title: Pharmacokinetics and Pharmacodynamics of Omarigliptin, a Once-Weekly Dipeptidyl Peptidase-4 (DPP-4) Inhibitor, After Single and Multiple Doses in Healthy Subjects.
abstract: The pharmacokinetics (PK) and pharmacodynamics (PD) of omarigliptin, a novel once-weekly DPP-4 inhibitor, were assessed following single and multiple doses in healthy subjects. Absorption was rapid, and food did not influence single-dose PK. Accumulation was minimal, and steady state was reached after 2 to 3 weeks. Weekly (area under the curve) AUC and Cmaxdisplayed dose proportionality within the dose range studied at steady state. The average renal clearance of omarigliptin was ∼2 L/h. DPP-4 inhibition ranged from ∼77% to 89% at 168 hours following the last of 3 once-weekly doses over the dose range studied. Omarigliptin resulted in ∼2-fold increases in weighted average postprandial active GLP-1. Omarigliptin acts by stabilizing active GLP-1, which is consistent with its mechanism of action as a DPP-4 inhibitor. Administration of omarigliptin was generally well tolerated in healthy subjects, and both the PK and PD profiles support once-weekly dosing. A model-based assessment of QTc interval risk from the single ascending dose study predicted a low risk of QTc prolongation within the likely clinical dose range, a finding later confirmed in a thorough QT trial.
authors.affiliation: Merck & Co, Kenilworth, NJ, USA.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Krishna
authors.affiliation: HMR Weight Management Services, Boston, MA, USA.
authors.forename: Carol
authors.initials: C
authors.lastname: Addy
authors.affiliation: Merck & Co, Kenilworth, NJ, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Tatosian
authors.affiliation: Merck & Co, Kenilworth, NJ, USA.
authors.forename: Xiaoli S
authors.initials: XS
authors.lastname: Glasgow
authors.affiliation: Merck & Co, Kenilworth, NJ, USA.
authors.forename: Isaias Noel
authors.initials: IN
authors.lastname: Gendrano Iii
authors.affiliation: Merck & Co, Kenilworth, NJ, USA.
authors.forename: Martine
authors.initials: M
authors.lastname: Robberechts
authors.affiliation: Johnson & Johnson, Belgium.
authors.forename: Wouter
authors.initials: W
authors.lastname: Haazen
authors.affiliation: U.Z. Gasthuisberg Center for Clinical Pharmacology, Leuven, Belgium.
authors.forename: J N
authors.initials: JN
authors.lastname: de Hoon
authors.affiliation: U.Z. Gasthuisberg Center for Clinical Pharmacology, Leuven, Belgium.
authors.forename: Marleen
authors.initials: M
authors.lastname: Depré
authors.affiliation: Merck & Co, Kenilworth, NJ, USA.
authors.forename: Ashley
authors.initials: A
authors.lastname: Martucci
authors.affiliation: Seattle Genetics, Bothell, WA, USA.
authors.forename: Joanna Z
authors.initials: JZ
authors.lastname: Peng
authors.affiliation: Merck & Co, Kenilworth, NJ, USA.
authors.forename: Amy O
authors.initials: AO
authors.lastname: Johnson-Levonas
authors.affiliation: Takeda Pharmaceuticals, Cambridge, MS, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Wagner
authors.affiliation: Merck & Co, Kenilworth, NJ, USA.
authors.forename: S Aubrey
authors.initials: SA
authors.lastname: Stoch
mesh_terms: D000328:Adult; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D064368:Healthy Volunteers; D006574:Heterocyclic Compounds, 2-Ring / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011714:Pyrans / Q000008:administration & dosage* / Q000493:pharmacokinetics*
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; D006574:Heterocyclic Compounds, 2-Ring; D011714:Pyrans
keywords: DPP-4 activity; omarigliptin; once-weekly; pharmacokinetics; type 2 diabetes mellitus