Clinical Pharmacology and Pharmacometrics, Janssen Research & Development LLC, 1400 McKean Rd, PA, 19477, Spring House, USA.
Clinical Pharmacology, Simcere Pharmaceuticals, MB, Cambridge, USA.
Eur J Drug Metab Pharmacokinet. 2022 Jul;47(4):537-548. doi: 10.1007/s13318-022-00768-7. Epub 2022 Apr 20.
Ustekinumab has been approved for the treatment of patients with plaque psoriasis (PSO), psoriatic arthritis (PSA), Crohn's disease (CD), and ulcerative colitis (UC). This study was performed to investigate whether the pharmacokinetics of ustekinumab differ across different disease populations.
An integrated population pharmacokinetic analysis was conducted to characterize ustekinumab pharmacokinetics across four disease indications (i.e., PSO, PSA, CD, and UC) and healthy subjects.
The pooled ustekinumab pharmacokinetic data consisted of 46,970 serum concentrations from 3,217 subjects (n = 356 for PSO, 696 for PSA, 1196 for CD, 823 for UC, and 24 for healthy subjects) in 7 clinical trials following subcutaneous or intravenous ustekinumab administrations. The pharmacokinetics of ustekinumab were adequately described by a two-compartment linear model with first-order absorption and elimination. Ustekinumab clearance (CL) and volume of distribution parameters increased nonlinearly with body weight, and the CL was higher in subjects with lower serum albumin, non-Caucasians, and positive antibodies to ustekinumab. Although CL in subjects with PSO and PSA appeared to be slightly different (- 12.7% and + 8.87%, respectively) from CL in other populations (including CD, UC, and healthy subjects), the model-derived post-hoc pharmacokinetic parameters were generally comparable across the 4 disease populations. Simulations also suggested overall comparable ustekinumab exposure (i.e., trough concentration and AUC) at steady state across the disease populations following the same subcutaneous dose regimen.
Ustekinumab pharmacokinetics are generally comparable across all approved inflammatory-mediated indications and healthy subjects after accounting for the body weight-related pharmacokinetic difference.
乌司奴单抗已被批准用于治疗斑块状银屑病（PSO）、银屑病关节炎（PSA）、克罗恩病（CD）和溃疡性结肠炎（UC）。本研究旨在探究乌司奴单抗在不同疾病人群中的药代动力学是否存在差异。
进行了一项综合群体药代动力学分析，以描述乌司奴单抗在四个疾病指征（即 PSO、PSA、CD 和 UC）和健康受试者中的药代动力学特征。
乌司奴单抗的汇总药代动力学数据来自 7 项临床试验中的 3217 名受试者（n=356 名 PSO、696 名 PSA、1196 名 CD、823 名 UC 和 24 名健康受试者）的 46970 个血清浓度。乌司奴单抗的药代动力学特征通过一个具有一级吸收和消除的两室线性模型得到了很好的描述。乌司奴单抗清除率（CL）和分布容积参数随体重呈非线性增加，血清白蛋白较低、非白种人以及对乌司奴单抗呈阳性抗体的受试者 CL 较高。虽然 PSO 和 PSA 受试者的 CL 似乎与其他人群（包括 CD、UC 和健康受试者）的 CL 略有不同（分别为-12.7%和+8.87%），但模型推导的事后药代动力学参数在 4 个疾病人群中通常是可比的。模拟还表明，在相同的皮下剂量方案下，稳态时，疾病人群的乌司奴单抗暴露（即谷浓度和 AUC）总体上是可比的。
在考虑到与体重相关的药代动力学差异后，乌司奴单抗的药代动力学在所有批准的炎症介导的适应症和健康受试者中通常是可比的。
