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

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.

Pharmacokinetic and Pharmacodynamic Effects of Multiple-dose Administration of Omarigliptin, a Once-weekly Dipeptidyl Peptidase-4 Inhibitor, in Obese Participants With and Without Type 2 Diabetes Mellitus.

PURPOSE: Omarigliptin (MK-3102) is a potent, oral, long-acting dipeptidyl peptidase (DPP)-4 inhibitor approved in Japan and in global development as a once-weekly treatment for type 2 diabetes mellitus (T2DM). The aim of this study was to investigate the pharmacokinetic (PK) and pharmacodynamic (PD) effects of omarigliptin in obese participants with and without T2DM. METHODS: This was a Phase I, randomized, double-blind, placebo-controlled, multiple-dose study of 50-mg omarigliptin administered once weekly for 4 weeks. Participants included 24 obese but otherwise healthy subjects (panel A; omarigliptin, n = 18; placebo, n = 6) and 8 obese patients with T2DM (treatment naive, hemoglobin A1c ≥ 6.5% and ≤ 10.0% [panel B]; omarigliptin, n = 6; placebo, n = 2). Participants were 45 to 65 years of age with a body mass index of ≥ 30 and ≤ 40 kg/m(2). Blood sampling occurred at select time points, depending on the study panel, to evaluate the PK properties of omarigliptin, DPP-4 activity, active glucagon-like peptide 1 levels, and plasma glucose concentrations. Body weight was an exploratory end point. Due to sparse sampling in panel A, a thorough PK analysis was performed in obese patients with T2DM (panel B) only. PD analyses were performed in the overall study population (pooled panels A and B). FINDINGS: PK profiles in obese participants with and without T2DM were similar to those observed in nonobese reference subjects (historical data). Steady state was achieved after 1 or 2 weekly doses in obese participants with and without T2DM. In obese patients with T2DM, omarigliptin was rapidly absorbed, with a median Tmax of 1 to 2.5 hours (days 1 and 22). Compared with those in reference subjects, the geometric mean ratios (95% CI) (Obese T2DM/reference) for steady-state plasma AUC0-168h, Cmax, and C168h were 0.80 (0.65-0.98), 0.86 (0.53-1.41), and 1.08 (0.88-1.33), respectively. Trough DPP-4 activity was inhibited by ~90%; postprandial (PP) 4-hour weighted mean active GLP-1 concentrations were increased ~2-fold; and PP glucose was significantly reduced with omarigliptin versus placebo in the pooled population. Omarigliptin was generally well-tolerated in the pooled population, and there were no hypoglycemic events. Consistent with other DPP-4 inhibitors, omarigliptin had no effect on body weight in this short-duration study. IMPLICATIONS: The administration of omarigliptin was generally well-tolerated in obese participants with and without T2DM, and the favorable PK and PD profiles support once-weekly dosing. Omarigliptin may provide an important once-weekly treatment option for patients with T2DM. ClinicalTrials.gov identifier: NCT01088711.

The Dose Proportionality of Telcagepant after Administration of Single Oral and Intravenous Doses in Healthy Adult Subjects.

INTRODUCTION: Telcagepant (MK-0974) is a novel, orally active and selective CGRP receptor antagonist being investigated for acute treatment of migraine. Early clinical data suggested greater than dose proportional increases in exposure following oral administration. The aim of the present studies was to definitively characterize the oral and IV dose proportionality of telcagepant. METHODS: Healthy adult subjects were enrolled in two separate open-label randomized dose proportionality studies: 1) single oral dose crossover from 50 to 600 mg (N = 19); 2) single IV dose parallel group from 5 to 250 mg (N = 10 per dose). Blood samples were collected at time points from 0 to 48 hours postdose. RESULTS: Telcagepant was rapidly absorbed with a T(max) of approximately 1 to 2 hours after oral administration. The terminal half-life was approximately 8 to 9 hours after IV dosing and approximately 4 to 7 hours after oral dosing. Oral administration of telcagepant resulted in greater than dose proportional increases in exposure, while IV administration resulted in approximately dose proportional increases in exposure. CONCLUSIONS: Telcagepant was generally well tolerated. Oral telcagepant exhibits non-linear pharmacokinetics.

A flexible and high throughput liquid chromatography-tandem mass spectrometric assay for the quantitation of telcagepant in human plasma.

Telcagepant (MK-0974) is a novel oral calcitonin gene-related peptide (CGRP) receptor antagonist and is currently under clinical development. Results from phases II and III clinical trials have suggested that telcagepant is effective for migraine treatment. A reliable and high throughput protein precipitation (PPT) method for determination of telcagepant in human plasma using liquid chromatography coupled with atmospheric pressure chemical ionization (APCI) tandem mass spectrometry has been developed. Clinical samples, internal standard (IS) and acetonitrile are transferred into 96-well plates using a robotic liquid handling system. An aliquot of 10 microL supernatant is directly injected into the LC-MS/MS system where separation is performed on a FluoPhase RP (150 x 2.1mm, 5 microm) column with an isocratic mobile phase (60% acetonitrile with 0.1% formic acid and 40% water with 0.1% formic acid) at 0.2 mL/min. The interfering 3S-diastereomer of telcagepant, which is observed in clinical samples, is chromatographically resolved from telcagepant. The PPT procedure significantly reduces the time required for sample processing and the assay is sufficiently sensitive for detection using both API 4000 and API 3000 mass spectrometers. The linear calibration range is 5-5000 nM using 200 microL of plasma. Assay intraday validation was conducted using six calibration curves derived from six lots of human control plasma. Calibration standard accuracy did not deviate by more than 3% and 6% of nominal values, and precision did not exceed 4% coefficient of variation (CV) and 10% CV, respectively on the API 4000 and API 3000. Several clinical phases IIb and III studies have been successfully supported with this assay.