Unité fonctionnelle de Pharmacocinétique et Pharmacochimie, Hôpital Cochin, Paris, France; Service de Pharmacie clinique, Hôpital Cochin, Paris, France.
Northern Institute for Cancer Research, Medical School, Newcastle University, Newcastle upon Tyne, UK.
Eur J Cancer. 2014 Aug;50(12):2005-9. doi: 10.1016/j.ejca.2014.04.013. Epub 2014 May 27.
Therapeutic drug monitoring (TDM) can be defined as the measurement of drug in biological samples to individualise treatment by adapting drug dose to improve efficacy and/or reduce toxicity. The cytotoxic drugs are characterised by steep dose-response relationships and narrow therapeutic windows. Inter-individual pharmacokinetic (PK) variability is often substantial. There are, however, a multitude of reasons why TDM has never been fully implemented in daily oncology practice. These include difficulties in establishing appropriate concentration target, common use of combination chemotherapies and the paucity of published data from pharmacological trials. The situation is different with targeted therapies. The large interindividual PK variability is influenced by the pharmacogenetic background of the patient (e.g. cytochrome P450 and ABC transporters polymorphisms), patient characteristics such as adherence to treatment and environmental factors (drug-drug interactions). Retrospective studies have shown that targeted drug exposure correlates with treatment response in various cancers. Evidence for imatinib currently exists, others are emerging for compounds including nilotinib, dasatinib, erlotinib, sunitinib, sorafenib and mammalian target of rapamycin (mTOR) inhibitors. Applications for TDM during oral targeted therapies may best be reserved for particular situations including lack of therapeutic response, severe or unexpected toxicities, anticipated drug-drug interactions and concerns over adherence treatment. There are still few data with monoclonal antibodies (mAbs) in favour of TDM approaches, even if data showed encouraging results with rituximab and cetuximab. TDM of mAbs is not yet supported by scientific evidence. Considerable effort should be made for targeted therapies to better define concentration-effect relationships and to perform comparative randomised trials of classic dosing versus pharmacokinetically-guided adaptive dosing.
治疗药物监测（therapeutic drug monitoring，TDM）可以定义为测量生物样本中的药物，通过调整药物剂量来实现个体化治疗，以提高疗效和/或降低毒性。细胞毒性药物具有陡峭的剂量-反应关系和狭窄的治疗窗口。个体间药代动力学（pharmacokinetic，PK）变异性通常很大。然而，有许多原因导致 TDM 从未在肿瘤学的日常实践中得到充分实施。这些原因包括难以确定适当的浓度目标、联合化疗的常用以及药理学试验中发表的数据很少。靶向治疗的情况则不同。较大的个体间 PK 变异性受患者的药物遗传学背景（如细胞色素 P450 和 ABC 转运蛋白多态性）、患者特征（如对治疗的依从性）和环境因素（药物相互作用）的影响。回顾性研究表明，靶向药物暴露与各种癌症的治疗反应相关。目前已有伊马替尼的证据，其他药物如尼洛替尼、达沙替尼、厄洛替尼、舒尼替尼、索拉非尼和哺乳动物雷帕霉素靶蛋白（mammalian target of rapamycin，mTOR）抑制剂也有相关证据。在口服靶向治疗中，TDM 最好应用于以下特殊情况，包括治疗无反应、严重或意外毒性、预期的药物相互作用以及对治疗依从性的担忧。目前针对单克隆抗体（monoclonal antibodies，mAbs）的 TDM 方法的数据仍然很少，尽管数据显示利妥昔单抗和西妥昔单抗有令人鼓舞的结果。mAbs 的 TDM 目前尚未得到科学证据的支持。对于靶向治疗，应进行大量的努力，以更好地确定浓度-效应关系，并进行经典剂量与基于药代动力学的适应性剂量比较随机试验。
