دورية أكاديمية
أعرض في EDS

Pharmacokinetic/Pharmacodynamic Evaluation of the Dipeptidyl Peptidase 1 Inhibitor Brensocatib for Non-cystic Fibrosis Bronchiectasis.

التفاصيل البيبلوغرافية
العنوان: Pharmacokinetic/Pharmacodynamic Evaluation of the Dipeptidyl Peptidase 1 Inhibitor Brensocatib for Non-cystic Fibrosis Bronchiectasis.
المؤلفون: Chalmers JD; Division of Molecular and Clinical Medicine, Ninewells Hospital and Medical School, Dundee, DD1 9SY, UK. jchalmers@dundee.ac.uk., Usansky H; Insmed Incorporated, Bridgewater, NJ, USA., Rubino CM; Institute for Clinical Pharmacodynamics, Inc, Schenectady, NY, USA., Teper A; Insmed Incorporated, Bridgewater, NJ, USA., Fernandez C; Insmed Incorporated, Bridgewater, NJ, USA., Zou J; Insmed Incorporated, Bridgewater, NJ, USA., Mange KC; Insmed Incorporated, Bridgewater, NJ, USA.
المصدر: Clinical pharmacokinetics [Clin Pharmacokinet] 2022 Oct; Vol. 61 (10), pp. 1457-1469. Date of Electronic Publication: 2022 Jul 25.
نوع المنشور: Clinical Trial, Phase I; Clinical Trial, Phase II; Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Country of Publication: Switzerland NLM ID: 7606849 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1179-1926 (Electronic) Linking ISSN: 03125963 NLM ISO Abbreviation: Clin Pharmacokinet Subsets: MEDLINE
أسماء مطبوعة: Publication: [Switzerland] : Adis, part of Springer Science+Business Media
Original Publication: New York, ADIS Press.
مواضيع طبية MeSH: Bronchiectasis*/drug therapy , Cystic Fibrosis*, Adult ; Benzoxazoles ; Cathepsin G ; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/therapeutic use ; Fibrosis ; Humans ; Leukocyte Elastase/therapeutic use ; Myeloblastin ; Oxazepines ; Serine Proteases/therapeutic use
مستخلص: Background and Objective: Brensocatib is an investigational, first-in-class, selective, and reversible dipeptidyl peptidase 1 inhibitor that blocks activation of neutrophil serine proteases (NSPs). The NSPs neutrophil elastase, cathepsin G, and proteinase 3 are believed to be central to the pathogenesis of several chronic inflammatory diseases, including bronchiectasis. In a phase II study, oral brensocatib 10 mg and 25 mg reduced sputum neutrophil elastase activity and prolonged the time to pulmonary exacerbation in patients with non-cystic fibrosis bronchiectasis (NCFBE). A population pharmacokinetic (PPK) model was developed to characterize brensocatib exposure, determine potential relationships between brensocatib exposure and efficacy and safety measures, and inform dose selection in clinical studies.
Methods: Pharmacokinetic (PK) data pooled from a phase I study of once-daily brensocatib (10, 25, and 40 mg) in healthy adults and a phase II study of once-daily brensocatib (10 mg and 25 mg) in adults with NCFBE were used to develop a PPK model and to evaluate potential covariate effects on brensocatib pharmacokinetics. PK-efficacy relationships for sputum neutrophil elastase below the level of quantification (BLQ) and reduction in pulmonary exacerbation and PK-safety relationships for adverse events of special interest (AESIs; periodontal disease, hyperkeratosis, and infections other than pulmonary infections) were evaluated based on model-predicted brensocatib exposure. A total of 1284 steady-state brensocatib concentrations from 225 individuals were included in the PPK data set; 241 patients with NCFBE from the phase II study were included in the pharmacodynamic (PD) population for the PK/PD analyses.
Results: The PPK model that best described the observed data consisted of two distributional compartments and linear clearance. Two significant covariates were found: age on volume of distribution and renal function on apparent oral clearance. PK-efficacy analysis revealed a threshold brensocatib exposure (area under the concentration-time curve) effect for attaining sputum neutrophil elastase BLQ and a strong relationship between sputum neutrophil elastase BLQ and reduction in pulmonary exacerbations. A PK-safety evaluation showed no noticeable trends between brensocatib exposure and the incidence of AESIs. Based on the predicted likelihood of clinical outcomes for sputum neutrophil elastase BLQ and pulmonary exacerbations, brensocatib doses of 10 mg and 25 mg once daily were selected for a phase III clinical trial in patients with NCFBE (ClinicalTrials.gov identifier: NCT04594369).
Conclusions: PPK results revealed that age and renal function have a moderate effect on brensocatib exposure. However, this finding does not warrant dose adjustments based on age or in those with mild or moderate renal impairment. The PK/PD evaluation demonstrated the clinically meaningful relationship between suppression of neutrophil elastase activity and reduction in exacerbations in brensocatib-treated patients with NCFBE, supporting further development of brensocatib for bronchiectasis.
(© 2022. The Author(s).)
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سلسلة جزيئية: ClinicalTrials.gov NCT04594369
المشرفين على المادة: 0 (Benzoxazoles)
0 (Oxazepines)
25CG88L0BB (brensocatib)
EC 3.4.- (Serine Proteases)
EC 3.4.14.- (Dipeptidyl-Peptidases and Tripeptidyl-Peptidases)
EC 3.4.21.20 (Cathepsin G)
EC 3.4.21.37 (Leukocyte Elastase)
EC 3.4.21.76 (Myeloblastin)
تواريخ الأحداث: Date Created: 20220817 Date Completed: 20221013 Latest Revision: 20221121
رمز التحديث: 20221213
مُعرف محوري في PubMed: PMC9553789
DOI: 10.1007/s40262-022-01147-w
PMID: 35976570
قاعدة البيانات: MEDLINE
الوصف
تدمد:1179-1926
DOI:10.1007/s40262-022-01147-w