Pharmacokinetics and Pharmacodynamics of Omarigliptin, a Once‐Weekly Dipeptidyl Peptidase‐4 (DPP‐4) Inhibitor, After Single and Multiple Doses in Healthy Subjects. (17th June 2016)

• Record Type: Journal Article
• Authors: Krishna, Rajesh; Addy, Carol; Tatosian, Daniel; Glasgow, Xiaoli S.; Gendrano III, Isaias Noel; Robberechts, Martine; Haazen, Wouter; de Hoon, J.N.; Depré, Marleen; Martucci, Ashley; Peng, Joanna Z.; Johnson‐Levonas, Amy O.; Wagner, John A.; Stoch, S. Aubrey
• Is Part Of: Journal of clinical pharmacology. Volume 56:Number 12(2016)
• Page Start: 1528
• Page End: 1537
• Publication Date: 2016-06-17
• Subjects: DPP‐4 activity -- omarigliptin -- once‐weekly -- pharmacokinetics -- type 2 diabetes mellitus; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Pharmacology, Clinical -- Periodicals; 615.1
• DOI: 10.1002/jcph.773
• Languages: English
• ISSNs: 0091-2700

Abstract

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 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% 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.