Brensocatib是一部小说,口服,选择性,二肽基肽酶1(DPP1)的可逆抑制剂,激活几种中性粒细胞丝氨酸蛋白酶(NSP),包括中性粒细胞弹性蛋白酶(NE),蛋白酶3(PR3),在中性粒细胞成熟的早期阶段,骨髓中的组织蛋白酶G(CatG)。这些NSP与病原体破坏和炎症介导相关;它们失调的激活可导致活性NSP的过度分泌,引起破坏性炎症并促成嗜中性粒细胞介导的炎症和自身免疫性疾病。因此,骨髓中DPP1的药理学抑制可以代表这些嗜中性粒细胞驱动的疾病的有吸引力的策略。在非囊性纤维化支气管扩张患者中已完成的2期试验(ClinicalTrials.gov编号NCT03218917;EudraCT编号:2017-002533-32)确实证明了brensocatib的给药通过抑制NSP的下游激活来减轻慢性炎症的损害作用。为了支持一系列临床前计划,并进一步了解啮齿动物种类和菌株如何影响brensocatib的药代动力学(PK)概况及其对NE的药效学(PD)影响,PR3和CatG,一项广泛的幼稚剂量研究,使用不同剂量水平的brensocatib,频率,并进行了持续时间。观察到剂量依赖性PK暴露反应(AUC和Cmax),而与啮齿动物种类和菌株无关。总的来说,与大鼠相比,小鼠的NSP活性降低更大。当QD剂量是BID日剂量的1.5倍时,与BID(每天两次)给药相比,每天一次(QD)给药的小鼠和大鼠具有相等的NSP活性降低。对于这两种小鼠品系,CatG活性降低最多,其次是NE,然后是PR3;然而,对于这两种大鼠品系,PR3活性降低最多,其次是CatG,然后是NE。〜7天后观察到NSP活性的最大减少,回收率几乎是对称的。这些结果可能有助于未来的体内brensocatib研究剂量考虑,如预防性或治疗性给药的时机,物种的选择,剂量和给药频率。
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.