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 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.

Keywords: DPP-4 activity; omarigliptin; once-weekly; pharmacokinetics; type 2 diabetes mellitus.

Figure 1

Mean (± SD) plasma concentration‐time profiles of omarigliptin (nM) in healthy men following the administration of single (A, linear scale; B, log‐linear scale) and multiple oral doses of omarigliptin (C).

Figure 2

(A) Inhibition of plasma DPP‐4 activity following the administration of multiple, once‐weekly (steady state, hours after day 15) oral doses of omarigliptin 10 mg to 100 mg. Data are percentage inhibition from baseline (predose), shown as mean ± standard error. (B) DPP‐4 inhibition vs omarigliptin plasma concentration following administration of single doses of omarigliptin. (Figure shows model fit line and 95% confidence band in dashed and dotted lines.)

Figure 3

Geometric mean ± standard error preprandial/postprandial plasma active GLP‐1 (pmol/L) vs time (day‐hours) at lunch following the last dose on day 15 after multiple weekly doses (days 1, 8, and 15) of omarigliptin or placebo in healthy male volunteers.

Figure 4

Time‐matched QTcF vs plasma omarigliptin concentration (μM) from subjects in the single ascending dose study, with linear mixed‐effect model fit line.