A Guide to Rational Dosing of Monoclonal Antibodies
A Guide to Rational Dosing of Monoclonal Antibodies
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DOI：
10.2165/11596370-000000000-00000
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发表时间：
2012-01-01
影响因子：
4.5
通讯作者：
Dresser, Mark J.
中科院分区：
文献类型：
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作者：
Bai, Shuang;Jorga, Karin;Dresser, Mark J.
背景和目的：治疗性单抗的剂量通常基于身体大小，认为基于身体大小的剂量将减少药物暴露的受试者之间的变异性。然而，大多数单抗是靶向性的，具有相对较大的治疗窗口，通常身体大小对药代动力学变异性的贡献很小。因此，单抗的给药模式应该在这些独特特征的背景下进行评估。这项研究的目的是回顾目前的给药策略，并利用建模和模拟的方法为mAbs的给药提供科学的理论依据。方法：在这项分析中，系统地评价了mAbs基于体重或不依赖于体重(固定)的给药方案。建立了一个通用的二室一阶消除模型。个体或群体的药代动力学曲线被模拟为体重对清除量(Bw_CL)和中心分布体积(Bw_Vi)的影响的函数。在整个人群中，比较了基于体重的剂量和固定剂量之间暴露的变异性(血清浓度-时间曲线下的面积[AUC]、低谷血清浓度[C-min]和峰值血清浓度[C-max])。还测量了轻体重和重体重受试者与中等体重受试者暴露的偏差。然后将模拟结果与病例研究中基于体重的给药和固定剂量给药的各种单抗的临床药代动力学特征进行评估。结果：本分析的结果表明，暴露的可变性依赖于体重对药代动力学影响的大小。与传统的假设相反，基于体重的剂量在减少暴露可变性方面并不总是比固定剂量提供优势。总体而言，当群体药代动力学模型中theta(BW_CL)和theta(BW_VI)的指数函数为0.5时，基于体重的给药比固定给药的变异性和偏差更小。在theta(BW_CL)或theta(BW_VI)为>；0.5的情况下，对暴露变异性的影响对于每种暴露措施是不同的。案例研究表明，大多数单抗对体重影响很小或中等(theta(BW_CL)和theta(BW_VI))
Background and Objective: Dosing of therapeutic monoclonal antibodies (mAbs) is often based on body size, with the perception that body size-based dosing would reduce inter-subject variability in drug exposure. However, most mAbs are target specific with a relatively large therapeutic window and generally a small contribution of body size to pharmacokinetic variability. Therefore, the dosing paradigm for mAbs should be assessed in the context of these unique characteristics. The objective of this study was to review the current dosing strategy and to provide a scientific rationale for dosing of mAbs using a modelling and simulation approach.Methods: In this analysis, the body weight-based or body weight-independent (fixed) dosing regimens for mAbs were systematically evaluated. A generic two-compartment first-order elimination model was developed. Individual or population pharmacokinetic profiles were simulated as a function of the body weight effects on clearance (theta(BW_CL)) and on the central volume of distribution (theta(BW_VI)). The variability in exposure (the area under the serum concentration-time curve [AUC], trough serum concentration [C-min] and peak serum concentration [C-max]) was compared between body weight-based dosing and fixed dosing in the entire population. The deviation of exposure for light and heavy subjects from median body weight subjects was also measured. The simulation results were then evaluated with clinical pharmacokinetic characteristics of various mAbs that were given either by body weight-based dosing or by fixed dosing in the case study.Results: Results from this analysis demonstrated that exposure variability was dependent on the magnitude of the body weight effect on pharmacokinetics. In contrast to the conventional assumption, body weight-based dosing does not always offer advantages over fixed dosing in reducing exposure variability. In general, when the exponential functions of theta(BW_CL) and theta(BW_VI) in the population pharmacokinetic model are 0.5, body weight-based dosing results in less variability and less deviation than fixed dosing. In the scenarios when either theta(BW_CL) or theta(BW_VI) is >0.5, the impact on exposure variability is different for each exposure measure. The case study demonstrated that most mAbs had little effect or a moderate body weight effect (theta(BW_CL) and theta(BW_VI)