Inter-individual variability in drug response pose significant challenges to treatment with tyrosine kinase inhibitors (TKIs) in patients with metastatic renal cell carcinoma (mRCC). TKIs meet traditional criteria for using therapeutic drug monitoring (TDM), but research is still limited. Understanding the role of TDM in individualizing treatment strategies could help optimize treatment. Here we review the state of knowledge of TDM for TKIs in mRCC treatment. A comprehensive literature review of original research studies focusing on TDM of TKIs in mRCC treatment, clinical in vivo studies reporting on pharmacokinetics-pharmacodynamics, therapeutic ranges, drug concentrations, dose adjustments, clinical outcomes, or other relevant aspects related to TDM. We reviewed studies involving human subjects published in peer-reviewed journals. A narrative synthesis approach was employed to summarize the findings. Key themes and trends related to TDM of TKIs in mRCC treatment were identified and synthesized to provide a comprehensive overview of the current state of knowledge. Our search yielded 25 articles. Most were observational. The most consistently reported association between plasma concentration and effect was pazopanib Ctrough >20 µg/mL, but this concentration was not significant across all studies. We found inconsistent evidence for sunitinib and cabozantinib. For axitinib, we found a clear exposure-response relationship, but research was too diverse to conclude on a therapeutic window to use for TDM. We found much heterogeneity between recommended time of measurement (minimum plasma concentration [C], maximal plasma concentration [C], area under the curve [AUC]) and large variation in plasma concentration associated with clinical outcomes, which makes it difficult to recommend specific concentration intervals based on 1 or more of these measurements. Results were more consistent with TKIs continuously administered. Further research is needed to elucidate the long-term impact of TDM to possibly establish standardized therapeutic intervals. Prospective studies are suggested. The application of TDM in TKI-combination therapy is warranted in future research.

中文翻译：

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转移性肾细胞癌中酪氨酸激酶抑制剂的治疗药物监测

药物反应的个体差异对转移性肾细胞癌 (mRCC) 患者的酪氨酸激酶抑制剂 (TKI) 治疗提出了重大挑战。 TKI 符合使用治疗药物监测 (TDM) 的传统标准，但研究仍然有限。了解 TDM 在个体化治疗策略中的作用有助于优化治疗。在此，我们回顾 TDM 在 mRCC 治疗中对 TKI 的了解。全面文献综述，重点关注 TKI 在 mRCC 治疗中的 TDM、报告药代动力学-药效、治疗范围、药物浓度、剂量调整、临床结果或与 TDM 相关的其他相关方面的临床体内研究。我们回顾了在同行评审期刊上发表的涉及人类受试者的研究。采用叙述综合方法来总结研究结果。确定并综合了与 mRCC 治疗中 TKI 的 TDM 相关的关键主题和趋势，以全面概述当前的知识状况。我们的搜索产生了 25 篇文章。大多数是观察性的。血浆浓度与效果之间报道最一致的关联是帕唑帕尼浓度 >20 µg/mL，但该浓度在所有研究中并不显着。我们发现舒尼替尼和卡博替尼的证据不一致。对于阿西替尼，我们发现了明确的暴露-反应关系，但研究过于多样化，无法得出用于 TDM 的治疗窗口。我们发现推荐的测量时间（最低血浆浓度[C]、最大血浆浓度[C]、曲线下面积[AUC]）与与临床结果相关的血浆浓度的巨大变化之间存在很大的异质性，这使得很难推荐具体的测量时间。基于其中一项或多项测量的浓度区间。结果与连续施用 TKI 更加一致。需要进一步的研究来阐明 TDM 的长期影响，以便可能建立标准化的治疗间隔。建议进行前瞻性研究。 TDM 在 TKI 联合治疗中的应用在未来的研究中是有必要的。