Background

Certolizumab pegol (CZP) is effective for moderately to severely active Crohn’s disease (CD). Higher plasma concentrations are associated with better outcomes and increased drug clearance is the driver of subtherapeutic CZP concentrations.

Objective

We aimed to develop a prediction model incorporating predicted CZP clearance and patient variables to allow estimation of the probability for remission prior to initiating therapy.

Methods

A population pharmacokinetic model estimated baseline CZP clearance in patients with CD from nine phase II and III trials. Multivariable prediction models were developed and validated using the PRECiSE 1 and PRECiSE 2 datasets to identify candidate predictors for a composite remission outcome (Crohn’s Disease Activity Index ≤ 150 and fecal calprotectin concentration ≤ 250 μg/g) at Weeks 6 or 26. An online clinical decision support tool (CDST) was developed.

Results

Baseline predicted CZP clearance ≥ 0.5 L/day was associated with subtherapeutic Week 6 CZP plasma concentrations. Baseline weight (odds ratio [OR] 1.04; 95% confidence interval [CI] 1.02–1.07), calculated CZP clearance (OR 0.92; 95% CI 0.87–0.96), hematocrit (OR 2.55; 95% CI 1.43–4.54), and fecal calprotectin (OR 0.66; 95% CI 0.54–0.80) were associated with Week 6 remission (p ≤ 0.0015 for all predictors). Baseline weight (OR 1.04; 95% CI 1.02–1.07), calculated CZP clearance (OR 0.93; 95% CI 0.88–0.97), and Patient-Reported Outcome-2 (PRO2) (OR 0.93; 95% CI 0.87–0.99) were associated with Week 26 remission (p ≤ 0.033 for all predictors).

Conclusions

Patients who are predicted to have accelerated baseline CZP clearance are at risk of subtherapeutic CZP concentrations. Patient-level probabilities for a composite remission outcome can be predicted for patients with CD by entering commonly available patient- and disease-related factors into an online CDST (https://premedibd.com) incorporating predicted CZP clearance.

中文翻译：

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一种临床预测模型，用于确定 Certolizumab Pegol 对克罗恩病的反应概率

背景

Certolizumab pegol (CZP) 对中度至重度活动性克罗恩病 (CD) 有效。更高的血浆浓度与更好的结果相关，增加的药物清除率是亚治疗 CZP 浓度的驱动因素。

客观的

我们的目标是开发一个预测模型，结合预测的 CZP 清除率和患者变量，以允许在开始治疗之前估计缓解的可能性。

方法

九项 II 期和 III 期试验的群体药代动力学模型估计了 CD 患者的基线 CZP 清除率。使用 PRECiSE 1 和 PRECiSE 2 数据集开发和验证多变量预测模型，以确定第 6 周或第 26 周复合缓解结果（克罗恩病活动指数 ≤ 150 和粪便钙卫蛋白浓度 ≤ 250 μg/g）的候选预测因子。在线临床开发了决策支持工具（CDST）。

结果

基线预测的 CZP 清除率≥ 0.5 L/天与亚治疗第 6 周 CZP 血浆浓度相关。基线体重（比值比 [OR] 1.04；95% 置信区间 [CI] 1.02–1.07），计算的 CZP 清除率（OR 0.92；95% CI 0.87–0.96），血细胞比容（OR 2.55；95% CI 1.43–4.54），和粪便钙卫蛋白（OR 0.66；95% CI 0.54–0.80）与第 6 周缓解相关（所有预测因子p  ≤ 0.0015）。基线体重（OR 1.04；95% CI 1.02–1.07）、计算的 CZP 清除率（OR 0.93；95% CI 0.88–0.97）和患者报告的结果 2 (PRO2)（OR 0.93；95% CI 0.87–0.99）与第 26 周缓解相关（所有预测因子p  ≤ 0.033）。

结论

预计基线 CZP 清除速度加快的患者处于亚治疗 CZP 浓度的风险中。通过将常见的患者和疾病相关因素输入在线 CDST (https://premedibd.com) 并结合预测的 CZP 清除率，可以预测 CD 患者复合缓解结果的患者水平概率。