Department of Medical Oncology, Academic Medical Center, University of Amsterdam, 1100DD Amsterdam, The Netherlands.
Cancer Treat Rev. 2011 Jun;37(4):251-60. doi: 10.1016/j.ctrv.2010.08.006. Epub 2010 Sep 15.
Molecular targeted therapies with tyrosine kinase inhibitors (TKIs) have been a recent breakthrough in cancer treatment. These small molecules are mainly used at a fixed dose ignoring the possible need for dose individualization. Fixed dosing may indeed result in suboptimal treatment or excessive toxicity considering the high inter-individual variability in the pharmacokinetics (PK) of these therapies. The PK, toxicity and efficacy of ten commonly used molecular targeted anti-cancer therapies were reviewed in order to optimize their prescription. A wide interpatient variability in the pharmacokinetics of these small molecules is demonstrated. Moreover associations between certain toxicities and the treatment efficacy have also been demonstrated for some agents, such as erlotinib and skin rash, that may be used as a surrogate marker. Other biomarkers intended to substitute for a clinical endpoint have been described for some TKIs and may be useful for dose individualization. Promising alternatives to fixed dosing were explored such as therapeutic drug monitoring, genotype and phenotype adjusted dosing, and toxicity-adjusted dosing. Prospective studies are needed to validate these methods so that dosing algorithms may be developed in the near future in order to personalize therapeutics to the individual needs of each cancer patient.
分子靶向治疗的酪氨酸激酶抑制剂（TKIs）是癌症治疗的一个新突破。这些小分子药物主要以固定剂量使用，而忽略了可能需要个体化剂量的情况。考虑到这些治疗药物的药代动力学（PK）在个体间存在高度变异性，固定剂量可能确实会导致治疗效果不佳或毒性过大。本文综述了十种常用的分子靶向抗癌治疗药物的 PK、毒性和疗效，以优化其处方。这些小分子药物的 PK 在患者间存在很大的变异性。此外，一些药物的某些毒性与治疗效果之间也存在关联，例如厄洛替尼和皮疹，这些关联可用作替代标志物。一些 TKI 还描述了其他旨在替代临床终点的生物标志物，可能有助于个体化剂量。已经探索了一些有前途的替代固定剂量的方法，例如治疗药物监测、基于基因型和表型的调整剂量以及基于毒性的调整剂量。需要进行前瞻性研究来验证这些方法，以便在不久的将来开发出剂量算法，从而根据每个癌症患者的个体需求对治疗进行个性化。
