Centanni Maddalena, Friberg Lena E
Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
Front Pharmacol. 2020 Mar 12;11:316. doi: 10.3389/fphar.2020.00316. eCollection 2020.
Tyrosine-kinase inhibitors (TKIs) demonstrate high inter-individual variability with respect to safety and efficacy and would therefore benefit from dose or schedule adjustments. This study investigated the efficacy, safety, and economical aspects of alternative dosing options for sunitinib in gastro-intestinal stromal tumors (GIST) and axitinib in metastatic renal cell carcinoma (mRCC). Dose individualization based on drug concentration, adverse effects, and sVEGFR-3 was explored using a modeling framework connecting pharmacokinetic and pharmacodynamic models, as well as overall survival. Model-based simulations were performed to investigate four different scenarios: (I) the predicted value of high-dose pulsatile schedules to improve clinical outcomes as compared to regular daily dosing, (II) the potential of biomarkers for dose individualizations, such as drug concentrations, toxicity measurements, and the biomarker sVEGFR-3, (III) the cost-effectiveness of biomarker-guided dose-individualizations, and (IV) model-based dosing approaches versus standard sample-based methods to guide dose adjustments in clinical practice. Simulations from the axitinib and sunitinib frameworks suggest that weekly or once every two weeks high-dosing result in lower overall survival in patients with mRCC and GIST, compared to continuous daily dosing. Moreover, sVEGFR-3 appears a safe and cost-effective biomarker to guide dose adjustments and improve overall survival (€36 784.- per QALY). Model-based estimations were for biomarkers in general found to correctly predict dose adjustments similar to or more accurately than single clinical measurements and might therefore guide dose adjustments. A simulation framework represents a rapid and resource saving method to explore various propositions for dose and schedule adjustments of TKIs, while accounting for complicating factors such as circulating biomarker dynamics and inter-or intra-individual variability.
酪氨酸激酶抑制剂（TKIs）在安全性和疗效方面表现出高度的个体间差异，因此需要调整剂量或给药方案。本研究调查了舒尼替尼用于胃肠道间质瘤（GIST）以及阿昔替尼用于转移性肾细胞癌（mRCC）时，替代给药方案的疗效、安全性和经济性。使用连接药代动力学和药效学模型以及总生存期的建模框架，探索基于药物浓度、不良反应和sVEGFR-3的剂量个体化。进行基于模型的模拟以研究四种不同情况：（I）与常规每日给药相比，高剂量脉冲给药方案改善临床结局的预测值；（II）生物标志物用于剂量个体化的潜力，如药物浓度、毒性测量和生物标志物sVEGFR-3；（III）生物标志物指导剂量个体化的成本效益；（IV）基于模型的给药方法与标准基于样本的方法在临床实践中指导剂量调整的比较。来自阿昔替尼和舒尼替尼框架的模拟表明，与持续每日给药相比，mRCC和GIST患者每周或每两周一次高剂量给药会导致总生存期降低。此外，sVEGFR-3似乎是一种安全且具有成本效益的生物标志物，可用于指导剂量调整并改善总生存期（每质量调整生命年36,784欧元）。总体而言，基于模型的生物标志物估计被发现能够正确预测剂量调整，其准确性与单次临床测量相似或更高，因此可能指导剂量调整。模拟框架是一种快速且节省资源的方法，可用于探索TKIs剂量和给药方案调整的各种提议，同时考虑循环生物标志物动态以及个体间或个体内差异等复杂因素。
