Janssen Research & Development, LLC., Spring House, Pennsylvania.
Janssen Research & Development, LLC., Spring House, Pennsylvania.
Gastroenterology. 2018 May;154(6):1660-1671. doi: 10.1053/j.gastro.2018.01.043. Epub 2018 Feb 1.
BACKGROUND & AIMS: Ustekinumab is a monoclonal antibody that binds with high affinity to the p40 subunit of human interleukin 12 (IL12 and IL23) that has been approved for treatment of patients with moderate to severe Crohn's disease (CD). However, there are few data on its pharmacokinetic properties or the relationship between drug exposure levels and patient response. We collected data from 2 Phase 3 induction studies and 1 maintenance study to determine ustekinumab's pharmacokinetic features, relationship between exposure and response, and optimal serum concentrations for efficacy.
We collected data on serum concentrations of ustekinumab and efficacy from induction studies of patients with moderate to severe CD given ustekinumab for 8 weeks following a single intravenous dose (either 130 mg or approximately 6 mg/kg). We collected the same data from a maintenance study of patients with a response to ustekinumab in the induction study who then received subcutaneous injections (90 mg) every 8 or 12 weeks for 44 weeks. At week 44 of the maintenance study (52 weeks after treatment began), patients were evaluated for the primary endpoint of clinical remission (defined as a CD activity index score below 150 points), endoscopic markers of efficacy, and serum level of C-reactive protein. Ustekinumab concentration data were categorized into quartiles and relationships between exposure and response were assessed. Optimal concentration cutoff values were evaluated using receiver operating characteristic curve analysis.
Serum concentrations of ustekinumab over time were proportional to dose and did not differ significantly between the induction studies. In the maintenance study, ustekinumab concentration reached the steady state by the second maintenance dose; the median trough concentration was approximately threefold higher in patients given ustekinumab at 8-week intervals compared with 12-week intervals. Ustekinumab serum concentrations associated with rates of clinical remission and endoscopic efficacy endpoints, correlated inversely with level of C-reactive protein, and did not associate with use of immunomodulators. Trough concentrations of ustekinumab of 0.8 (or even up to 1.4 μg/mL) or greater were associated with maintenance of clinical remission in a higher proportion of patients than patients with lower trough concentrations.
In an analysis of data from Phase 3 studies of patients with moderate to severe CD, we found serum concentrations of ustekinumab to be proportional to dose and associate with treatment efficacy. Concentrations of ustekinumab did not seem to be affected by cotreatment with immunomodulators. Clinicaltrials.gov no. NCT01369329 (UNITI 1), NCT01369342 (UNITI 2), and NCT01369355 (IM-UNITI).
乌司奴单抗是一种单克隆抗体，能与人类白细胞介素 12（IL12 和 IL23）的 p40 亚单位高亲和力结合，已被批准用于治疗中重度克罗恩病（CD）患者。然而，关于其药代动力学特征或药物暴露水平与患者反应之间的关系的数据很少。我们收集了来自 2 项 3 期诱导研究和 1 项维持研究的数据，以确定乌司奴单抗的药代动力学特征、暴露与反应之间的关系以及疗效的最佳血清浓度。
我们收集了中重度 CD 患者接受乌司奴单抗单剂量静脉注射（130mg 或约 6mg/kg）后 8 周诱导研究中血清乌司奴单抗浓度和疗效的数据。我们还收集了在诱导研究中对乌司奴单抗有反应的患者接受乌司奴单抗维持治疗（90mg，每 8 或 12 周皮下注射一次）的 44 周维持研究中的相同数据。在维持研究的第 44 周（治疗开始后 52 周），评估患者的主要终点为临床缓解（定义为 CD 活动指数评分低于 150 分）、内镜疗效标志物和血清 C 反应蛋白。将乌司奴单抗浓度数据分为四分之一，并评估暴露与反应之间的关系。使用受试者工作特征曲线分析评估最佳浓度截断值。
随着时间的推移，乌司奴单抗的血清浓度与剂量成正比，并且在诱导研究中没有显著差异。在维持研究中，乌司奴单抗的浓度在第二次维持剂量时达到稳定状态；与每 12 周间隔给药的患者相比，每 8 周间隔给药的患者的谷浓度中位数高约 3 倍。乌司奴单抗的血清浓度与临床缓解率和内镜疗效终点相关，与 C 反应蛋白水平呈负相关，与免疫调节剂的使用无关。与较低谷浓度的患者相比，乌司奴单抗的谷浓度为 0.8（甚至高达 1.4μg/ml）或更高与维持临床缓解的患者比例更高。
在对中重度 CD 患者的 3 期研究数据进行分析时，我们发现乌司奴单抗的血清浓度与剂量成正比，并与治疗效果相关。乌司奴单抗的浓度似乎不受免疫调节剂联合治疗的影响。Clinicaltrials.gov 编号 NCT01369329（UNITI 1）、NCT01369342（UNITI 2）和 NCT01369355（IM-UNITI）。
