背景:为了成功植入供体造血干细胞(HSC),需要在造血细胞移植(HCT)前进行化疗和/或放疗,以打开骨髓生态位空间并将免疫排斥的风险降至最低.Briquilimab,一种人源化IgG1单克隆抗体,可阻断c-Kit受体和干细胞因子在各种C-Kit表达组织(包括HSC)上的相互作用,是严重联合免疫缺陷(SCID)患者临床开发中的潜在非清髓性调理剂,骨髓增生异常综合征(MDS),和急性髓细胞性白血病(AML)。
目的:本研究旨在表征药代动力学(PK),并开发一种在SCID患者中单次静脉注射4种不同剂量的Bluquilimab的群体PK模型,MDS,或接受HCT的AML。
方法:PK数据来自2项不同的研究:JAS-BMT-CP-001和JSP-CP-003。JAS-BMT-CP-001是在SCID患者中进行同种异体HCT之前,将煤球单抗作为调理剂的1/2期开放标签研究。参与者接受0.1、0.3、0.6或1.0mg/kg的单次静脉输注。JSP-CP-003是接受HCT的MDS或AML受试者中,与低剂量全身照射和氟达拉滨的标准预处理方案相结合的混合物的1a/b期开放标签研究。参与者接受单次静脉内剂量0.6mg/kg煤球。在两项研究中,在预处理时获得briquilimabPK样品,输液结束后5分钟,开始输注后4-和24小时,输液后2天至30天之间的任何时间,以及在供体细胞输注前的HCT当天。利用这2项临床研究的PK数据建立了群体PK模型,并评估了参与者的基线特征对煤球PK的影响。使用开发的PK模型进行PK模拟以计算达到HCT的目标浓度的时间。
结果:共有49名参与者(21名SCID成人和儿科参与者,中位年龄为12岁,28名MDS/AML成人参与者,中位年龄为70岁)纳入PK分析。线性和非线性消除相结合的两室模型最好地描述了煤球的PK。体重被确定为探索的协变量中PK参数的唯一协变量。对于体重70公斤的典型受试者,估计的净空参数,消除米氏Menten的最大代谢率,米迦勒·门顿常数,中央容积,外周体积,室间清除率为17.6mL/hr,51434.8纳克/小时,71.5ng/mL,3444.0mL,1613.3mL,和21.2毫升/小时,分别。单剂量0.6mg/kg后达到目标浓度500、1000和2000ng/mL的中位时间计算为12.3、10.4和7.7天,分别。
结论:在患有SCID的受试者中,MDS,或接受HCT的AML,并开发了一个群体PK模型来估计煤球清除率,以作为煤球后供体细胞输注时间的指导。体重被确定为对团块的消除和分布量的重要协变量。
For successful engraftment of donor hematopoietic stem cells (HSC),
conditioning with chemotherapy and/or radiation prior to hematopoietic cell transplantation (HCT) has been required to open marrow niche space and minimize the risk of immune rejection. Briquilimab, a humanized IgG1 monoclonal antibody that blocks the interaction between the c-Kit receptor and stem cell factor on various C-Kit expressing tissues including HSC, is a potential nonmyeloablative
conditioning agent in clinical development for patients with severe combined immunodeficiency (SCID), myelodysplastic syndromes (MDS), and acute myeloid leukemia (AML). This study aimed to characterize pharmacokinetics (PK) and develop a population PK model of briquilimab after single intravenous infusions of 4 different doses in patients with SCID, MDS, or AML receiving HCT. The PK data was collected from 2 different studies: JAS-BMT-CP-001 and JSP-CP-003. JAS-BMT-CP-001 is a phase 1/2 open-label study of briquilimab as a
conditioning agent prior to allogenic HCT in SCID patients. The participants received single intravenous infusions of 0.1, 0.3, 0.6, or 1.0 mg/kg. JSP-CP-003 was a phase 1a/b open-label study of briquilimab in combination with a standard
conditioning regimen of low dose total body irradiation and fludarabine in MDS or AML subjects undergoing HCT. The participants received a single intravenous dose of 0.6 mg/kg briquilimab. In both studies, briquilimab PK samples were obtained at pre-treatment, 5 minutes post-end of infusion, 4- and 24-hours post-start of infusion, any time between 2 days and 30 days postinfusion, and on the day of HCT prior to donor cell infusion.The population PK model was developed using the PK data from these 2 clinical studies, and the effect of participants\' baseline characteristics on the briquilimab PK was evaluated. PK simulations were performed using the developed PK model to calculate the time to reach target concentrations for HCT. A total of 49 participants (21 SCID adult and pediatric participants with a median age of 12 yr and 28 MDS/AML adult participants with a median age of 70 yr) were included in the PK analysis. A 2-compartment model with combined linear and non-linear elimination best described the PK of briquilimab. Body weight was determined as the sole covariate of the PK parameters among the explored covariates. For a typical subject with a body weight 70 kg, the estimated parameters for clearance, maximum metabolic rate of Michaelis Menten elimination, Michaelis Menten constant, central volume, peripheral volume, and intercompartmental clearance were 17.6 mL/h, 51,434.8 ng/h, 71.5 ng/mL, 3444.0 mL, 1613.3 mL, and 21.2 mL/h, respectively. The median time to reach target concentrations of 500, 1000, and 2000 ng/mL after a single dose of 0.6 mg/kg was calculated as 12.3, 10.4, and 7.7 days, respectively. The PK of intravenous briquilimab was characterized in subjects with SCID, MDS, or AML receiving HCT, and a population PK model was developed to estimate briquilimab clearance to use as a guide to the timing of donor cell infusion post-briquilimab. Body weight was identified as a significant covariate on elimination and volume of distribution of briquilimab.