Abstract
Aim
Brensocatib is an oral, competitive, and reversible dipeptidyl peptidase 1 (DPP1) inhibitor in development for the treatment of neutrophil-mediated diseases. Brensocatib is a substrate of CYP3A, P-glycoprotein, and breast cancer resistance protein (BCRP). Its absorption, distribution, metabolism, and elimination could be potentially affected by a decrease in hepatic function. This study evaluated the pharmacokinetics (PK), safety, and tolerability of brensocatib in participants with varying degrees of hepatic impairment and matched participants with normal hepatic function.
Methods
In this phase 1, multicenter, open-label study, 27 participants with normal hepatic function or mild, moderate, and severe hepatic impairment, based on numerical Child–Pugh classifications, received a single, oral 25-mg dose of brensocatib. Blood and urine samples were collected to evaluate brensocatib PK, urinary excretion, and plasma protein binding.
Results
Demographic and baseline characteristics were generally similar across hepatic impairment groups and matched healthy participants. The systemic exposure (area under the curve, AUC) and renal clearance (CLr) of brensocatib were generally comparable across all groups (≤ 20% difference in AUC compared with healthy participants and CLr 1.34–1.84 L/h versus 1.66 L/h in healthy participants). The mean elimination half-life was also similar across all hepatic function groups (27.9–31.4 h). Regression analyses indicated no significant relationships between brensocatib systemic exposure and Child–Pugh scores. Unbound brensocatib in plasma slightly increased by the severity of hepatic impairment. The fraction of unbound brensocatib (Funb) was correlated with serum albumin, suggesting that brensocatib is mainly bound to albumin in plasma. Treatment-emergent adverse events (TEAEs) occurred in 14.8% (4/27) of participants; most TEAEs were mild, and two TEAEs occurring in one participant were considered severe. No new safety findings were observed.
Conclusions
No new safety signals were identified in participants with or without hepatic impairment treated with a single dose of 25 mg brensocatib. The oral absorption and elimination of brensocatib were not significantly altered in participants with mild, moderate, or severe hepatic impairment, suggesting that dose adjustment for brensocatib treatment in patients with hepatic impairment is not necessary.
Trial Registry
Clinical Trial Registration Number: NCT05517525.
Supplementary Information
The online version contains supplementary material available at 10.1007/s40262-025-01614-0.
Key Points
| A single dose of brensocatib 25 mg did not show any new safety signals in participants with and without hepatic impairment. |
| The consistency of the rate and extent of brensocatib oral absorption and elimination among participants with hepatic impairment suggests that no dose adjustment is necessary in this population. |
Introduction
Dysregulated neutrophilic inflammation is a key driver in neutrophil-mediated diseases such as non-cystic fibrosis bronchiectasis (hereafter bronchiectasis), which can lead to prolonged inflammation and tissue damage, and has been associated with increased disease severity [1–4]. Neutrophil serine proteases (NSPs), such as neutrophil elastase, are activated during neutrophil maturation in the bone marrow by dipeptidyl peptidase-1 (DPP1) [5]. A recent late-phase clinical trial of brensocatib, an oral, competitive, reversible inhibitor of DPP1 approved in the USA by the Food and Drug Administration (FDA) for the treatment of patients with bronchiectasis [6, 7], supports the concept of NSP inhibition through DPP1 [8].
The safety, tolerability, and pharmacokinetics (PK) of brensocatib have been investigated in several phase 1 studies covering a dose range of 5–120 mg after a single dose and 10–40 mg after once-daily dosing for 28 days. In these studies, brensocatib exposure was dose-dependent with approximately twofold accumulation at steady state and low-to-moderate inter-participant variability after single or multiple daily dosing. The elimination half-life (t½) of brensocatib was approximately 20–30 h, with approximately 20% urinary excretion at steady state [9–11]. In healthy participants, brensocatib was moderately metabolized (~50–60%) following a single dose of radiolabeled brensocatib. Although brensocatib is a substrate of CYP3A (CYP3A4 and CYP3A5), P-glycoprotein (Pgp), and breast cancer resistance protein (BCRP), clinical data showed its exposure is not significantly altered when co-administered with strong CYP3A or Pgp inhibitors or with a strong CYP3A inducer [7, 9]. Participants with mild, moderate, and severe renal impairment showed no clinically meaningful alterations in brensocatib elimination and systemic exposure, suggesting that dose adjustment of brensocatib is not necessary in participants with various degrees of renal impairment [12]. In all phase 1 studies, brensocatib was well tolerated with no serious adverse events (SAEs) or treatment-emergent adverse events (TEAEs) reported [9, 11].
In the phase 2 WILLOW study in patients with bronchiectasis, brensocatib 10 and 25 mg once-daily prolonged the time to first pulmonary exacerbation with a low incidence of AEs of special interest (e.g., periodontal disease, hyperkeratosis, and infection) and a manageable safety profile [13]. In the phase 3 ASPEN trial, once-daily brensocatib (10 and 25 mg) significantly reduced the annualized rate of exacerbations, prolonged time to first exacerbation, and increased the proportion of patients remaining exacerbation-free compared with placebo [8]. Brensocatib 25 mg also significantly reduced lung function decline compared with placebo, as measured with post-bronchodilator forced expiratory volume in 1 s (FEV1), and nominally significantly improved Quality of Life-Bronchiectasis Questionnaire Respiratory Symptoms Domain score compared with placebo at week 52. The overall incidence of AEs and AEs of special interest was similar across treatment groups.
As brensocatib is a substrate of CYP3A, Pgp and BCRP and subject to hepatic metabolism, biliary excretion, and plasma protein binding, a decrease in hepatic function could potentially affect the PK of brensocatib. The objective of the study was to examine the safety and PK of brensocatib in participants with mild, moderate, and severe hepatic impairment according to the numerical Child–Pugh classifications, in accordance with FDA guidance. Healthy participants with normal hepatic function who were matched for age, sex, and body mass index were used as a control comparison.
Methods
Trial Design and Participants
In this phase 1, open-label, multi-site, single-dose parallel-group study (NCT05517525), participants with mild, moderate, or severe hepatic impairment and healthy participants with normal hepatic function and matched age (± 10 years of age), sex, and body mass index (± 20%) were enrolled. Participants were considered to have mild hepatic impairment with Child–Pugh scores of 5–6, moderate hepatic impairment with Child–Pugh scores of 7–9, and severe hepatic impairment with Child–Pugh scores of 10–15.
Classification was based on Child–Pugh score (Supplementary Table 1) at screening and classification was repeated on day −1. If the participant’s classification was not similar at two timepoints, study group enrollment was based on the classification at screening.
The study design planned for up to 30 participants, including up to 12 healthy controls and 6 in each hepatic impairment group. A full list of inclusion and exclusion criteria can be found in Supplementary Table 2. Key inclusion criteria included: males or females, of any race, between 18 and 70 years of age (inclusive); a body mass index between 18.0 and 35.0 kg/m2 (inclusive); participants with hepatic impairment (clinical diagnosis of chronic hepatic disease; hepatic impairment was classified using the Child–Pugh criteria, participant had not had an abdominal paracentesis within 2 weeks of dosing, and one was not planned during the study); and participants with normal hepatic function, defined as participants in good health, determined by no clinically significant findings as assessed by the investigator.
Participants were admitted to the study site on day −1 then discharged on day 10. On day 1, participants received a single oral film-coated tablet of brensocatib 25 mg after overnight fasting for at least 8 h. Participants returned to the study site 5–7 days after discharge for a follow-up visit. The study drug was administered at the clinical sites under direct observation of clinic personnel who confirmed that the participant received the entire dose of study drug. Participants who received a single dose of brensocatib were included in the safety population.
PK Sample Collection
Blood samples were collected for 9 days at the following timepoints: pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, and 216 h postdose. Urine samples were collected at pre-dose and during the following intervals: 0–6, 6–12, 12–24, 24–48, 48–72, 72–96, 96–120, 120–144, 144–168, 168–192, and 192–216 h postdose. Sample collection for 216 h (9 days) was to ensure capture of completed elimination of the drug given its moderate rate of elimination with an elimination t1/2 of ~20–40 h in prior studies [9, 12].
PK Parameters
PK parameters for total drug in plasma were determined on the basis of the plasma concentrations of brensocatib using noncompartmental methods with actual sampling times (Phoenix® WinNonlin® Version 8.3.5, Certara USA, Inc., Princeton, NJ). This included maximum observed concentration (Cmax), time of maximum observed concentration (tmax), area under the concentration–time curve from time 0 to time of last quantifiable concentration (AUClast), area under the concentration–time curve from time 0 extrapolated to infinity (AUC∞), elimination of half-life (t½), total clearance following extravascular administration (CL/F), and volume of distribution at terminal phase following extravascular administration (Vz/F).
Urine PK parameters, including the cumulative amount of brensocatib excreted in urine (Ae0–216h), percentage of dose recovered in urine as unchanged brensocatib (fe0–216h) over 216 h, and renal clearance (CLr), were determined on the basis of the urine concentrations of brensocatib and urine volumes at each urine collection interval.
Determination of Fraction of Plasma Protein Binding
Plasma samples (4- and 24-h postdose) from all participants were utilized to determine the fraction of brensocatib bound to plasma proteins by equilibrium dialysis, conducted by Labcorp Early Development Laboratories Inc. (Madison, WI). Plasma samples in replicates were added to the donor side of the HTD96b equilibrium dialysis plate, and the plate was sealed. The dialysis samples were incubated at 37 °C under 5% CO2 and saturated humidity and were rotated at 300 rpm for 7 h. At the end of the incubation, dialysate samples were collected. The time to equilibrium (~7 h) was determined on the basis of a separate dialysis experiment where blank human plasma with brensocatib (150 ng/mL) was incubated for 3–8 h.
The equilibrium dialysis assay was verified using warfarin (3000 ng/mL) as a positive control, demonstrating accuracy (> 97% bound across three plasma lots) and high precision (CV% range, 0.04–0.06%). Nonspecific binding of brensocatib was negligible on the basis of the percent recovery of 88.9–91.4% (CV% range, 4.3–7.4%). These findings confirm the robustness of the method for protein-binding assessments in clinical samples.
Bioanalytical Methods
The plasma and urine samples were analyzed using validated liquid chromatography–tandem mass spectrometry (LC–MS/MS) methods (Labcorp Early Development Laboratories Inc., Madison, WI) with the quantitation ranges of 0.841–841 ng/mL for plasma and 42.0–42,000 ng/mL for urine. Undiluted quality control samples were considered acceptable if the overall accuracy and precision of the samples from all accepted analytical runs at each level was within ± 15.0% of the nominal concentration and ≤ 15.0%, respectively. Brensocatib concentrations in the donor side before the equilibrium dialysis and in the receiver side at the end of dialysis were analyzed using a similar LC–MS/MS method as for human plasma.
Determination of Fraction of Unbound and PK Parameters
The fraction of unbound (Funb) brensocatib in plasma was determined on the basis of the drug concentrations in the donor side and in dialysate at the end of incubation: Funb = 1 − ((Cm − Cd)/Cm), where Cm is the drug concentration at the donor side at the beginning of equilibrium dialysis and the Cd is the drug concentration in dialysate at the end of incubation.
Unbound brensocatib PK parameters were calculated using the mean Funb for each participant as appropriate. The mean Funb for each participant was calculated from the protein binding sampling timepoints at 4 and 24 h postdose. The unbound plasma PK parameters, including unbound Cmax (Cmax,unb), unbound AUClast (AUClast,unb), and unbound AUC∞ (AUC∞,unb), were determined by the product of the total PK parameters and Funb. Unbound CL/F (CLu/F) was calculated as Dose/AUC∞,unb and unbound Vz,u/F was calculated as Dose/λz × AUC∞,unb, where λz is the apparent terminal elimination rate constant.
Safety
Safety endpoints monitored included TEAEs, clinical laboratory results (hematology, serum chemistry, and urinalysis), vital signs, electrocardiogram, and physical exams. Participants were monitored for 10 days after dosing and follow-up was conducted 5–7 days after discharge. TEAEs were coded by preferred term and system organ class using the Medical Dictionary for Regulatory Activities (MedDRA, version 25.0).
Ethical Conduct
The study was performed in accordance with the ethical principles of the Declaration of Helsinki [14], the Good Clinical Practice guidelines of the International Council for Harmonisation [15], and applicable regulatory requirements. Independent ethics approval from Salus IRB, Austin, TX, was obtained and all participants provided written informed consent.
Statistical Analyses
The sample size chosen for this study was consistent with FDA guidance and prior PK studies of a similar nature and was not based on power calculations. A statistical analysis was conducted to investigate the hepatic impairment effect on the treatment by comparing mild, moderate, or severe hepatic impairment to normal hepatic function.
The natural log (ln)-transformed values of AUClast, AUC∞, and Cmax (for both total and unbound drug) were analyzed using analysis of variance with main effect group (hepatic impaired versus normal controls; 1 degree of freedom). The analysis was performed separately for the participants with mild, moderate, or severe hepatic impairment when compared with normal hepatic function.
The regression analysis of numerical Child–Pugh score versus selected PK parameters assigned participants with normal hepatic function a Child–Pugh score of 0 owing to no hepatic impairment being present.
For each PK parameter the least squares mean (LSM) for each hepatic function, difference in LSMs between the test and reference hepatic functions, and corresponding 90% confidence interval (CI) were separately calculated; these values were then back transformed to give the geometric least squares mean (GLSM), ratio of GLSMs %, and corresponding 90% CI. All statistical analyses were conducted using SAS® version 9.4 (SAS Institute, Cary, NC).
Results
Participants
Overall, 27 participants enrolled in the study: 9 participants in the normal hepatic function group and 6 in each of the hepatic impairment groups. In total, 25 participants (92.6%) completed the study. Of the two participants who did not complete the study, one was attributed to adverse events (AEs) not related to the study drug and the other self-withdrew from the study, not because of AEs. Participants that were enrolled in the severe hepatic impairment group had Child–Pugh scores of 10–12, as no participants with scores of 13–15 met eligibility at the clinical sites during the study conduct.
Demographic and baseline characteristics were generally similar across all groups (Table 1). Overall, the participants had a mean age of 56.8 years (range 41–70 years) and a mean BMI of 29.3 kg/m2 (range 21.0–34.9 kg/m2). Most participants were white (23 [85.2%]) and male (20 [74.1%]), and approximately half were of Hispanic or Latino ethnicity (14 [51.9%]).
Table 1.
Baseline characteristics by hepatic function group
| Normal (n = 9) | Mild HI (n = 6) | Moderate HI (n = 6) | Severe HI (n = 6) | Overall (n = 27) | |
|---|---|---|---|---|---|
| Age (years), mean (SD) | 55.9 (8.7) | 61.0 (12.2) | 56.0 (12.2) | 54.7 (6.4) | 56.8 (9.7) |
| Sex, n (%) | |||||
| Male | 6 (66.7) | 3 (50.0) | 6 (100) | 5 (83.3) | 20 (74.1) |
| Female | 3 (33.3) | 3 (50.0) | 0 | 1 (16.7) | 7 (25.9) |
| Race, n (%) | |||||
| White | 5 (55.6) | 6 (100) | 6 (100) | 6 (100) | 23 (85.2) |
| Black or African American | 3 (33.3) | 0 | 0 | 0 | 3 (11.1) |
| American Indian or Alaska Native | 1 (11.1) | 0 | 0 | 0 | 1 (3.7) |
| Ethnicity, n (%) | |||||
| Hispanic or Latino | 2 (22.2) | 3 (50.0) | 4 (66.7) | 5 (83.3) | 14 (51.9) |
| Not Hispanic or Latino | 7 (77.8) | 3 (50.0) | 2 (33.3) | 1 (16.7) | 13 (48.1) |
| Height (cm), mean (SD) | 171.4 (13.6) | 170.1 (10.0) | 176.1 (6.2) | 173.9 (15.2) | 172.7 (11.5) |
| Body weight (kg), mean (SD) | 82.2 (14.6) | 88.9 (20.2) | 87.8 (17.7) | 95.4 (24.2) | 87.9 (18.5) |
| BMI (kg/m2), mean (SD), [range] | 28.1 (4.4) | 30.6 (5.3) | 28.1 (4.3) | 31.1 (4.0) |
29.3 (4.5) [21.0–34.9] |
| Median Child–Pugh total score (min, max) | N/A | 5.5 (5.0, 6.0) | 7.5 (7.0, 9.0) | 10.5 (10.0, 12.0) | – |
Normal hepatic function: participants in good health, determined by no clinically significant findings as assessed by the investigator. Mild hepatic impairment: Child–Pugh score of 5–6. Moderate hepatic impairment: Child–Pugh score of 7–9. Severe hepatic impairment: Child–Pugh score of 10–15
BMI body mass index, HF hepatic function, HI hepatic impairment, N/A not applicable, SD standard deviation
Pharmacokinetics of Brensocatib
Plasma Concentration Profiles
The arithmetic mean (+ SD in linear scale) plasma concentration–time profiles of total brensocatib are summarized in Fig. 1. The mean plasma concentration-over-time profiles in participants with hepatic impairment and normal hepatic function were overlapping, showing a rapid oral absorption and a biphasic elimination. The individual variability at each timepoint was low.
Fig. 1.
Arithmetic mean pharmacokinetic concentration–time profiles of total brensocatib by hepatic function group. A Linear (+ SD) scale. B Semi-logarithmic scale
PK Parameters
The median tmax ranged from 1.0 to 2.0 h and was similar across the groups (Table 2). The mean elimination t½ was similar across all hepatic function groups, 27.9–31.4 h. Total brensocatib PK parameters of AUCs and Cmax were numerically lower in the severe hepatic impairment group compared with the other groups (Table 2). For the severe hepatic impairment group, arithmetic mean AUClast, AUC∞, and Cmax values were 2050 h*ng/mL, 2120 h*ng/mL, and 90.7 ng/mL, respectively. Within the other hepatic impairment groups and the normal hepatic function group AUClast, AUC∞, and Cmax values ranged from 2510 to 3210 h*ng/mL, 2570 to 3370 h*ng/mL, and 113 to 133 ng/mL, respectively.
Table 2.
Pharmacokinetic parameters of brensocatib in the plasma (total and unbound) and urine by hepatic function group
| Parameter | Statistics | Normal (n = 9) | Mild HI (n = 6) | Moderate HI (n = 6) | Severe HI (n = 6) |
|---|---|---|---|---|---|
| Cmax (ng/mL) | Mean (CV%) | 122 (40.7) | 133 (21.6) | 113 (37.0) | 90.7 (51.5) |
| tmax (h) | Median (min, max) | 1.0 (1.0–3.0) | 2.0 (1.5–3.0) | 1.25 (1.0–6.0) | 1.25 (0.50–24) |
| AUClast (h*ng/mL) | Mean (CV%) | 2930 (48.1) | 3210 (12.4) | 2510 (10.9) | 2050 (38.3) |
| AUC∞ (h*ng/mL) | Mean (CV%) | 2980 (47.7) | 3370 (16.2) | 2570 (10.4) | 2120 (38.2) |
| t½ (h) | Mean (CV%) | 30.3 (26.6) | 31.4 (24.5) | 27.9 (14.5) | 28.5 (24.3) |
| CL/F (L/h) | Mean (CV%) | 10.7 (58.5) | 7.58 (16.5) | 9.83 (10.2) | 13.3 (37.7) |
| Vz/F (L) | Mean (CV%) | 413 (30.6) | 353 (40.3) | 396 (18.3) | 515 (25.1) |
| Funb (%) | Mean (CV%) | 17.8 (17.2) | 16.9 (5.7) | 19.7 (12.6) | 26.9 (35.2) |
| fe0–216h (%) | Mean (CV%) | 16.4 (36.6) | 18.0 (37.1)a | 19.1 (45.8)b | 12.5 (7.7)a |
| CLr (L/h) | Mean (CV%) | 1.66 (48.0) | 1.34 (39.4) | 1.84 (41.3)b | 1.72 (27.2) |
Normal hepatic function: participants in good health, determined by no clinically significant findings as assessed by the investigator. Mild hepatic impairment: Child–Pugh score of 5–6. Moderate hepatic impairment: Child–Pugh score of 7–9. Severe hepatic impairment: Child–Pugh score of 10–15
AUC∞ area under the curve versus time from time 0 extrapolated to infinity, AUClast area under the curve versus time from time 0 to the last quantifiable measurement (calculated using the linear up log down trapezoidal rule), CL/F total oral clearance, Cmax maximum observed plasma concentration, CV coefficient of variation, Funb cumulative percentage of the dose administered recovered over the unbound time interval, fe0–216h (total) fraction recovered in urine as cumulative percentage of the dose administered over the time interval 0–216 h postdose, HI hepatic impairment, n number of participants, PK pharmacokinetic, t½ elimination half-life, tmax time to reach maximum observed plasma concentration, Vz/F apparent volume of distribution
aOne participant's urine sample weight was missing between 0 h and 6 h, Ae0–216 not calculated, and PK parameter underestimated; excluded from summary statistics
bOne participant in the mild HI group and one participant in the severe HI group did not complete the study and did not have all urine samples up to 216 h collected
Mean CL/F and Vz/F values were slightly higher in the severe hepatic impairment group (13.3 L/h and 515 L) than in the other groups (CL/F values ranged from 7.58 to 10.7 L/h and Vz/F values ranged from 353 to 413 L). Renal clearance ranged from 1.34 to 1.84 L/h for the hepatic impairment groups, compared with 1.66 L/h in the normal hepatic function group.
The fraction excreted in urine as percentage of the dose (fe0–216h, %) for unchanged drug was moderate for the hepatic impairment groups (12.5–19.1%) and the normal hepatic function group (16.4%), with most excretion occurring within 96 h postdose. Three participants had partial urinary excretion data (n = 1 in the mild group at 0–6 h, n = 1 in the severe group at 120–216 h, and n = 1 in the moderate group at 72–216 h). These missing data had minimal impact on the mean excretion data. A sensitivity analysis excluding these participants yielded similar mean CLr values.
All unbound PK parameters were comparable across all groups.
The Relationships Between Fraction Unbound and Serum Albumin
The percentage of Funb was highly correlated with the baseline serum albumin concentration (Fig. 2). The significant correlation between Funb and serum albumin levels at screening indicates that brensocatib is mainly bound to albumin in plasma. As noted in Tables 2 and 3, the free (absolute) concentrations of brensocatib were similar across all groups.
Fig. 2.
The relationship between percent of unbound brensocatib in plasma and serum albumin levels. Percent brensocatib unbound = 42.8 − 6.06 × serum albumin, R-squared = 0.54; p-value ≤ 0.0001. For the albumin data, the following time points/collection intervals are used for the scatterplot: 4 h plot—day −1 (baseline) collection, 24 h plot—day 2 (24 h) collection, and mean plot—average of day −1 and 24 h
Table 3.
Comparison of total and unbound brensocatib exposure parameters between hepatic function groups
| Parameter | Cohort | Total drug exposure | Unbound drug exposure | ||||
|---|---|---|---|---|---|---|---|
| GLSM | GMR (90% CI) | GLSM | GMR (90% CI) | ||||
| HI (n) | Normal (n) | HI (n) | Normal (n) | ||||
| AUClast (ng*h/mL) | Mild | 3190 (6) | 2730 (6) | 1.17 (0.715, 1.90) | 539 (6) | 479 (6) | 1.13 (0.774, 1.64) |
| Moderate | 2500 (6) | 2430 (6) | 1.03 (0.690, 1.54) | 489 (6) | 428 (6) | 1.14 (0.845, 1.55) | |
| Severe | 1930 (6) | 2410 (6) | 0.802 (0.495, 1.30) | 496 (6) | 425 (6) | 1.17 (0.717, 1.90) | |
| AUC∞ (ng*h/mL) | Mild | 3330 (6) | 2780 (6) | 1.20 (0.732, 1.96) | 564 (6) | 487 (6) | 1.16 (0.793, 1.69) |
| Moderate | 2560 (6) | 2480 (6) | 1.03 (0.692, 1.54) | 500 (6) | 437 (6) | 1.14 (0.847, 1.55) | |
| Severe | 1990 (6) | 2460 (6) | 0.810 (0.500, 1.31) | 511 (6) | 435 (6) | 1.18 (0.723, 1.91) | |
| Cmax (ng/mL) | Mild | 131 (6) | 117 (6) | 1.12 (0.771, 1.63) | 22.1 (6) | 20.4 (6) | 1.08 (0.803, 1.46) |
| Moderate | 106 (6) | 111 (6) | 0.960 (0.670, 1.38) | 20.8 (6) | 19.5 (6) | 1.07 (0.767, 1.48) | |
| Severe | 77.8 (6) | 105 (6) | 0.741 (0.437, 1.26) | 20.0 (6) | 18.6 (6) | 1.08 (0.710, 1.63) | |
Normal hepatic function: participants in good health, determined by no clinically significant findings as assessed by the investigator. Mild hepatic impairment: Child–Pugh score of 5–6. Moderate hepatic impairment: Child–Pugh score of 7–9. Severe hepatic impairment: Child–Pugh score of 10–15
AUClast area under the concentration curve versus time from time 0 to the last time point with quantifiable concentration, AUC∞ area under the concentration curve versus time from time 0 extrapolated to infinity, Cmax maximum observed plasma concentration, GLSM geometric least squares mean, GMR geometric mean ratio, HI hepatic impairment
Brensocatib Systemic Exposure Comparison Between Groups
The AUClast, AUC∞, and Cmax values for the mild hepatic impairment group were 17, 20, and 12% higher, respectively, compared with the normal hepatic function group (Table 3), and the unbound values for AUClast,unb, AUC∞,unb, and Cmax,unb were 13, 16, and 8% higher, respectively, compared with the normal hepatic function group.
The AUClast, AUC∞, and Cmax values for the moderate hepatic impairment group were generally similar to the normal hepatic function group (Table 3), with the AUClast,unb, AUC∞,unb, and Cmax values for the moderate hepatic impairment group being 14, 14, and 7% higher, respectively, compared with the normal hepatic function group.
The AUClast, AUC∞, and Cmax values for the severe hepatic impairment group were 20, 19, and 26% lower, compared with the normal hepatic function group (Table 3), with AUClast,unb, AUC∞,unb, and Cmax,unb values for the severe hepatic impairment group being 17, 18, and 8% higher, respectively, compared with the normal hepatic function group.
The Impact of Liver Function on Brensocatib PK
The relationships between brensocatib systemic exposure (total and unbound Cmax and AUC) and the degree of hepatic impairment (Child–Pugh scores) were evaluated using linear regression (Fig. 3). The lack of a significant relationship is visually apparent from the near-horizontal regression lines and the extensive overlap of the 90% CIs with the null slope (0) for brensocatib exposure (total and unbound Cmax or AUCs) and the Child–Pugh scores (p-values > 0.05). The regression analysis results indicate that brensocatib PK is not significantly affected by the severity of hepatic impairment.
Fig. 3.
Relationship between brensocatib systemic exposure and Child–Pugh scores. AUC∞: p-value (90% CI) for the linear regression slope: 0.1283 (−145, 5.97); Spearman’s rank coefficient: −0.299; p-value: 0.130. Cmax: p-value (90% CI) for the linear regression slope: 0.1613 (−6.06, 0.509); Spearman’s rank coefficient: −0.218; p-value 0.274. AUC∞,unb: p-value (90% CI) for the linear regression slope: 0.3905 (−6.34, 19.6); Spearman’s rank coefficient: 0.082; p-value: 0.683. Cmax,unb: p-value (90% CI) for the linear regression slope: 0.7975 (−0.506, 0.687); Spearman’s rank coefficient: −0.003; p-value 0.988. AUC∞ area under the curve vs time from time 0 extrapolated to infinity, CI confidence interval, N number of participants
Safety
Of 27 participants, 4 participants (14.8%) experienced 9 TEAEs (no participants in the normal hepatic function group, 1 each in mild and moderate, and 2 in the severe hepatic impairment group) (Table 4).
Table 4.
Summary of TEAEs by system organ class and preferred term by hepatic function groups
| Normal (n = 9) | Mild HI (n = 6) | Moderate HI (n = 6) | Severe HI (n = 6) | Overall (n = 27) | |
|---|---|---|---|---|---|
| System organ class, preferred term, n (%) | |||||
| Overall | 0 | 1 (16.7) | 1 (16.7) | 2 (33.3) | 4 (14.8) |
| Gastrointestinal disorders | 0 | 1 (16.7) | 0 | 1 (16.7) | 2 (7.4) |
| Abdominal pain | 0 | 0 | 0 | 1 (16.7) | 1 (3.7) |
| Diarrhea | 0 | 1 (16.7) | 0 | 0 | 1 (3.7) |
| Metabolism and nutrition disorders | 0 | 0 | 1 (16.7) | 1 (16.7) | 2 (7.4) |
| Hypoglycemia | 0 | 0 | 1 (16.7) | 0 | 1 (3.7) |
| Hyponatremia | 0 | 0 | 0 | 1 (16.7) | 1 (3.7) |
| Vascular disorders | 0 | 0 | 0 | 2 (33.3) | 2 (7.4) |
| Hypotension | 0 | 0 | 0 | 2 (33.3) | 2 (7.4) |
| Hepatobiliary disorders | 0 | 0 | 0 | 1 (16.7) | 1 (3.7) |
| Hepatic cirrhosis | 0 | 0 | 0 | 1 (16.7) | 1 (3.7) |
| Nervous system disorders | 0 | 1 (16.7) | 0 | 0 | 1 (3.7) |
| Dizziness | 0 | 1 (16.7) | 0 | 0 | 1 (3.7) |
| Headache | 0 | 1 (16.7) | 0 | 0 | 1 (3.7) |
Adverse events were coded using the MedDRA version 25.0. A TEAE was defined as an adverse event that started during or after dosing or started prior to dosing and increased in severity after dosing. A treatment-related TEAE was defined as a TEAE with a relationship of related to the study treatment, as determined by the investigator
HI hepatic impairment, MedDRA Medical Dictionary for Regulatory Activities, n number of patients, TEAE treatment-emergent adverse event
The majority of TEAEs (77.8%) were considered mild (grade 1) in severity. Two TEAEs were considered severe (grade 3) and reported as SAEs. One participant with severe hepatic impairment had two non-drug-related SAEs of grade 3 worsening decompensated cirrhosis and grade 3 hyponatremia. The SAE of hyponatremia led to the participant being withdrawn from the study. Two TEAEs were considered to be related to brensocatib (n = 2). All TEAEs resolved by the end of the study.
No deaths occurred during the course of this study. No notable differences in mean changes from baseline for clinical laboratory evaluations, vital signs, electrocardiogram (ECG), or physical examination data among the hepatic function groups were observed.
Discussion
The results of this open-label, multi-site, single-dose, parallel-group study demonstrate that, following a single 25-mg dose, brensocatib PK (both total and free drug) in participants with varying severities of hepatic impairment was generally comparable to that in participants with normal hepatic function. There was no evidence of significant relationships between brensocatib systemic exposure (total and free Cmax or AUCs) and the Child–Pugh scores. Owing to the exclusion of patients with hepatic encephalopathy or significant risk of bleeding, enrollment was only possible up to a Child–Pugh score of 13, with the highest Child–Pugh score in the study being 12.
Across all groups, the elimination t½ (mean values ranging from 27.9 to 31.4 h) and CLr (mean values ranging from 1.34 to 1.84 L/h) indicate that brensocatib elimination was not significantly altered by the presence of hepatic impairment. The percentage of unbound brensocatib in plasma appeared to slightly increase with hepatic impairment severity and significantly correlated with baseline serum albumin, suggesting that brensocatib is mainly bound to albumin in the circulation. The AUClast, AUC∞, and Cmax values in participants with mild and moderate impairment were comparable or slightly higher than those with normal hepatic functions, while the parameters in participants with severe hepatic impairment group were 20, 19, and 26% lower. The lower brensocatib exposure in the severe group was probably associated with the lower albumin levels and higher drug clearance (CL/F for severe 13.3 L/h versus normal 10.7 L/h). The lack of a significant relationship between Child–Pugh scores and brensocatib exposure parameters is visually apparent from the near-horizontal regression lines and the extensive overlap of the 90% CIs with the null slope (0). The 90% CI of geometric mean ratio (GMR) in AUClast, AUC∞, and Cmax for all comparators includes 1.0, indicating the comparability and overlapping of the parameters between groups. However, the ranges of 90% CI of the GMR values were wide, which can be attributed to the limited sample size of the groups. Brensocatib was generally safe and well tolerated in all participants.
The total brensocatib AUC∞ and Cmax and their variabilities from this study were comparable to those observed in a previous clinical pharmacology study of brensocatib with a single dose of 25 mg in healthy participants (mean Cmax [CV%] 161 ng/mL [38.3]; mean AUC∞ [CV%] 3205 ng*h/mL [17.6]) [9]. A population PK analysis pooling PK data collected from phase 1–3 studies detected that hepatic impairment had a mild effect on brensocatib PK; however, the magnitude (18.7% higher on CL/F) was considered not clinically meaningful [16].
The PK data in healthy participants from this study are consistent with those from previous brensocatib studies [9–11]. Overall, the small differences in PK parameters between hepatic function groups were in line with the inter-individual variability and are not considered clinically meaningful.
The study is limited by the small sample size (N = 27) and short duration; however, while the sample size was not selected on the basis of statistical power, the study design and the sample size selection were aligned with the regulatory authority guidance for hepatic impairment studies [17, 18]. Owing to the limitation of study enrolment for Child–Pugh scores of ≤ 12, extrapolation of the study results to patients with Child–Pugh scores of 13–15 should be applied with caution.
Conclusions
Overall, the oral absorption and elimination of brensocatib were not significantly altered in participants with varying degrees of hepatic impairment. A single dose of 25 mg brensocatib did not show any new safety signals in participants with hepatic impairment or in participants with normal hepatic function. The PK and safety data from this study support that dose adjustment for brensocatib is not necessary in patients with mild, moderate, and severe hepatic impairment.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgements
We thank the participants and their families for their support and participation, as well as the study investigators, study coordinators, and support staff across all sites. Medical writing support was provided by Brooke Bartram, BSc (Hons), MSc, of Envision Pharma Group and was funded by Insmed Incorporated.
Funding
This study was funded by Insmed Incorporated (Bridgewater, NJ, USA).
Declarations
Conflict of interest
Helen Usansky, Sam Au Yeung, Sherry Li, and Daniel S. Stein are employees and shareholders in Insmed Incorporated. Thomas C. Marbury is an employee and equity owner of Orlando Clinical Research Center. Eric Lawitz is an employee and owner of Texas Liver Institute. Zeid Kayali reports honoraria from AbbVie, Gilead, and Madrigal Pharmaceuticals.
Availability of data and materials
The datasets generated and/or analyzed during the current study are not publicly available owing to patients not providing consent to individual data being shared publicly.
Ethics approval
The study was performed in accordance with the ethical principles of the Declaration of Helsinki, the Good Clinical Practice guidelines of the International Council for Harmonisation, and applicable regulatory requirements. Approval was obtained from Salus IRB (Austin, TX) under the study number INS1007-105.
Consent to participate
Participants and/or their legally authorized representative were informed that their participation was voluntary. Participants, or their legally authorized representative, were required to sign a statement of informed consent that met the requirements of ICH E6 (R2) Guideline for GCP and any additional elements required by local regulations.
Consent for publication
Not applicable.
Code availability
Not applicable.
Author contributions
Helen Usansky, Sam Au Yeung, Sherry Li, and Daniel S. Stein contributed to the study conception, design, and study conduct. Eric Lawitz, Zeid Kayali, and Thomas C. Marbury were principal investigators of this study. All authors contributed to data collection, analysis, and interpretation. All authors critically reviewed all manuscript drafts, approved the submitted version of the manuscript, and made the decision to submit the manuscript for publication.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The datasets generated and/or analyzed during the current study are not publicly available owing to patients not providing consent to individual data being shared publicly.