Dipeptidyl Peptidase 1 Inhibitor AZD7986 Induces a Sustained, Exposure-Dependent Reduction in Neutrophil Elastase Activity in Healthy Subjects

Clinical Pharmacology and Therapeutics
Robert PalmérPhilip Gardiner

Abstract

Neutrophil serine proteases (NSPs), such as neutrophil elastase (NE), are activated by dipeptidyl peptidase 1 (DPP1) during neutrophil maturation. High NSP levels can be detrimental, particularly in lung tissue, and inhibition of NSPs is therefore an interesting therapeutic opportunity in multiple lung diseases, including chronic obstructive pulmonary disease (COPD) and bronchiectasis. We conducted a randomized, placebo-controlled, first-in-human study to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple oral doses of the DPP1 inhibitor AZD7986 in healthy subjects. Pharmacokinetic and pharmacodynamic data were analyzed using nonlinear mixed effects modeling and showed that AZD7986 inhibits whole blood NE activity in an exposure-dependent, indirect manner-consistent with in vitro and preclinical predictions. Several dose-dependent, possibly DPP1-related, nonserious skin findings were observed, but these were not considered to prevent further clinical development. Overall, the study results provided confidence to progress AZD7986 to phase II and supported selection of a clinically relevant dose.

References

Mar 1, 1989·The Journal of Experimental Medicine·P FouretR G Crystal
Mar 8, 1996·The Journal of Biological Chemistry·A M Westley, J Westley
Dec 2, 1999·Nature Genetics·G H Nuckolls, H C Slavkin
Dec 20, 2002·Clinical Pharmacokinetics·Jiunn H Lin, Masayo Yamazaki
Jan 7, 2004·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Lauretta M S ChanBarry H Hirst
Dec 9, 2004·The Journal of Immunology : Official Journal of the American Association of Immunologists·Christine T N PhamTimothy J Ley
Mar 8, 2008·Molecular Pharmacology·Nathalie MéthotM David Percival
Apr 29, 2009·The AAPS Journal·Anita Grover, Leslie Z Benet
Jul 14, 2010·Trends in Immunology·Charlotte SummersEdwin R Chilvers
Nov 17, 2010·Pharmacological Reviews·Brice KorkmazFrancis Gauthier
Nov 26, 2010·Journal of Pharmacokinetics and Pharmacodynamics·Wojciech Krzyzanski
Dec 18, 2010·European Journal of Pediatrics·Buket DalgıcSinan Sarı
Feb 9, 2011·The AAPS Journal·Martin BergstrandMats O Karlsson
Nov 19, 2011·Respiration; International Review of Thoracic Diseases·Javier MilaraJulio Cortijo
Feb 9, 2013·International Journal of Clinical Pharmacology and Therapeutics·Kulasiri A GunawardenaJohn Perrett
Apr 3, 2013·COPD·Robert A Sandhaus, Gerard Turino
Feb 11, 2014·Clinics in Chest Medicine·Robert A Stockley
Mar 29, 2014·Proteomics. Clinical Applications·Simon J de VeerAlain Hovnanian
Sep 23, 2014·The Journal of Clinical Investigation·Ole E SørensenNiels Borregaard
Aug 26, 2016·Immunological Reviews·Jack B Cowland, Niels Borregaard
Dec 3, 2016·American Journal of Respiratory and Critical Care Medicine·James D ChalmersThomas C Fardon
Apr 27, 2017·Chest·Eva PolverinoAntoni Torres
Aug 12, 2017·British Journal of Clinical Pharmacology·Bruce E MillerAili L Lazaar

❮ Previous
Next ❯

Citations

Sep 23, 2018·Respirology : Official Journal of the Asian Pacific Society of Respirology·Kate H Regan, Adam T Hill
Apr 2, 2020·Expert Opinion on Therapeutic Targets·Matej VizovišekBoris Turk
Jun 15, 2019·The European Respiratory Journal·Grace Oscullo YepezMiguel Ángel Martínez-García
Sep 9, 2020·The New England Journal of Medicine·James D ChalmersUNKNOWN WILLOW Investigators
Nov 18, 2018·Nature Reviews. Disease Primers·James D ChalmersPamela J McShane
Nov 10, 2020·Frontiers in Pharmacology·Chih-Chao ChiangTsong-Long Hwang
May 8, 2020·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Luciana P TavaresFrancesca Levi-Schaffer
May 31, 2019·Journal of Medicinal Chemistry·Weijie HouZhiyuan Zhang
Jul 22, 2020·Journal of Medicinal Chemistry·Brice KorkmazDieter E Jenne
Oct 23, 2021·Biochemical Pharmacology·Brice KorkmazRalph Kettritz

❮ Previous
Next ❯

Clinical Trials Mentioned

NCT03218917

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.