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 2-3 weeks. Weekly AUC and Cmax displayed 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 ∼77-89% 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 post-prandial 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 profile 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. This article is protected by copyright. All rights reserved.