Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands.
Institute of Pharmacy, Clinical Pharmacy, University of Bonn, Bonn, Germany.
CPT Pharmacometrics Syst Pharmacol. 2017 Sep;6(9):604-613. doi: 10.1002/psp4.12210. Epub 2017 Jul 13.
The tyrosine kinase inhibitor sunitinib is used as first-line therapy in patients with metastasized renal cell carcinoma (mRCC), given in fixed-dose regimens despite its high variability in pharmacokinetics (PKs). Interindividual variability of drug exposure may be responsible for differences in response. Therefore, dosing strategies based on pharmacokinetic/pharmacodynamic (PK/PD) models may be useful to optimize treatment. Plasma concentrations of sunitinib, its active metabolite SU12662, and the soluble vascular endothelial growth factor receptors sVEGFR-2 and sVEGFR-3, were measured in 26 patients with mRCC within the EuroTARGET project and 21 patients with metastasized colorectal cancer (mCRC) from the C-II-005 study. Based on these observations, PK/PD models with potential influence of genetic predictors were developed and linked to time-to-event (TTE) models. Baseline sVEGFR-2 levels were associated with clinical outcome in patients with mRCC, whereas active drug PKs seemed to be more predictive in patients with mCRC. The models provide the basis of PK/PD-guided strategies for the individualization of anti-angiogenic therapies.
酪氨酸激酶抑制剂舒尼替尼被用作转移性肾细胞癌（mRCC）患者的一线治疗药物，尽管其药代动力学（PKs）存在高度变异性，但仍采用固定剂量方案。药物暴露的个体间差异可能是导致反应差异的原因。因此，基于药代动力学/药效动力学（PK/PD）模型的给药策略可能有助于优化治疗。在 EuroTARGET 项目中，对 26 名 mRCC 患者和 C-II-005 研究中的 21 名转移性结直肠癌（mCRC）患者的血浆舒尼替尼、其活性代谢物 SU12662 以及可溶性血管内皮生长因子受体 sVEGFR-2 和 sVEGFR-3 浓度进行了测量。基于这些观察结果，开发了具有遗传预测因子潜在影响的 PK/PD 模型，并将其与时间事件（TTE）模型相关联。mRCC 患者的基线 sVEGFR-2 水平与临床结局相关，而 mCRC 患者的活性药物 PKs 似乎更具预测性。这些模型为个体化抗血管生成治疗提供了 PK/PD 指导策略的基础。
