Dartois Céline, Freyer Gilles, Michallet Mauricette, Hénin Emilie, You Benoît, Darlavoix Isabelle, Vermot-Desroches Claudine, Tranchand Brigitte, Girard Pascal
Université Lyon 1, EA3738 CTO, Faculté de Médecine Lyon Sud, Oullins, France.
Clin Pharmacokinet. 2007;46(5):417-32. doi: 10.2165/00003088-200746050-00004.
Inolimomab, a monoclonal antibody against interleukin (IL)-2Ralpha (CD25) has shown promising results in the treatment of corticosteroid-resistant acute graft-versus-host disease (GvHD). The objective of the present study was to characterise the pharmacokinetic and pharmacodynamic properties of inolimomab as first-line treatment in this condition.
The data came from 21 patients with acute GvHD (8 with an International Bone Marrow Transplant Registry [IBMTR] score of B, 11 with a score of C and 2 with a score of D) following haematopoietic stem cell transplantation after a median delay of 26 days (range 10-127 days). Inolimomab was administered at 0.1, 0.2, 0.3 or 0.4 mg/kg daily in association with methylprednisolone (2 mg/kg) for 8 or 16 days depending on the status at day 9. Then, for responder patients, administrations were continued three times weekly until day 28. Inolimomab concentrations and pharmacodynamic data (acute GvHD scores) were recorded during the study. The pharmacodynamic data were assessed in four grades according to the IBMTR and Glucksberg classification in parallel with Karnofsky scores. A population analysis was developed using a nonlinear mixed-effects model to define the pharmacokinetic model, to test covariates and, when apparent, to model the exposure-effect relationship by a proportional odds model. The modelling was finally qualified by a predictive check.
The best pharmacokinetic model was two-compartmental. For each score, the most demonstrative exposure-effect graphics linked the cumulative area under the concentration-time curve to cumulated probabilities of observing a specific score. This relationship was identified as a maximum effect model for the skin (with two patient subpopulations: sensitive/less sensitive) and a linear model for the intestinal tract and liver. No covariate was identified as influencing any of these parameters.
Inolimomab exposure-effect relationships as first-line treatment for acute GvHD have been identified and modelled. The discovered dose-effect relationship allows confirmation of the treatment response, thereby establishing the first step towards optimising the inolimomab dosage in future trials.
抗白细胞介素（IL）-2Rα（CD25）单克隆抗体依诺利单抗在治疗对皮质类固醇耐药的急性移植物抗宿主病（GvHD）方面已显示出有前景的结果。本研究的目的是表征依诺利单抗作为这种情况下一线治疗的药代动力学和药效学特性。
数据来自21例急性GvHD患者（8例国际骨髓移植登记处[IBMTR]评分为B，11例评分为C，2例评分为D），这些患者在造血干细胞移植后中位延迟26天（范围10 - 127天）。依诺利单抗以0.1、0.2、0.3或0.4mg/kg每日给药，联合甲泼尼龙（2mg/kg），根据第9天的情况给药8天或16天。然后，对于有反应的患者，给药持续至第28天，每周三次。在研究期间记录依诺利单抗浓度和药效学数据（急性GvHD评分）。根据IBMTR和Glucksberg分类将药效学数据分为四个等级，同时记录卡诺夫斯基评分。使用非线性混合效应模型进行群体分析，以定义药代动力学模型、测试协变量，并在明显时通过比例优势模型对暴露 - 效应关系进行建模。最终通过预测检验对模型进行验证。
最佳药代动力学模型为二室模型。对于每个评分，最具说明性的暴露 - 效应图将浓度 - 时间曲线下的累积面积与观察到特定评分的累积概率联系起来。这种关系被确定为皮肤的最大效应模型（有两个患者亚群：敏感/不太敏感）以及肠道和肝脏的线性模型。未发现有协变量影响这些参数中的任何一个。
已确定并建模了依诺利单抗作为急性GvHD一线治疗的暴露 - 效应关系。发现的剂量 - 效应关系有助于确认治疗反应，从而为未来试验中优化依诺利单抗剂量迈出第一步。
