很好地拟合观察到的数据。总胆红素（TBIL）是外周室分布体积（V2）的协变量，V2随TBIL的增加而增加。
■西格列汀的耐受性良好，抑制血浆DPP-4活性，血浆活性GLP-1水平升高，2型糖尿病患者有一定的降糖作用趋势。建立的群体PK/PD模型充分描述了西格列汀的PK和PD特征。
