Pharmacokinetic and Pharmacodynamic Effects of Multiple-dose Administration of Omarigliptin, a Once-weekly Dipeptidyl Peptidase-4 Inhibitor, in Obese Participants With and Without Type 2 Diabetes Mellitus

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• 作者：Carol Addy ; MD ; MMSc¹ ; ^&dagger ; ; ^{caddy@hmrboston.com" class="auth_mail" title="E-mail the corresponding author} ; Daniel Tatosian ; PhD¹ ; Xiaoli S. Glasgow ; PhD¹ ; Isaias N. Gendrano III ; MPH¹ ; Eunkyung Kauh ; MD ; PhD¹ ; Ashley Martucci¹ ; Amy O. Johnson-Levonas ; PhD¹ ; Diana Selverian ; RN ; BSN¹ ; Catherine Z. Matthews ; MS¹ ; Marie Gutierrez ; MD² ; ^&Dagger ; ; John A. Wagner ; MD ; PhD¹ ; ^§ ; ; S. Aubrey Stoch ; MD¹
• 关键词：obese ; omarigliptin ; pharmacodynamics ; pharmacokinetics ; type 2 diabetes mellitus
• 刊名：Clinical Therapeutics
• 出版年：2016
• 出版时间：March 2016
• 年：2016
• 卷：38
• 期：3
• 页码：516-530
• 全文大小：318 K

文摘

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.

Methods

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 A_1c ≥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/m². 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).

Findings

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 T_max 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 AUC_0–168h, C_max, and C_168h 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.

Implications

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.