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首页> 外文期刊>Inflammatory bowel diseases >The Safety, Tolerability, and Pharmacokinetics Profile of BT-11, an Oral, Gut-Restricted Lanthionine Synthetase C-Like 2 Agonist Investigational New Drug for Inflammatory Bowel Disease: A Randomized, Double-Blind, Placebo-Controlled Phase I Clinical Trial
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The Safety, Tolerability, and Pharmacokinetics Profile of BT-11, an Oral, Gut-Restricted Lanthionine Synthetase C-Like 2 Agonist Investigational New Drug for Inflammatory Bowel Disease: A Randomized, Double-Blind, Placebo-Controlled Phase I Clinical Trial

机译：BT-11的安全性，耐受性和药代动力学分布，口服，肠道限制兰尼硫氨酸合成酶C样炎肠道疾病的激动性调查新药物：随机，双盲，安慰剂对照期I临床试验

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BT-11 is a new oral, gut-restricted, first-in-class investigational drug for Crohn disease (CD) and ulcerative colitis (UC) that targets the lanthionine synthetase C-like 2 (LANCL2) pathway and immunometabolic mechanisms. Oral BT-11 was assessed for safety, tolerability, and pharmacokinetics (PK) in normal healthy volunteers (n = 70) in a randomized, double-blind, placebo-controlled trial. Subjects (n = 70) were randomly assigned to one of five single ascending dose cohorts (up to 100 mg/kg, p.o.) and three multiple ascending dose cohorts [up to 100 mg/kg daily (QD) for seven days, orally]. Safety and tolerability were assessed by adverse event (AE) reporting, vital signs, electrocardiogram, hematology, and clinical chemistry. BT-11 did not increase total or gastrointestinal AE rates, as compared with placebo, and no serious adverse events were observed. Oral BT-11 dosing does not result in any clinically significant findings by biochemistry, coagulation, electrocardiogram, hematology, or urinalysis as compared with placebo. Mean fecal concentrations of BT-11 increased linearly with increasing oral doses, with 2.39 mg/g at 7.7 mg/kg on day 7 of the multiple ascending dose (MAD). Analysis of plasma pharmacokinetics indicates that maximum systemic concentrations are approximately 1/6000(th) of observed concentrations in feces and the distal gastrointestinal tract. Fecal calprotectin levels were lower in BT-11 treated groups as compared to placebo. BT-11 significantly decreases interferon gamma positive (IFN gamma+) and tumor necrosis factor alpha positive (TNF alpha+) cluster of differentiation 4 positive (CD4+) T cells and increases forkhead box P3 positive (FOXP3+) CD4+ T cells in colonic lamina propria mononuclear cells from patients with CD and patients with UC at concentrations of 0.01 mu M when treated ex vivo. BT-11 treatment is well-tolerated with no dose-limiting toxicities up to daily oral doses of 100 mg/kg (16 tablets); whereas the efficacious dose is a single tablet (8 mg/kg). Phase II studies in CD and UC patients are ongoing.
机译：BT-11是一种新的口腔，肠道限制，用于CROHN疾病（CD）和溃疡性结肠炎（UC）的新的一类调查药物，其靶向兰硫氨酸合成酶C样2（LANCL2）途径和免疫素机构。在随机，双盲，安慰剂对照试验中评估了在正常健康志愿者（n = 70）中的安全性，耐受性和药代动力学（PK）的口服BT-11。受试者（n = 70）被随机分配到五种单一升序的剂量队列中的一种（高达100mg / kg，po）和三个多个上升剂量队列[每日高达100mg / kg每日（qd），七天，口服] 。通过不良事件（AE）报告，生命体征，心电图，血液学和临床化学评估安全性和耐受性。与安慰剂相比，BT-11未增加总量或胃肠道AE率，并且没有观察到严重的不良事件。与安慰剂相比，口服BT-11给药不会导致生物化学，凝血，心电图，血液学或尿液分析的任何临床显着发现。 BT-11的平均粪便浓度随着口服剂量增加而线性增加，在多个上升剂量（MOD）的第7天，在第7天，在7.7mg / kg下，2.39mg / g。血浆药代动力学的分析表明，最大的全身浓度约为观察到的粪便和远端胃肠道的1/6000（TH）。与安慰剂相比，BT-11处理基团的粪便酸蛋白水平较低。 BT-11显着降低干扰素γ阳性（IFNγ+）和肿瘤坏死因子α阳性（TNFα+）分化4阳性（CD4 +）T细胞簇，并增加结肠椎相色带单核细胞中的叉头箱P3阳性（Foxp3 +）CD4 + T细胞从CD和UC的患者患者，在处理前体内时浓度为0.01μm。 BT-11治疗耐受良好的毒性，无剂量限制毒性，每日口服10mg / kg（16片）;虽然有效剂量是单片（8mg / kg）。 CD和UC患者的II期研究正在进行中。

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