Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
Biomed Pharmacother. 2022 Sep;153:113393. doi: 10.1016/j.biopha.2022.113393. Epub 2022 Jul 11.
Sorafenib is a tyrosine-kinase inhibitor approved for the treatment of renal cell carcinoma, hepatocellular carcinoma, thyroid carcinoma, and desmoid fibromatosis. As high inter-individual variability exists in exposure, there is a scientific rationale to pursue therapeutic drug monitoring (TDM). We investigated the feasibility of TDM in patients on sorafenib and tried to identify sub-groups in whom pharmacokinetically (PK) guided-dosing might be of added value.
We included patients who started on sorafenib (between October 2017 and June 2020) at the recommended dose of 400 mg BID or with a step-up dosing schedule. Plasma trough levels (C) were measured at pre-specified time-points. Increasing the dose was advised if C was below the target of 3750 ng/mL and toxicity was manageable.
A total of 150 samples from 36 patients were collected. Thirty patients (83 %) had a C below the prespecified target concentration at a certain time point during treatment. Toxicity from sorafenib hampered dosing according to target C in almost half of the patients. In 11 patients, dosing was adjusted based on C. In three patients, this resulted in an adequate C without additional toxicity four weeks after the dose increase. In the remaining eight patients, dose adjustment based on C did not result in a C above the target or caused excessive toxicity.
TDM for sorafenib is not of added value in daily clinical practice. In most cases, toxicity restricts the possibility of dose escalations.
索拉非尼是一种酪氨酸激酶抑制剂，已被批准用于治疗肾细胞癌、肝细胞癌、甲状腺癌和硬纤维瘤。由于个体间的药物暴露存在很大差异，因此有科学依据支持进行治疗药物监测（TDM）。我们研究了索拉非尼患者进行 TDM 的可行性，并试图确定哪些亚组患者可能从基于药代动力学（PK）的剂量调整中获益。
我们纳入了自 2017 年 10 月至 2020 年 6 月期间，以推荐剂量 400mg 每日两次或逐步加量方案起始服用索拉非尼的患者。在预定时间点测量血药谷浓度（C）。若 C 低于 3750ng/ml 的目标值且毒性可管理，则建议增加剂量。
共采集了 36 名患者的 150 份样本。30 名患者（83%）在治疗过程中的某个时间点 C 低于预设目标浓度。由于索拉非尼的毒性，近一半的患者无法按照目标 C 进行剂量调整。根据 C 调整剂量的 11 名患者中，有 3 名在剂量增加四周后 C 达到了目标值且没有出现额外毒性。而在其余 8 名患者中，基于 C 的剂量调整并未使 C 达到目标值或导致毒性增加。
在日常临床实践中，索拉非尼的 TDM 没有额外价值。在大多数情况下，毒性限制了剂量增加的可能性。
