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 2-3 weeks. Weekly 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 ~77-89% 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 post-prandial 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 profile support once-weekly dosing. A model-based assessment of QTc interval risk from the single ascending dose study indicated low risk of QTc prolongation within the likely clinical dose rangestatus: publishe

Rhinovirus-16 induced temporal interferon responses in nasal epithelium links with viral clearance and symptoms

Background: The temporal in vivo response of epithelial cells to a viral challenge and its association with viral clearance and clinical outcomes has been largely unexplored in asthma. Objective: To determine gene expression profiles over time in nasal epithelial cells (NECs) challenged in vivo with rhinovirus-16 (RV16) and compare to nasal symptoms and viral clearance. Methods: Patients with stable mild to moderate asthma (n = 20) were challenged intranasally with RV16. Nasal brush samples for RNA sequencing were taken 7 days prior to infection and 3, 6 and 14 days post-infection, and blood samples 4 days prior to infection and day 6 post-infection. Viral load was measured in nasal lavage fluid at day 3, 6 and 14. Results: Top differentially (>2.5-fold increase) expressed gene sets in NECs post-RV16 at days 3 and 6, compared with baseline, were interferon alpha and gamma response genes. Patients clearing the virus within 6 days (early resolvers) had a significantly increased interferon response at day 6, whereas those having cleared the virus by day 14 (late resolvers) had significantly increased responses at day 3, 6 and 14. Interestingly, patients not having cleared the virus by day 14 (non-resolvers) had no enhanced interferon responses at any of these days. The daily Cold Symptom Scores (CSS) peaked at days 3 to 5 and correlated positively with interferon response genes at day 3 (R = 0.48), but not at other time-points. Interferon response genes were also enhanced in blood at day 6 after RV16 challenge. Conclusion and Clinical Relevance: This study shows that viral load and clearance varies markedly over time in mild to moderate asthma patients exposed to a fixed RV16 dose. The host's nasal interferon response to RV16 at day 3 is associated with upper respiratory tract symptoms. The temporal interferon response in nasal epithelium associates with viral clearance in the nasal compartment

Rhinovirus Challenge in Asthmatics and Healthy Volunteers to Evaluate the Safety and Appropriate Dose of a GMP Human Rhinovirus 16 Preparation for Challenge Studies in Mild-Moderate Asthmatics taking ICS

Introduction: Rhinovirus (RV) infection is the most important trigger for asthma exacerbation. However, no GMP grade RV preparation and established protocols are available for human RV challenge studies. Aim: To establish safety and tolerability of a new GMP grade U-BIOPRED human RV16 (RV16UB) and to identify an appropriate dose to study biomarkers in asthmatics following RV challenge. Methods: Study 1: Single doses of 10, 100 and 1000 TCID50 of RV16UB were administered intranasally in healthy subjects (n=18) and 10 and 100 TCID50 in mild-moderate asthmatics on ICS control therapy (n=18), taking LABA and not taking LABA. Study 2: Single doses of 100 TCID50 were given to asthmatics on ICS not taking LABA (n=23) and changes from baseline in lung function, Asthma Control Diary (ACD), Common Cold Symptoms Score (CSS) and FeNO were determined (time weighted average days 1-7; TWA1-7). Results: Study 1: All doses of RV16UB were well tolerated in asthma and controls. A dose of 100 TCID50 induced cold symptoms and detectable viral RNA titers in most asthmatics. Study 2: Following challenge with 100 TCID50 morning and evening TWA1-7 FEV1 were significantly reduced by -1.7% and – 2.1% respectively. Max. FEV1 drop post challenge was 6.8%. TWA1-7 ACD and CSS were significantly increased after challenge (2.7 and 4.0 respectively). No significant changes in FeNO were found. Conclusion: A dose of 100 TCID50 of RV16UB was safe in asthmatics and induced a small, but significant reduction in FEV1 (-2%). Significant increases in ACD and CSS were found. Changes in biomarkers are under investigation