title: 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.
abstract: OBJECTIVE
  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 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).
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors: Merck & Co., Inc., Kenilworth, New Jersey. Electronic address: caddy@hmrboston.com.
authors: Carol
authors: C
authors: Addy
authors: Merck & Co., Inc., Kenilworth, New Jersey.
authors: Daniel
authors: D
authors: Tatosian
authors: Merck & Co., Inc., Kenilworth, New Jersey.
authors: Xiaoli S
authors: XS
authors: Glasgow
authors: Merck & Co., Inc., Kenilworth, New Jersey.
authors: Isaias N
authors: IN
authors: Gendrano
authors: Merck & Co., Inc., Kenilworth, New Jersey.
authors: Eunkyung
authors: E
authors: Kauh
authors: Merck & Co., Inc., Kenilworth, New Jersey.
authors: Ashley
authors: A
authors: Martucci
authors: Merck & Co., Inc., Kenilworth, New Jersey.
authors: Amy O
authors: AO
authors: Johnson-Levonas
authors: Merck & Co., Inc., Kenilworth, New Jersey.
authors: Diana
authors: D
authors: Selverian
authors: Merck & Co., Inc., Kenilworth, New Jersey.
authors: Catherine Z
authors: CZ
authors: Matthews
authors: Comprehensive Clinical Development, Miramar, Florida.
authors: Marie
authors: M
authors: Gutierrez
authors: Merck & Co., Inc., Kenilworth, New Jersey.
authors: John A
authors: JA
authors: Wagner
authors: Merck & Co., Inc., Kenilworth, New Jersey.
authors: S
authors: S
authors: Aubrey Stoch
mesh_terms: D000284:Administration, Oral; D000368:Aged; D019540:Area Under Curve; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000150:complications / Q000188:drug therapy*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000097:blood / Q000187:drug effects; D006442:Glycated Hemoglobin / Q000187:drug effects / Q000378:metabolism; D006574:Heterocyclic Compounds, 2-Ring / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000097:blood* / Q000150:complications; D011714:Pyrans / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; D052216:Glucagon-Like Peptide 1; D006442:Glycated Hemoglobin; D006574:Heterocyclic Compounds, 2-Ring; D007004:Hypoglycemic Agents; D011714:Pyrans; C587539:2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl)-2,6-dihydropyrrolo(3,4-c)pyrazol-5(4H)-yl)tetrahydro-2H-pyran-3-amine
keywords: obese; omarigliptin; pharmacodynamics; pharmacokinetics; type 2 diabetes mellitus