Konstan Michael W, Tolle James J, DiMango Emily, Flume Patrick A, Usansky Helen, Teper Ariel, Ramirez Christina N, Flarakos Jimmy, Basso Jessica, Li Sherry, Vergara Marcela
Case Western Reserve University School of Medicine, Cleveland, OH, USA.
Vanderbilt University Medical Center, Nashville, TN, USA.
Clin Pharmacokinet. 2025 Aug 3. doi: 10.1007/s40262-025-01550-z.
Brensocatib, an oral, competitive, and reversible inhibitor of dipeptidyl peptidase 1 (DPP1), reduces exacerbations and lung function decline in non-cystic fibrosis bronchiectasis (NCFBE). This study aimed to evaluate the pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of brensocatib in adults with cystic fibrosis (CF), comparing these findings with data from previous trials in healthy adults and in those with NCFBE to inform dose selection for future clinical trials.
A phase IIa, single-blind, randomized, placebo-controlled trial was conducted to assess the PK, PD, safety, and tolerability of brensocatib in adults with CF. Participants were randomly assigned to receive once-daily brensocatib (10 mg, 25 mg, or 40 mg) or placebo for 28 days. The study planned enrollment of up to 34 adults, stratified on the basis of their CF transmembrane conductance regulator (CFTR) modulator use, to evaluate the PK profile of brensocatib and its safety compared with placebo. Primary PK parameters, including maximum plasma concentration (C), time to maximum concentration (T), area under the concentration-time curve from 0 to 24 h (AUC), and half-life (t), were determined on day 1 and day 28. Dose-dependency of brensocatib exposure was analyzed, and safety and tolerability were assessed through treatment-emergent adverse events. Data from participants were compared with previous data from healthy adults and from those with NCFBE.
A total of 29 participants were randomized to treatment, with 21 stratified to the CFTR modulator group. Baseline characteristics were similar among cohorts. Mean age was 37.9 (standard deviation (SD) 14.6) years, and most participants exhibited mild-to-moderate lung disease. PK analysis showed dose-dependent and predictable brensocatib exposure, with comparable profiles between participants with and without use of CFTR modulators. In addition, PK profiles in participants were comparable to those of healthy adults and of those with NCFBE. Pharmacodynamic analysis revealed dose-dependent reduction in neutrophil serine protease (NSP) activity, reaching saturation around the 25-mg dose, particularly in blood. Brensocatib at all doses was well tolerated with no new identified safety signals.
Brensocatib demonstrated consistent PK profiles independent of CFTR therapy and comparable to those of healthy and NCFBE adults. Brensocatib reduced blood and sputum NSP levels. The safety profile was comparable to previous studies, with no new safety concerns identified, supporting the use of similar dosing for adults with CF as for other populations. These findings advocate for further investigation of brensocatib in CF.
NCT05090904.
布瑞索卡替是一种口服、竞争性且可逆的二肽基肽酶1（DPP1）抑制剂，可减少非囊性纤维化支气管扩张症（NCFBE）的病情加重及肺功能下降。本研究旨在评估布瑞索卡替在成年囊性纤维化（CF）患者中的药代动力学（PK）、药效学（PD）、安全性和耐受性，并将这些结果与先前在健康成年人和NCFBE患者中进行的试验数据进行比较，以为未来临床试验的剂量选择提供依据。
开展一项IIa期、单盲、随机、安慰剂对照试验，以评估布瑞索卡替在成年CF患者中的PK、PD、安全性和耐受性。参与者被随机分配接受每日一次的布瑞索卡替（10毫克、25毫克或40毫克）或安慰剂，为期28天。该研究计划招募多达34名成年人，根据其CF跨膜传导调节因子（CFTR）调节剂的使用情况进行分层，以评估布瑞索卡替的PK特征及其与安慰剂相比的安全性。在第1天和第28天测定主要PK参数，包括最大血浆浓度（C）、达峰时间（T）、0至24小时浓度-时间曲线下面积（AUC）和半衰期（t）。分析布瑞索卡替暴露的剂量依赖性，并通过治疗期间出现的不良事件评估安全性和耐受性。将参与者的数据与先前健康成年人和NCFBE患者的数据进行比较。
共有29名参与者被随机分配接受治疗，其中21名被分层至CFTR调节剂组。各队列的基线特征相似。平均年龄为37.9（标准差（SD）14.6）岁，大多数参与者表现为轻至中度肺部疾病。PK分析显示布瑞索卡替暴露具有剂量依赖性且可预测，使用和未使用CFTR调节剂的参与者之间的特征相当。此外，参与者的PK特征与健康成年人和NCFBE患者的特征相当。药效学分析显示中性粒细胞丝氨酸蛋白酶（NSP）活性呈剂量依赖性降低，在25毫克剂量左右达到饱和，尤其是在血液中。所有剂量的布瑞索卡替耐受性良好，未发现新的安全信号。
布瑞索卡替表现出与CFTR治疗无关的一致PK特征，且与健康成年人和NCFBE患者的特征相当。布瑞索卡替降低了血液和痰液中的NSP水平。安全性与先前研究相当，未发现新的安全问题，支持对成年CF患者使用与其他人群相似的剂量。这些发现支持对布瑞索卡替在CF患者中进行进一步研究。
NCT05090904。
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