Bergan Stein, Vethe Nils Tore
Department of Pharmacology, Oslo University Hospital, Oslo, Norway.
Department of Pharmacy, University of Oslo, Oslo, Norway.
Br J Clin Pharmacol. 2025 Jun;91(6):1542-1550. doi: 10.1111/bcp.16170. Epub 2024 Jul 26.
In solid organ transplantation (SOT), biologicals such as recombinant therapeutic proteins, monoclonal antibodies, fusion proteins and conjugates are increasingly used for immunosuppression, desensitization, ABO (blood group) incompatibility, antibody-mediated rejections and atypical haemolytic uremic syndrome. In this paper, we review the medical evidence available for biologicals used in SOT and the potential for improvement by the application of therapeutic drug monitoring (TDM) and model-informed precision dosing. Biologicals are used for off-label indications within the field of SOT, building on the experience from their use on labelled indications. Dosing is currently mostly standard, and experience vs. effect and toxicity is limited. Pharmacokinetic characteristics of these large, partly also immunogenic molecules differ from those of traditional small molecules. Individualization by concentration measurements and modelling has mostly been proof-of-concept or feasibility studies that lack the power to provide evidence for improvement in clinical outcome. For some drugs such as alemtuzumab, eculizumab, rituximab, tocilizumab and belatacept, studies have demonstrated significant interindividual variability in pharmacokinetics. Variability in absorption from subcutaneous administration may increase interindividual variability. There is also an economic aspect of appropriate dosing that needs to be pursued. Available assays and models to refine interpretation are in place, but trials of adequate size to document the usefulness of TDM and MIPD are scarce. Collaboration within the TDM community seems mandatory to establish studies of sufficient strength to provide evidence for the use of biologicals that are currently used off-label in SOT and furthermore to identify the settings where TDM may be beneficial.
在实体器官移植（SOT）中，重组治疗蛋白、单克隆抗体、融合蛋白和偶联物等生物制品越来越多地用于免疫抑制、脱敏、ABO（血型）不相容、抗体介导的排斥反应和非典型溶血尿毒综合征。在本文中，我们综述了SOT中使用生物制品的现有医学证据，以及应用治疗药物监测（TDM）和模型指导的精准给药改善疗效的潜力。基于生物制品在标签适应证上的使用经验，它们被用于SOT领域的非标签适应证。目前给药大多是标准化的，经验与疗效及毒性之间的关系有限。这些大分子（部分还具有免疫原性）的药代动力学特征与传统小分子不同。通过浓度测量和建模进行个体化给药大多是概念验证或可行性研究，缺乏为改善临床结局提供证据的能力。对于一些药物，如阿仑单抗、依库珠单抗、利妥昔单抗、托珠单抗和贝拉西普，研究表明其药代动力学存在显著的个体间差异。皮下给药吸收的变异性可能会增加个体间差异。适当给药还存在经济方面的问题需要探讨。现有的用于优化解释的检测方法和模型已经具备，但规模足以证明TDM和MIPD有用性的试验却很少。TDM领域内的合作似乎是必要的，以开展有足够力度的研究，为SOT中目前用于非标签适应证的生物制品的使用提供证据，并进一步确定TDM可能有益的情况。
