Pharmacokinetics and Pharmacodynamics of Omarigliptin, a Once-Weekly Dipeptidyl Peptidase-4 (DPP-4) Inhibitor, After Single and Multiple Doses in Healthy Subjects.
J Clin Pharmacol
; 56(12): 1528-1537, 2016 12.
Article
in En
| MEDLINE
| ID: mdl-27225334
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 â¼2 L/h. DPP-4 inhibition ranged from â¼77% to 89% at 168 hours following the last of 3 once-weekly doses over the dose range studied. Omarigliptin resulted in â¼2-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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Pyrans
/
Dipeptidyl-Peptidase IV Inhibitors
/
Heterocyclic Compounds, 2-Ring
Type of study:
Clinical_trials
/
Prognostic_studies
Limits:
Adult
/
Humans
/
Male
/
Middle aged
Language:
En
Journal:
J Clin Pharmacol
Year:
2016
Type:
Article
Affiliation country:
United States