Chemical formula: C₂₃H₂₄N₄O₄ Molecular mass: 420.18 g/mol PubChem compound: 118253852
Brensocatib is a competitive and reversible inhibitor of dipeptidyl peptidase 1 (DPP1). DPP1 activates pro-inflammatory neutrophil serine proteases (NSPs) during neutrophil maturation in the bone marrow. Brensocatib reduces the activity of NSPs implicated in the pathogenesis of bronchiectasis, including neutrophil elastase, cathepsin G and proteinase 3.
At 5 times the maximum recommended daily dose of brensocatib, there was no effect on QTc prolongation.
The absolute oral bioavailability of brensocatib has not been studied in humans. Brensocatib is rapidly absorbed after oral administration. Tmax for tablets is approximately 1 hour in patients. Brensocatib oral absorption is not affected by food intake. Co-administration with a high fat meal delayed the time to reach peak concentration by 0.75 hours, however, the extent of brensocatib absorption remained the same.
After oral administration, the volume of distribution at steady state was 126-138 L (CV: 22.4-23.3%) in adult patients and 71.3-83.6 L (CV: 19.9-26.3%) in adolescents with NCFB. The protein binding of brensocatib to human plasma was 82.2%-87.2%.
Brensocatib undergoes metabolism primarily by CYP3A. Brensocatib accounted for 16.2% of the total radioactivity in plasma. Only one major circulating metabolite, thiocyanate, was detected in plasma. Thiocyanate is an endogenous compound, and clinical data showed that thiocyanate plasma concentrations were not affected and remained in the normal range on brensocatib treatment.
CYP450 enzymes:
Brensocatib is a substrate of CYP3A. Brensocatib does not inhibit CYP1A2, CYP2C8, CYP2C9, CYP2C19, or CYP2D6. In vitro studies are inconclusive regarding the potential of brensocatib to induce CYP2B6 and CYP3A4. In vivo induction cannot be excluded.
Transporter systems:
Brensocatib is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Brensocatib is not a substrate of MATE1, MATE2-K, OAT1, OAT3, OATP1B1, OATP1B3, OCT1 and OCT2. Brensocatib is not an inhibitor of P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, OCT2, MATE1, and MATE2-K.
In vitro data and population pharmacokinetic analyses indicate that brensocatib is unlikely to inhibit or significantly induce the activity of CYP isozymes or drug transporters at clinically relevant dose levels. However, in vitro studies were inconclusive regarding the potential of brensocatib to induce CYP2B6 and CYP3A4, and in vivo induction cannot be excluded.
Brensocatib AUC and Cmax increased by 55% and 68% with a strong CYP3A inhibitor (e.g. clarithromycin) and by 32% and 53% with a strong P-gp inhibitor (e.g. verapamil) but decreased by 33% and 15% with a strong CYP3A inducer (e.g. rifampicin). Cmax and AUC remained unchanged with a potent proton-pump inhibitor (e.g. esomeprazole). The interaction effect on brensocatib systemic exposure is not clinically meaningful.
Following a single oral dose of radiolabelled brensocatib, 54.2% of dose was excreted in urine and 28.3% in faeces with most radioactivity excreted within 72 hours. The unchanged brensocatib in urine and faeces were 22.8% and 2.41% of dose, respectively.
Terminal half-life was 32.6-39.6 hours (CV: 26.6-33.0%) in adult patients and 26.9-27.8 hours (CV: 26.8-37.3%) in adolescent patients.
Brensocatib exhibits linear and time-independent pharmacokinetics with low to moderate intra- and inter-subject variability over a dose range of 5-120 mg following single administration and a dose range of 10-40 mg following once-daily administration. Population pharmacokinetics analysis using pooled data from 11 clinical studies in healthy subjects (n = 291) and patients with NCFB (n = 783) showed that brensocatib pharmacokinetics can be adequately described by a 2-disposition compartments with first-order oral absorption.
Exposure-response relationships were observed between brensocatib exposure (AUC) and clinical efficacy (i.e. decline of lung function measured as FEV1). At 25 mg, >99% NCFB patients in the ASPEN trial achieved an AUC threshold that was associated with clinically meaningful improvement in FEV1. No exposure-response relationships were detected for the occurrence of periodontal disease or pneumonia. A relationship between brensocatib exposure (AUC) and hyperkeratosis (mild and moderate) was observed. However, the predicted probability of mild or moderate hyperkeratosis was low at brensocatib 25 mg (3.01% in adults and 3.36% in adolescents).
Population pharmacokinetic analysis showed no evidence of a clinically significant effect of age (range: 12 to 85 years), sex, race/ethnicity or body weight (range: 32 to 155 kg) on the pharmacokinetics of brensocatib.
Based on the population pharmacokinetic analysis, there was no clinically meaningful age-related difference in the pharmacokinetics of brensocatib between adults and adolescents aged 12 to 17 years. Brensocatib has not been studied in children under 12 years of age.
In subjects with mild, moderate or severe hepatic impairment (Child-Pugh scores 5 to 12), brensocatib clearance following a single dose was comparable to that in healthy subjects. No dose adjustments are recommended for patients with mild, moderate or severe hepatic impairment.
In subjects with mild, moderate or severe renal impairment, (creatinine clearance ≥15 mL/min/1.73 m² and not requiring dialysis), brensocatib clearance following a single dose was comparable to that in healthy subjects. No dose adjustments are recommended for patients with mild, moderate or severe renal impairment.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity and carcinogenic potential. Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.
In a 6-month rat study microscopic changes in the kidney (basophilic tubules in the outer medulla) and the lung (perivascular neutrophil infiltration and vacuolated macrophage accumulation consistent with phospholipids) were observed at 50 mg/kg/day. The no-observed-adverse-effect-level was considered to be 9 mg/kg/day (AUC 20 times the maximum recommended human dose [MRHD]).
In a 9-month dog study no adverse findings were observed at any dose (AUC 5 times the MRHD). In a preceding 6-month dog study, administration of brensocatib at 50 mg/kg/day caused periodontal disease resulting in early termination of the group. At ≥8 mg/kg/day, dose-dependent microscopic findings were noted in the testis (seminiferous tubule degeneration and atrophy), in the epididymis (decreased number of spermatozoa and cellular debris), and in the lung (accumulations of vacuolated macrophages consistent with phospholipids). At 50 mg/kg/day, additional microscopic findings were noted in the kidney (tubular regeneration) and in the lymphoid tissues (axillary, mandibular and mesenteric lymph nodes, gut associated lymphoid tissue and spleen) as indicated by the accumulations of vacuolated macrophages.
In a rat fertility and embryo-foetal development study, following treatment with brensocatib from 2 weeks prior to mating, during mating and up to the end of major embryonic organogenesis, recoverable minor malformations of bent scapula and wavy ribs were noted at plasma exposure (AUC) 128-times the human exposure at the MRHD. There was an increased incidence of skeletal variations (malpositioned pelvic girdle and vestigial supernumerary full and/or short ribs in both cervical and thoracolumbar regions) and differences in ossification at AUC ≥42-times the human exposure at the MRHD. The no effect dose for developmental toxicity was at AUC of 3-times the human exposure at the MRHD. In a rabbit embryo-foetal development study, treatment with brensocatib during implantation and major organogenesis induced maternal toxicity (reductions in body weight gain and food consumption) at AUC ≥5-times the human exposure at the MRHD. There were no adverse developmental effects at AUC 20-times the human exposure at the MRHD.
In a pre- and post-natal development study in rats treated from gestation day 6 through lactation day 20, no adverse findings were observed at any dose (up to AUC 17-times the human exposure at the MRHD). Brensocatib was detected in pups, suggesting that male and female pups were likely exposed via maternal milk during lactation.
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