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 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.

A Thorough QTc Study Confirms Early Pharmacokinetics/QTc Modeling: A Supratherapeutic Dose of Omarigliptin, a Once‐Weekly DPP‐4 Inhibitor, Does Not Prolong the QTc Interval

“…7 The upper bound of the 95%CI for the between-group difference in QTcP between omarigliptin and placebo was less than 10 milliseconds at all postdose times (range, 3.89-5.76 milliseconds; Table 2). The maximum placeboadjusted least-squares difference in QTcP during the postdose observation period was 3.66 milliseconds with a 90%CI of 1.56-5.76 milliseconds.…”

“…In a previous multipledose study, the observed arithmetic mean C max and AUC 0-168 h values for 25 mg omarigliptin administered once weekly for 3 weeks were 579 nM (231 ng/mL) and 22.1 μM·h (8.81 ug·h/mL), respectively. 7 Therefore, the supratherapeutic omarigliptin dose administered in this study yielded an approximate 8-fold exposure margin to the C max previously seen at the clinical dose (25 mg). A review of the pharmacokinetic data available to date from the omarigliptin clinical program demonstrates that the median T max generally occurs between 1 and 6 hours postdose in normal healthy subjects.…”

“…6 The QT prolongation risk of omarigliptin was assessed as an exploratory analysis in a previously conducted double-blind, randomized, placebo-controlled, multiple-period, alternating-panel rising single oral dose study (Clinical Protocol MK-3102 PN001; Merck & Co., Inc., Kenilworth, New Jersey) in healthy male subjects. 7 In this first-in-human study, plasma omarigliptin samples and corresponding triplicate 12-lead electrocardiograms (ECGs) were obtained. The results of an exploratory linear concentration-QTc (corrected using the Fridericia method) model demonstrated a nonsignificant slope of the linear QTcFversus-omarigliptin concentration curve (95%CI of slope contains zero), with a point estimate and 95%CI of 0.2797 ms/μM (−0.2523 to 0.8117 ms/μM).…”

Ultra‐high pressure liquid chromatography–tandem mass spectrometry method for the determination of omarigliptin in rat plasma and its application to a pharmacokinetic study in rats

“…Although many anti-hyperglycemic agents are available, most of them still fail to achieve optimal glycemic control resulting from poor medication adherence (Krishna et al, 2016). More than 100 million people in China are affected by Diabetes Mellitus; T2DM is the most common form, accounting for approximately 90% of all cases (Chapman et al, 2016;Chen et al, 2015b).…”

“…Compared to once-daily DPP-4 inhibitor (sitagliptin, linagliptin, vildagliptin, saxagliptin and alogliptin), omarigliptin is more potent to inhibit DPP-4 enzyme (Tan, 2016). Previous study of pharmacokinetics and pharmacodynamics in health subject showed that omarigliptin was supportive of a sustained and clinically meaningful effect; it enhanced medication persistence and adherence of patients, optimized glycemic control and also reduced the risk of complications (Krishna et al, 2016).…”