The pharmacokinetic profile of brensocatib and its effect on pharmacodynamic biomarkers including NE, PR3, and CatG in various rodent species

Abstract

Brensocatib is a novel, oral, selective, reversible inhibitor of dipeptidyl peptidase 1 (DPP1), which activates several neutrophil serine proteases (NSPs), including neutrophil elastase (NE), proteinase 3 (PR3), and cathepsin G (CatG) in the bone marrow during the early stage of neutrophil maturation. These NSPs are associated with pathogen destruction and inflammatory mediation; their dysregulated activation can result in excess secretion of active NSPs causing damaging inflammation and contributing to neutrophil-mediated inflammatory and autoimmune diseases. Pharmacological inhibition of DPP1 in the bone marrow could therefore represent an attractive strategy for these neutrophil-driven diseases. A completed Phase 2 trial in non-cystic fibrosis bronchiectasis patients (ClinicalTrials.gov number NCT03218917; EudraCT number: 2017-002533-32) indeed demonstrated that administration of brensocatib attenuated the damaging effects of chronic inflammation by inhibiting the downstream activation of NSPs. To support a range of preclinical programs and further understand how rodent species and strains may affect brensocatib's pharmacokinetic (PK) profile and its pharmacodynamic (PD) effects on NE, PR3, and CatG, an extensive naïve dosing study with brensocatib at different dosing levels, frequencies, and durations was undertaken. Dose-dependent PK exposure responses (AUC and Cmax) were observed regardless of the rodent species and strain. Overall, mice showed greater reduction in NSP activities compared to rats. Both mice and rats dosed once daily (QD) had equivalent NSP activity reduction compared to BID (twice a day) dosing when the QD dose was 1.5-times the BID daily dose. For both mouse strains, CatG activity was reduced the most, followed by NE, then PR3; whereas, for both rat strains, PR3 activity was reduced the most, followed by CatG, and then NE. Maximum reduction in NSP activities was observed after ∼7 days and recoveries were nearly symmetrical. These results may facilitate future in vivo brensocatib study dosing considerations, such as the timing of prophylactic or therapeutic administration, choice of species, dosage and dosing frequency.

Keywords: brensocatib; cathepsin C (CatC); cathepsin G (CatG); dipeptidyl peptidase 1 (DPP1); neutrophil elastase (NE); proteinase 3 (PR3).

FIGURE 1

Brensocatib Plasma Concentrations from Repeated Dose Administration of Brensocatib by Oral Gavage. (A) BID in C57BL/6 mice, (B) QD in C57BL/6 mice, (C) BID in BALB/c mice (D) QD in BALB/c mice. Data are plotted as mean ± SEM (n = 4, except for 11 h of 20 mg/kg BID in C57 where n = 3; 3 mg/kg QD in C57 for all time points where n = 6; 30 mg/kg QD in C57 for all time points where n = 6; and 1 h of 2 mg/kg BID in BALB/c where n = 3). mpk/day = mg/kg/day.

FIGURE 2

NSP Activities in Bone Marrow of (A–C) C57BL/6 and (D–F) BALB/c Mice Administered 7-Day Repeated Doses of Brensocatib. Reported NSP activities are 16 and 24 h post final BID and QD dose, respectively. Data are the plotted as mean ± SEM (n = 4, except for mid and high C57 QD groups where n = 6; and C57 NE and PR3 mid-dose BID and CatG low dose brensocatib BID where n = 3 due to outlier which was determined by Grubb’s test). *, p < 0.05 vs. vehicle; **, p < 0.01 vs. vehicle; ***, p < 0.001 vs. vehicle; ****, p < 0.0001 vs. vehicle; #, p < 0.05 vs. BID-QD.

FIGURE 3

Bensocatib Plasma Concentration from Repeated Dose Administration of Brensocatib by Oral Gavage. (A) BID in Sprague Dawley (SD) rats, (B) QD in SD rats, (C) BID in Wistar rats, (D) QD in Wistar rats. Data are plotted as mean ± SEM (n = 4, except for 0.2 mpk/day BID for SD at 1, 3, 9, and 24 h where n = 3; 2 mpk/day BID at 11 h for SD where n = 3; 0.3 mpk/day QD at 3 h for SD where n = 3; 3 mpk/day BID for SD at 3 and 24 h where n = 3; 30 mpk/day BID at 7.5 h for SD where n = 3; 0.2 mpk/day BID at 16 h for Wistar where n = 3; and 30 mpk/day QD at 8 h for Wistar where n = 3). mpk/day = mg/kg/day.

FIGURE 4

NSP Activities in Bone Marrow of Sprague Dawley (A–C) and (D–F) Wistar Rats Administered Repeated Doses of Brensocatib. Data are plotted as mean ± SEM (n = 4, except for SD NE QD vehicle, SD PR3 QD vehicle, and SD CatG QD vehicle where n = 3). *, p < 0.05 vs. vehicle.

FIGURE 5

(A–C) Onset and (D–F) Recovery of NSP Activities in Bone Marrow of C57BL/6 Mice Administered Repeated Doses of Brensocatib. The dotted horizontal lines represent the average (black) ± 1 SD (red) for the vehicle control. Data are plotted as mean ± SD (n = 4 for all brensocatib treatment groups, except for onset NE day 10, recovery PR3 day 6, and recovery CatG day 8 where n = 3 after removal of an outlier determined by Grubb’s test; n = 20 for vehicle control, except onset PR3 and recovery CatG where n = 19 after removal of outlier determined by Grubb’s test). *, p < 0.05 vs. vehicle; **, p < 0.01 vs. vehicle; ***, p < 0.001 vs. vehicle; ****, p < 0.0001 vs. vehicle.