Pharmacokinetics and Safety of a Single Dose of Brensocatib in Participants with Hepatic Impairment and Matched Participants with Normal Hepatic Functions.
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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.