Dipeptidyl Peptidase 1 Inhibitor AZD7986 Induces a Sustained, Exposure-Dependent Reduction in Neutrophil Elastase Activity in Healthy Subjects.
Clin Pharmacol Ther
; 104(6): 1155-1164, 2018 12.
Article
em En
| MEDLINE
| ID: mdl-29484635
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.
Texto completo:
1
Coleções:
01-internacional
Temas:
Geral
Base de dados:
MEDLINE
Assunto principal:
Oxazepinas
/
Benzoxazóis
/
Inibidores de Cisteína Proteinase
/
Inibidores de Serina Proteinase
/
Elastase de Leucócito
/
Catepsina C
/
Neutrófilos
Tipo de estudo:
Clinical_trials
/
Prognostic_studies
Limite:
Humans
/
Male
Idioma:
En
Revista:
Clin Pharmacol Ther
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Suécia