Relationship between omalizumab pharmacokinetics, IgE pharmacodynamics and symptoms in patients with severe persistent allergic (IgE-mediated) asthma
Relationship between omalizumab pharmacokinetics, IgE pharmacodynamics and symptoms in patients with severe persistent allergic (IgE-mediated) asthma
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DOI：
10.1111/j.1365-2125.2009.03401.x
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发表时间：
2009-07-01
影响因子：
3.4
通讯作者：
Jimenez, Pablo
中科院分区：
文献类型：
--
作者：
Lowe, Philip J.;Tannenbaum, Stacey;Jimenez, Pablo
中心点曾经假设，在游离IgE浓度和哮喘的体征和症状之间一定有关系--毕竟，这是奥马利单抗发展的原因。然而，尽管对服用奥马利单抗的患者的游离IgE和肺活量测定数据的许多统计分析表明，安慰剂和治疗之间的差异，由于在第三阶段试验中研究的游离IgE的范围很窄，并且采样和临床测量的稀疏性，没有显示出一致的时间和IgE依赖关系。在本研究中，使用药代动力学-药效学(PK-PD)模型来解决上述问题，以估计奥马珠单抗治疗期间和治疗后所有时间点的游离IgE浓度，以及患者每日日记数据。中心点首次允许观察到游离IgE与哮喘体征和症状之间的直接相关性。然后，通过PK-PD模型模拟，可以推导出奥马珠单抗的中心点剂量和方案，将游离IgE抑制到与临床症状改善相关的程度。AIMSOMalizumab是一种皮下注射的抗IgE抗体，对中到重度持续性过敏性哮喘有效。这些研究的目的是(I)用基于机制的、非线性的、omalizumab-IgE结合模型来描述游离IgE的群体药效学；(Ii)通过与临床结果的相关性来推断无靶点的IgE抑制水平；以及(Iii)检查当前批准的剂量表的充分性，并探索潜在的剂量和方案。方法从1781名12-79岁的患者、4个稀疏抽样的随机、安慰剂对照研究和152名受试者中获得浓度数据(奥马利单抗、游离和总IgE)。通过模拟检查在体重(39-150公斤)和基线IgE(19-1055IU ml(-1))范围内的NONMEM预测性能。预测的游离IgE水平与时间平均的患者日记临床结果相关。结果该模型准确地预测了观察的奥马珠单抗、游离和总IgE浓度。游离IgE浓度与临床症状和体征有很好的相关性，允许在4周临床观察期的中点将目标浓度设定为14ngml(-1)，以确定奥马利单抗的剂量和方案。结论奥马利单抗-IgE结合模型可预测游离IgE，并显示出哮喘患者游离IgE抑制与临床结果之间的非线性时间依赖关系。虽然目前批准的剂量表接近最佳，但如果可以给予更高剂量，应该可以治疗基线IgE水平更高的患者。
center dot It had been hypothesized that there must be a relationship between free IgE concentrations and the signs and symptoms of asthma - after all, this is what drove the development of omalizumab.center dot However, although many statistical analyses of free IgE and spirometry data for patients equilibrated on omalizumab had shown a difference between placebo and treatment, no consistent time- and IgE-dependent relationship had been shown due to the narrow range of free IgE being studied and the sparse nature of the sampling and clinical measurements in Phase III trials.WHAT THIS STUDY ADDScenter dot The above problem was solved using a pharmacokinetic-pharmacodynamic (PK-PD) model to estimate free IgE concentrations for all time points throughout and after treatment with omalizumab, together with patient daily diary data.center dot This allowed for the first time the direct correlation between free IgE and signs and symptoms of asthma to be observed.center dot Doses and regimens for omalizumab could then be derived, through PK-PD model simulation, for suppressing free IgE to a point correlated with an improvement in clinical symptoms.AIMSOmalizumab, a subcutaneously administered anti-IgE antibody, is effective for moderate-to-severe persistent allergic asthma. The aims were to (i) describe the population pharmacodynamics of free IgE with a mechanism-based, nonlinear, omalizumab-IgE binding model; (ii) deduce a target-free IgE suppression level by correlation with clinical outcomes; and (iii) check the adequacy of current approved dosing tables and explore potential doses and regimens beyond.METHODSConcentration data (omalizumab, free and total IgE) were obtained from 1781 patients aged 12-79 years, in four sparsely sampled randomized, placebo-controlled studies and 152 subjects in a richly sampled single-dose study. NONMEM predictive performance across the range of bodyweights (39-150 kg) and baseline IgE (19-1055 IU ml(-1)) was checked by simulation. Predicted free IgE levels were correlated with time-averaged patient diary clinical outcomes.RESULTSThe model accurately predicted observed omalizumab, free and total IgE concentrations. Free IgE concentrations correlated well with clinical signs and symptoms, allowing a target concentration of 14 ng ml(-1), at the midpoint of 4-week clinical observation periods, to be set for determining the dose and regimen for omalizumab.CONCLUSIONSThe omalizumab-IgE binding model is predictive for free IgE and demonstrates a nonlinear time-dependent relationship between free IgE suppression and clinical outcomes in asthma. Although currently approved dosing tables are close to optimal, it should be possible to treat patients with higher levels of baseline IgE if higher doses can be administered.