Population Pharmacokinetic (Pk) Evaluation Of The Dipeptidyl Peptidase 1 (Dpp1) Inhibitor Brensocatib In Healthy Participants And Patients With Bronchiectasis

Rationale: Brensocatib is an investigational small-molecule, orally bioavailable, selective, and reversible DPP1 inhibitor that blocks activation of neutrophil serine proteases, which are believed to be central to the pathogenesis of several chronic inflammatory diseases.In a phase 2 study, brensocatib reduced sputum neutrophil elastase activity and prolonged time to exacerbation in patients with non-cystic fibrosis bronchiectasis (NCFBE).Methods: A population PK model was developed using data pooled from 2 studies: a 2-part phase 1 study of once-daily oral brensocatib (10, 25, or 40 mg) in healthy adults and a phase 2 double-blind, placebocontrolled study of once-daily brensocatib (10 and 25 mg) in patients with NCFB (Chalmers NEJM 2020).Intensive PK data from phase 1 were used to develop the base structural model, which was then fit to the pooled data set.A formal covariate analysis was conducted, and the final model was qualified.Bayesian PK parameter estimates obtained from the final population PK model were used to generate individual concentration-time profiles, which were then used to estimate individual steady-state brensocatib exposure parameters.Results: The data set used for PK model development included 1284 steady-state brensocatib concentrations from 225 individuals (mean age, 60.0 years [range, 20-83]; 63.1% female).Demographics in both studies were similarly variable; patients in the phase 2 study were older, with lower renal function, than the healthy participants in the phase 1 study.The final population PK model that best described the observed data consisted of 2 distributional compartments and linear clearance.Covariate analyses revealed 2 significant covariates: age on volume of distribution [Vc/F × (Age/60) 0.396 ] and renal function (creatinine clearance; total clearance [CL/F × (CL cr /75.2) 0.276 ]) on CL/F.Sex, race, body weight, and serum albumin levels were not significant PK covariates for brensocatib.Estimated steady-state area under the concentration curve from time of dose to 24 hours (AUC 0-24 ) in patients with NCFBE treated with brensocatib 10 or 25 mg was 1760 and 4540 ng•h/mL, and elimination half-life was 38.5 and 39.1 hours, respectively.The model was qualified for estimation of exposure in phase 2 patients and for the conduct of model-based simulations to support doses for future studies.Conclusions: The population PK model provided a robust fit to observed brensocatib concentration-time data pooled from healthy participants and patients with NCFBE.For patients with NCFBE, dose adjustments based on age or in those with mild or moderate renal impairment will likely be unnecessary.