title: A Thorough QTc Study Confirms Early Pharmacokinetics/QTc Modeling: A Supratherapeutic Dose of Omarigliptin, a Once-Weekly DPP-4 Inhibitor, Does Not Prolong the QTc Interval.
abstract: Omarigliptin is a dipeptidyl peptidase-4 inhibitor being developed as a once-weekly treatment for type 2 diabetes. This double-blind, double-dummy, randomized, 3-period balanced crossover study definitively evaluated the effects of a supratherapeutic omarigliptin dose on QTc interval. Population-specific correction of QT interval (QTcP) was used for the primary analysis. Healthy subjects (n = 60) were enrolled and received treatments separated by a ≥4-week washout: (1) single-dose 25 mg omarigliptin (day 1), single-dose 175 mg omarigliptin (day 2); (2) placebo (day 1) followed by single-dose 400 mg moxifloxacin (day 2); (3) placebo (days 1 and 2). Day 2 QTcP intervals were analyzed. The primary hypothesis was supported if the 90%CIs for the least-squares mean differences between omarigliptin 175 mg and placebo in QTcP interval change from baseline were all < 10 milliseconds at every postdose point on day 2. The upper bounds of the 90%CIs for the differences (omarigliptin-placebo) in QTcP change from baseline for omarigliptin 175 mg were < 10 milliseconds at all postdose times on day 2. In conclusion, a supratherapeutic dose of omarigliptin does not prolong the QTcP interval to a clinically meaningful degree relative to placebo, confirming the results of the earlier concentration-QTc analysis.
authors.affiliation: Merck & Co., Inc, Kenilworth, NJ, USA. daniel_tatosian@merck.com.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Tatosian
authors.affiliation: Celerion, Lincoln, NE, USA.
authors.forename: Nadia
authors.initials: N
authors.lastname: Cardillo Marricco
authors.affiliation: Merck & Co., Inc, Kenilworth, NJ, USA.
authors.forename: Xiaoli Shirley
authors.initials: XS
authors.lastname: Glasgow
authors.affiliation: Celerion, Lincoln, NE, USA.
authors.forename: Bruce
authors.initials: B
authors.lastname: DeGroot
authors.affiliation: Celerion, Lincoln, NE, USA.
authors.forename: Katherine
authors.initials: K
authors.lastname: Dunnington
authors.affiliation: Merck & Co., Inc, Kenilworth, NJ, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: George
authors.affiliation: Merck & Co., Inc, Kenilworth, NJ, USA.
authors.forename: Isaias Noel
authors.initials: IN
authors.lastname: Gendrano
authors.affiliation: Merck & Co., Inc, Kenilworth, NJ, USA.
authors.forename: Amy O
authors.initials: AO
authors.lastname: Johnson-Levonas
authors.affiliation: Celerion, Lincoln, NE, USA.
authors.forename: Dennis
authors.initials: D
authors.lastname: Swearingen
authors.affiliation: Merck & Co., Inc, Kenilworth, NJ, USA.
authors.forename: Eunkyung
authors.initials: E
authors.lastname: Kauh
mesh_terms: D000293:Adolescent; D000328:Adult; D018592:Cross-Over Studies; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004562:Electrocardiography; D005260:Female; D024841:Fluoroquinolones / Q000008:administration & dosage* / Q000009:adverse effects; D006574:Heterocyclic Compounds, 2-Ring / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D008133:Long QT Syndrome / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D000077266:Moxifloxacin; D011714:Pyrans / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: C587539:2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl)-2,6-dihydropyrrolo(3,4-c)pyrazol-5(4H)-yl)tetrahydro-2H-pyran-3-amine; D054873:Dipeptidyl-Peptidase IV Inhibitors; D024841:Fluoroquinolones; D006574:Heterocyclic Compounds, 2-Ring; D007004:Hypoglycemic Agents; D011714:Pyrans; D000077266:Moxifloxacin
keywords: DPP-4; ECG; QTc; omarigliptin; type 2 diabetes