Laboratoire de pharmacologie-toxicologie, Service de Pharmacie, Hôpital Cochin, 75014, Paris, France.
Invest New Drugs. 2012 Oct;30(5):1991-2000. doi: 10.1007/s10637-011-9760-z. Epub 2011 Oct 18.
Sorafenib is an oral tyrosine kinase inhibitor approved for the treatment of advanced renal cell carcinoma and hepatocellular carcinoma. By using a population approach, this study aimed to characterise its pharmacokinetics. Plasma concentration-time data (n = 372) from 71 patients under sorafenib were analysed using nonlinear mixed-effect modelling to estimate population pharmacokinetic parameters, as well as relationships between these parameters and different covariates (demographic, biological). Simulations were done to compare different daily dosing regimens in a context of dose-escalation. A 1-compartment model with saturated absorption, first-order intestinal loss and elimination best described the pharmacokinetics of sorafenib. Absolute bioavailability significantly dropped with increasing daily doses of sorafenib. AUC increased less than proportionally with increasing doses [47.3 (41.3-63.3), 60.3 (56.3-64.4), 71.4 (51.3-99.1), 75.9 (45.5-100.9) mg/L.h for 400, 800, 1,200 and 1,600 mg/day, respectively]. According to the simulations, dividing the daily dose in three or four doses for daily dose >800 mg would significantly increase AUC compared with a twice daily dosing regimen (101.7 vs 81.6 mg/L.h for 400 mg q8h and 600 mg q12h respectively; 131.6 vs 91.5 mg/L.h for 400 mg q6h and 800 mg q12h, respectively). Thrice daily regimen may be most suitable in a context of dose-escalation (>800 mg/day) in non-responders to standard-dosing regimen.
索拉非尼是一种口服酪氨酸激酶抑制剂，已被批准用于治疗晚期肾细胞癌和肝细胞癌。本研究采用群体分析方法，旨在描述其药代动力学特征。对 71 例接受索拉非尼治疗的患者的血浆浓度-时间数据（n=372）进行非线性混合效应模型分析，以估算群体药代动力学参数，以及这些参数与不同协变量（人口统计学、生物学）之间的关系。在剂量递增的情况下，进行模拟以比较不同的每日给药方案。一个 1 室模型，具有饱和吸收、一级肠内损失和消除，最能描述索拉非尼的药代动力学。随着索拉非尼每日剂量的增加，绝对生物利用度显著下降。AUC 的增加与剂量不成比例[47.3（41.3-63.3）、60.3（56.3-64.4）、71.4（51.3-99.1）、75.9（45.5-100.9）mg/L·h，分别为 400、800、1200 和 1600 mg/天]。根据模拟结果，与每日两次给药方案相比，将每日剂量分为三次或四次给药（对于每日剂量>800 mg）可显著增加 AUC（400 mg q8h 和 600 mg q12h 分别为 101.7 和 81.6 mg/L·h；400 mg q6h 和 800 mg q12h 分别为 131.6 和 91.5 mg/L·h）。对于标准剂量方案无反应者，在剂量递增的情况下（>800 mg/天），每日三次给药方案可能最适合。
