Dubinsky Marla C, Rabizadeh Shervin, Panetta John C, Spencer Elizabeth A, Everts-van der Wind Annelie, Dervieux Thierry
Mount Sinai Medical Center, New York, NY 10029, USA.
Cedars Sinai Medical Center, Los Angeles, CA 90048, USA.
Pharmaceutics. 2023 Sep 30;15(10):2408. doi: 10.3390/pharmaceutics15102408.
Infliximab (IFX) concentrations are a predictive factor (PF) of pharmacokinetic (PK) origin in the treatment of Crohn's disease (CD). We evaluated Clearance, another PF of PK origin, either alone or in combination with concentrations. They were evaluated from two cohorts, the first designed to receive standard dosing (n = 37), and the second designed to proactively target therapeutic IFX concentrations (n = 108). Concentrations were measured using homogeneous mobility shift assay. Clearance was estimated using the nonlinear mixed effects methods with Bayesian priors. C-reactive protein-based clinical remission (<3 mg/L in the absence of symptoms) was used for the disease control outcome measure. Longitudinal changes in disease control due to factors including time, IFX concentration, and Clearance were analyzed using repeated event analysis. Change in objective function value (∆OFV) was calculated to compare concentration and Clearance. The results indicated that lower baseline Clearance and proactive dosing associated with enhanced disease control during induction ( < 0.01). Higher IFX concentrations and lower Clearance measured at the second, third, and fourth infusion yielded improved disease control during maintenance ( < 0.032). During maintenance, the association with disease control was better with Clearance than with concentrations (∆OFV = -19.2; < 0.001), and the combination of both further minimized OFV ( < 0.001) with markedly improved clinical yield in the presence of both PF of PK origin. We conclude that the combination of IFX concentration and Clearance are better predictors of therapeutic outcome compared with either one alone.
英夫利昔单抗（IFX）浓度是克罗恩病（CD）治疗中药代动力学（PK）来源的预测因子（PF）。我们评估了清除率，这是另一个PK来源的PF，单独评估或与浓度联合评估。它们来自两个队列，第一个队列设计接受标准剂量（n = 37），第二个队列设计主动靶向治疗性IFX浓度（n = 108）。使用均相迁移率变动分析测量浓度。使用带有贝叶斯先验的非线性混合效应方法估计清除率。基于C反应蛋白的临床缓解（无症状时<3 mg/L）用于疾病控制结局测量。使用重复事件分析分析包括时间、IFX浓度和清除率等因素导致的疾病控制的纵向变化。计算目标函数值的变化（∆OFV）以比较浓度和清除率。结果表明，较低的基线清除率和诱导期的主动给药与疾病控制增强相关（<0.01）。在第二次、第三次和第四次输注时测量的较高IFX浓度和较低清除率在维持期产生了更好的疾病控制（<0.032）。在维持期，与疾病控制的关联清除率比浓度更好（∆OFV = -19.2；<0.001），并且两者的组合进一步最小化了OFV（<0.001），在存在两个PK来源的PF时临床疗效显著提高。我们得出结论，与单独的任一因素相比，IFX浓度和清除率的组合是治疗结局更好的预测指标。
