Division of Clinical Pharmacology, University Hospital Center and University of Lausanne, Lausanne, Switzerland; Pharmacie des Hôpitaux de l'Est Lémanique, Vevey, Switzerland.
Unité fonctionnelle de Pharmacocinétique et Pharmacochimie, Hôpital Cochin, Paris, France; Service de Pharmacie clinique, Hôpital Cochin, Paris, France.
Eur J Cancer. 2014 Aug;50(12):2020-36. doi: 10.1016/j.ejca.2014.04.015. Epub 2014 Jun 10.
Most of oral targeted therapies are tyrosine kinase inhibitors (TKIs). Oral administration generates a complex step in the pharmacokinetics (PK) of these drugs. Inter-individual PK variability is often large and variability observed in response is influenced not only by the genetic heterogeneity of drug targets, but also by the pharmacogenetic background of the patient (e.g. cytochome P450 and ABC transporter polymorphisms), patient characteristics such as adherence to treatment and environmental factors (drug-drug interactions). Retrospective studies have shown that targeted drug exposure, reflected in the area under the plasma concentration-time curve (AUC) correlates with treatment response (efficacy/toxicity) in various cancers. Nevertheless levels of evidence for therapeutic drug monitoring (TDM) are however heterogeneous among these agents and TDM is still uncommon for the majority of them. 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/or concerns over adherence treatment. Interpatient PK variability observed with monoclonal antibodies (mAbs) is comparable or slightly lower to that observed with TKIs. There are still few data with these agents in favour of TDM approaches, even if data showed encouraging results with rituximab, cetuximab and bevacizumab. At this time, 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.
大多数口服靶向治疗药物都是酪氨酸激酶抑制剂（TKI）。这些药物的药代动力学（PK）具有复杂的口服给药步骤。个体间 PK 变异性通常较大，观察到的反应变异性不仅受药物靶点遗传异质性的影响，还受患者的药物遗传学背景（如细胞色素 P450 和 ABC 转运体多态性）、患者特征（如对治疗的依从性和环境因素（药物-药物相互作用）的影响。回顾性研究表明，靶向药物暴露量，反映在血浆浓度-时间曲线下面积（AUC）与各种癌症的治疗反应（疗效/毒性）相关。然而，这些药物的治疗药物监测（TDM）的证据水平存在差异，并且大多数药物仍未进行 TDM。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（mTOR）抑制剂也有新的证据。TDM 应用于口服靶向治疗可能最好保留在特殊情况下，包括治疗反应不佳、严重或意外毒性、预期的药物-药物相互作用和/或对治疗依从性的担忧。与 TKI 相比，单克隆抗体（mAb）的个体间 PK 变异性相当或略低。尽管数据显示利妥昔单抗、西妥昔单抗和贝伐单抗有令人鼓舞的结果，但这些药物的 TDM 数据仍然很少。目前，mAb 的 TDM 尚未得到科学证据的支持。应努力针对靶向治疗药物更好地定义浓度-效应关系，并进行经典剂量与基于 PK 的适应性剂量的比较随机试验。
