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.

Methods

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.

Results

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.

Conclusions

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).

中文翻译：

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Ustekinumab在克罗恩病患者中的药代动力学和暴露反应关系

背景与目标

Ustekinumab是与人白介素12（IL12和IL23）的p40亚基具有高亲和力结合的单克隆抗体，该抗体已被批准用于治疗中度至重症克罗恩病（CD）的患者。但是，关于其药代动力学性质或药物暴露水平与患者反应之间关系的数据很少。我们从2项3期诱导研究和1项维持研究中收集了数据，以确定ustekinumab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。

方法

我们从单次静脉注射剂量（130 mg或约6 mg / kg）给予ustekinumab的8周中度至重度CD患者的诱导研究中收集了ustekinumab血清浓度和疗效的数据。我们在诱导研究中从对ustekinumab有反应的患者的维持研究中收集了相同的数据，然后每8或12周接受皮下注射（90 mg），持续44周。在维持研究的第44周（开始治疗后52周），评估患者的临床缓解的主要终点（定义为CD活性指数评分低于150分），内窥镜疗效指标和血清C反应性水平蛋白质。Ustekinumab浓度数据​​分为四分位数，并评估了暴露与反应之间的关系。

结果

随时间推移，ustekinumab的血清浓度与剂量成正比，在诱导研究之间无显着差异。在维持研究中，在第二次维持剂量下，ustekinumab的浓度达到了稳态。与间隔12周的患者相比，间隔8周使用ustekinumab的患者的谷值中位数浓度大约高出三倍。Ustekinumab血清浓度与临床缓解率和内窥镜疗效终点相关，与C反应蛋白水平呈反相关，与免疫调节剂的使用无关。Ustekinumab的低谷浓度为0.8（甚至高达1.4μg/ mL）或更高，与低谷浓度患者相比，在较高比例的患者中维持临床缓解率相关。

结论

在对中度至重度CD患者的3期研究数据的分析中，我们发现ustekinumab的血清浓度与剂量成正比，并与治疗效果相关。Ustekinumab的浓度似乎不受免疫调节剂共同治疗的影响。Clinicaltrials.gov号。NCT01369329（UNITI 1），NCT01369342（UNITI 2）和NCT01369355（IM-UNITI）。