Addy Carol, Tatosian Daniel, Glasgow Xiaoli S, Gendrano Isaias N, Kauh Eunkyung, Martucci Ashley, Johnson-Levonas Amy O, Selverian Diana, Matthews Catherine Z, Gutierrez Marie, Wagner John A, Aubrey Stoch S
Merck & Co., Inc., Kenilworth, New Jersey.
Merck & Co., Inc., Kenilworth, New Jersey.
Clin Ther. 2016 Mar;38(3):516-30. doi: 10.1016/j.clinthera.2015.12.020. Epub 2016 Feb 9.
Omarigliptin (MK-3102) is a potent, oral, long-acting dipeptidyl peptidase (DPP)-4 inhibitor approved in Japan and in global development as a once-weekly treatment for type 2 diabetes mellitus (T2DM). The aim of this study was to investigate the pharmacokinetic (PK) and pharmacodynamic (PD) effects of omarigliptin in obese participants with and without T2DM.
This was a Phase I, randomized, double-blind, placebo-controlled, multiple-dose study of 50-mg omarigliptin administered once weekly for 4 weeks. Participants included 24 obese but otherwise healthy subjects (panel A; omarigliptin, n = 18; placebo, n = 6) and 8 obese patients with T2DM (treatment naive, hemoglobin A1c ≥ 6.5% and ≤ 10.0% [panel B]; omarigliptin, n = 6; placebo, n = 2). Participants were 45 to 65 years of age with a body mass index of ≥ 30 and ≤ 40 kg/m(2). Blood sampling occurred at select time points, depending on the study panel, to evaluate the PK properties of omarigliptin, DPP-4 activity, active glucagon-like peptide 1 levels, and plasma glucose concentrations. Body weight was an exploratory end point. Due to sparse sampling in panel A, a thorough PK analysis was performed in obese patients with T2DM (panel B) only. PD analyses were performed in the overall study population (pooled panels A and B).
PK profiles in obese participants with and without T2DM were similar to those observed in nonobese reference subjects (historical data). Steady state was achieved after 1 or 2 weekly doses in obese participants with and without T2DM. In obese patients with T2DM, omarigliptin was rapidly absorbed, with a median Tmax of 1 to 2.5 hours (days 1 and 22). Compared with those in reference subjects, the geometric mean ratios (95% CI) (Obese T2DM/reference) for steady-state plasma AUC0-168h, Cmax, and C168h were 0.80 (0.65-0.98), 0.86 (0.53-1.41), and 1.08 (0.88-1.33), respectively. Trough DPP-4 activity was inhibited by ~90%; postprandial (PP) 4-hour weighted mean active GLP-1 concentrations were increased ~2-fold; and PP glucose was significantly reduced with omarigliptin versus placebo in the pooled population. Omarigliptin was generally well-tolerated in the pooled population, and there were no hypoglycemic events. Consistent with other DPP-4 inhibitors, omarigliptin had no effect on body weight in this short-duration study.
The administration of omarigliptin was generally well-tolerated in obese participants with and without T2DM, and the favorable PK and PD profiles support once-weekly dosing. Omarigliptin may provide an important once-weekly treatment option for patients with T2DM. ClinicalTrials.gov identifier: NCT01088711.
奥格列汀（MK-3102）是一种强效的口服长效二肽基肽酶（DPP）-4抑制剂，已在日本获批，目前正处于全球研发阶段，用于2型糖尿病（T2DM）的每周一次治疗。本研究旨在调查奥格列汀在有和没有T2DM的肥胖受试者中的药代动力学（PK）和药效学（PD）效应。
这是一项I期随机、双盲、安慰剂对照的多剂量研究，每周一次给予50 mg奥格列汀，持续4周。参与者包括24名肥胖但其他方面健康的受试者（A组；奥格列汀，n = 18；安慰剂，n = 6）和8名肥胖的T2DM患者（初治患者，糖化血红蛋白A1c≥6.5%且≤10.0%[B组]；奥格列汀，n = 6；安慰剂，n = 2）。参与者年龄在45至65岁之间，体重指数≥30且≤40 kg/m²。根据研究组的不同，在选定的时间点进行血样采集，以评估奥格列汀的PK特性、DPP-4活性、活性胰高血糖素样肽1水平和血浆葡萄糖浓度。体重是一个探索性终点。由于A组采样稀疏，仅在肥胖的T2DM患者（B组）中进行了全面的PK分析。在整个研究人群（A组和B组合并）中进行了PD分析。
有和没有T2DM的肥胖受试者的PK曲线与在非肥胖参考受试者中观察到的相似（历史数据）。有和没有T2DM的肥胖受试者在每周1或2次给药后达到稳态。在肥胖的T2DM患者中，奥格列汀吸收迅速，中位达峰时间为1至2.5小时（第1天和第22天）。与参考受试者相比，稳态血浆AUC0-168h、Cmax和C168h的几何平均比值（95%CI）（肥胖T2DM/参考）分别为0.80（0.65-0.98）、0.86（0.53-1.41）和1.08（0.88-1.33）。谷值DPP-4活性被抑制约90%；餐后（PP）4小时加权平均活性GLP-1浓度增加约2倍；在合并人群中，与安慰剂相比，奥格列汀使PP血糖显著降低。奥格列汀在合并人群中总体耐受性良好，且无低血糖事件。与其他DPP-4抑制剂一致，在这项短期研究中，奥格列汀对体重没有影响。
奥格列汀在有和没有T2DM的肥胖受试者中总体耐受性良好，其良好的PK和PD曲线支持每周一次给药。奥格列汀可能为T2DM患者提供一种重要的每周一次治疗选择。ClinicalTrials.gov标识符：NCT01088711。
