(T-094) Population Pharmacokinetics of Brensocatib in Adult and Adolescent Patients with Non-Cystic Fibrosis Bronchiectasis (BE)

Helen Usansky – Insmed Incorporated; Anthony Cammarata – Institute for Clinical Pharmacodynamics; ChongHua Li – Insmed Incorporated; Sam Au Yeung – Insmed Incorporated; Chris Rubino – Institute for Clinical Pharmacodynamics; Lin Wang – Insmed Incorporated; Ariel Teper – Insmed Incorporated; Carlos Fernandez – Insmed Incorporated; Kevin Mange – Insmed Incorporated

Objectives: Brensocatib, a selective, reversible inhibitor of dipeptidyl peptidase-1 (DPP-1), has demonstrated its clinically statistically significant effect by reducing the rate of pulmonary exacerbations and lung function decline at 25 mg in a phase 3 study. The objectives of this evaluation were to develop a population PK (PPK) model and to support brensocatib dose selection for adult and adolescent patients with BE.

Methods: Data from one phase 3 study, two phase 2 studies, and eight phase 1 studies were pooled for analysis. Nonlinear mixed-effects modeling using FOCE-I algorithm was performed using NONMEM v7.4. Covariate model was developed via a stepwise approach. The clinical relevance of the statistically significant covariates was assessed by simulated brensocatib exposure at steady state (AUC24 and Cmax) in various subgroups (n = 1000 subjects per subgroup) with different characteristics relative to a reference subject (Caucasian healthy male, 49 years old, 70 kg, fasted, and no concomitant medications). Forest plots were used to assess the clinical impact of the covariates.

Results: A total of 11,643 brensocatib plasma concentrations collected from 783 patients with BE including 31 adolescents (12 to < 18 years of age), 24 patients with CF, and 291 healthy volunteers were used for the construction of the PPK model. The structural model consisted of two compartments with linear elimination to describe the overall drug disposition and an oral depot compartment followed by a 3-compartment transit chain with first-order kinetics describing the absorption process. The final brensocatib PPK model integrated body weight as a scaling factor of 0.75 on total and inter-compartment clearance (CL/F and Q/F), and 1.0 on central and peripheral volume of distribution (Vc/F and Vp/F). Statistically significant covariates included hepatic impairment, sex, race, and concomitant use of strong CYP3A and Pgp modulators (rifampin, clarithromycin, or verapamil) on CL/F, age on Vc/F, and food effect on Ka (absorption rate constant). Relative bioavailability (relF) was dose-dependent which was defined by a standard sigmoidal maximum obtainable percent change from baseline (Emax) function and was significantly related to concomitant medications with clarithromycin or verapamil. Median systemic exposure in adolescents was slightly higher compared to adults but distributions were overlapping. Despite the statistical significance, none of the covariate relationships identified was considered clinically relevant given the magnitude of effect ( < 2-fold changes in AUC for any single covariate) and the acceptable safety profiles of brensocatib in BE patients at 10 and 25 mg QD. Disease populations, renal impairment, and tablet formulations were not statistically significant covariates for brensocatib PK.

Conclusions: A PPK model was constructed that provides a robust fit to the observed brensocatib concentration time profiles in patients with BE. The impact of patient demographics, organ impairment, food, and potential DDI effects on brensocatib exposures was limited and not clinically relevant.

Citations: N/A

Keywords: Brensocatib, bronchiectasis, population PK