Genentech Inc., South San Francisco, CA, USA.
Clin Pharmacokinet. 2012 Feb 1;51(2):119-35. doi: 10.2165/11596370-000000000-00000.
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.
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 (θ(BW_CL)) and on the central volume of distribution (θ(BW_V1)). 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 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 θ(BW_CL) and θ(BW_V1) in the population pharmacokinetic model are <0.5, fixed dosing results in less variability and less deviation than body weight-based dosing; when both θ(BW_CL) and θ(BW_V1) are >0.5, body weight-based dosing results in less variability and less deviation than fixed dosing. In the scenarios when either θ(BW_CL) or θ(BW_V1) 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 (θ(BW_CL) and θ(BW_V1) <0.5 or ∼0.5). The difference of variability in exposure between body weight-based and fixed dosing is generally less than 20% and the percentages of deviation for light and heavy subpopulations are less than 40%.
The analysis provided insights into the conditions under which either fixed or body weight-based dosing would be superior in reducing pharmacokinetic variability and exposure differences between light and heavy subjects across the population. The pharmacokinetic variability introduced by either dosing regimen is moderate relative to the variability generally observed in pharmacodynamics, efficacy and safety. Therefore, mAb dosing can be flexible. Given many practical advantages, fixed dosing is recommended to be the first option in first-in-human studies with mAbs. The dosing strategy in later stages of clinical development could then be determined based on combined knowledge of the body weight effect on pharmacokinetics, safety and efficacy from the early clinical trials.
治疗性单克隆抗体（mAb）的给药通常基于体表面积，人们认为基于体表面积的给药可以降低药物暴露的个体间变异性。然而，大多数 mAb 具有特定的靶标，治疗窗相对较大，并且药代动力学变异性通常与体表面积的关系较小。因此，mAb 的给药方案应根据这些独特的特征进行评估。本研究的目的是回顾当前的给药策略，并通过建模和模拟方法为 mAb 的给药提供科学依据。
在本分析中，系统评估了 mAb 的基于体重或与体重无关（固定）的给药方案。开发了一个通用的两室一阶消除模型。个体或群体药代动力学特征被模拟为清除率（θ（BW_CL））和中央分布容积（θ（BW_V1））对体表面积影响的函数。比较了整个人群中基于体重的给药和固定给药对暴露（血清浓度-时间曲线下面积[AUC]、谷血清浓度[C（min）]和峰血清浓度[C（max）]）的影响。还测量了轻体重和重体重受试者与中位数体重受试者的暴露偏差。然后，使用在案例研究中以基于体重的剂量或固定剂量给予的各种 mAb 的临床药代动力学特征评估模拟结果。
该分析结果表明，暴露变异性取决于药代动力学中体表面积影响的大小。与传统假设相反，基于体重的给药并不总是比固定剂量给药更能降低暴露变异性。一般来说，当群体药代动力学模型中θ（BW_CL）和θ（BW_V1）的指数函数<0.5 时，固定剂量给药比基于体重的给药产生的变异性和偏差更小；当θ（BW_CL）和θ（BW_V1）均>0.5 时，基于体重的给药比固定剂量给药产生的变异性和偏差更小。在θ（BW_CL）或θ（BW_V1）中任一个>0.5 的情况下，暴露变异性的影响因每种暴露测量方法而异。案例研究表明，大多数 mAb 影响较小或具有中度体质量效应（θ（BW_CL）和θ（BW_V1）<0.5 或∼0.5）。基于体重的给药和固定剂量给药之间暴露变异性的差异通常小于 20%，轻体重和重体重亚群的偏差百分比小于 40%。
该分析深入了解了在何种情况下，固定剂量或基于体重的剂量给药在降低整个人群中药物变异性和轻体重和重体重受试者之间的暴露差异方面更具优势。两种给药方案引起的药代动力学变异性相对于药效学、疗效和安全性通常观察到的变异性相对适中。因此，mAb 给药可以具有灵活性。鉴于许多实际优势，固定剂量给药被推荐作为 mAb 首次人体研究的首选方案。然后，可以根据早期临床试验中对药代动力学、安全性和疗效的体表面积影响的综合知识来确定临床开发后期的给药策略。
