Premium
Pharmacokinetics and Pharmacodynamics of Omarigliptin, a Once‐Weekly Dipeptidyl Peptidase‐4 (DPP‐4) Inhibitor, After Single and Multiple Doses in Healthy Subjects
Author(s) -
Krishna Rajesh,
Addy Carol,
Tatosian Daniel,
Glasgow Xiaoli S.,
Gendrano III Isaias Noel,
Robberechts Martine,
Haazen Wouter,
Hoon J.N.,
Depré Marleen,
Martucci Ashley,
Peng Joanna Z.,
JohnsonLevonas Amy O.,
Wagner John A.,
Stoch S. Aubrey
Publication year - 2016
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/jcph.773
Subject(s) - pharmacokinetics , cmax , medicine , pharmacodynamics , pharmacology , dosing , qt interval , dipeptidyl peptidase 4 , postprandial , endocrinology , diabetes mellitus , type 2 diabetes , insulin
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 C max 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.