1. Dipeptidyl Peptidase 1 Inhibitor AZD7986 Induces a Sustained, Exposure‐Dependent Reduction in Neutrophil Elastase Activity in Healthy Subjects
- Author
-
Pablo Forte, Jukka Mäenpää, Robert Palmér, Alexandra Jauhiainen, Susanne Prothon, James Root, Philip Gardiner, Muir Russell, Ligia Chialda, Bengt Larsson, Torbjörn Egelrud, Kristina Stenvall, and John Mo
- Subjects
0301 basic medicine ,Male ,Proteases ,Serine Proteinase Inhibitors ,Neutrophils ,Administration, Oral ,Pharmacology ,Cysteine Proteinase Inhibitors ,Models, Biological ,Dipeptidyl peptidase ,Cathepsin C ,Drug Administration Schedule ,Serine ,03 medical and health sciences ,0302 clinical medicine ,Healthy volunteers ,Humans ,Pharmacology (medical) ,Benzoxazoles ,biology ,Dose-Response Relationship, Drug ,Chemistry ,Research ,Healthy subjects ,food and beverages ,Articles ,humanities ,Healthy Volunteers ,Dose–response relationship ,Oxazepines ,030104 developmental biology ,Nonlinear Dynamics ,030220 oncology & carcinogenesis ,Neutrophil elastase ,Neutrophil maturation ,biology.protein ,Leukocyte Elastase - 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.
- Published
- 2018